Distribution and properties of adrenergic storage vesicles in nerve terminals. The subcellular distribution of adrenergic storage vesicles was determined in rat spleen, heart and superior cervical ganglion and in dog spleen using dopamine-beta-hydroxylase (DBH) as a marker for vesicle membranes and norepinephrine (NE) as a marker for the soluble contents of the storage vesicles. Density gradient centrifugation revealed populations of vesicles in the rat heart and spleen with equilibrium densities of 1.05 and 1.15 g/ml. There was a consistent shoulder on the low-density peak at a density of 1.08 g/ml. Several populations of NE-and DBH-containing vesicles were also found in homogenates of dog spleen. In homogenates of superior cervical ganglia, most of the NE was nonsedimentable while the DBH activity formed a broad poorly resolved band within the gradient. Although NE and DBH were present in each of several populations of vesicles in nerve terminals of rat and dog organs, the ratio of NE/DBH varied as a function of the species and organ examined. Mitochondrial contamination  did not, as has been previously claimed, influence the distribution of DBH which was observed. Both light and heavy vesicles were able to take up and retain NE-[3H].


Centrally mediated increased reflex vagal bradycardia after L-dopa in monoamine oxidase-inhibited anesthetized dogs. In monoamine oxidase-inhibited dogs whose peripheral dopa decarboxylase was inhibited with MK-486, L-dopa (K mg/kg i.v.) caused significant hypotension and bradycardia. In addition, reflex bradycardia but not pressor responses to norepinephrine were markedly enhanced by the drug. Similar results were obtained after intracerebroventricular administration of L-dopa (0.5 mg/kg) in monoamine oxidase-inhibited dogs not receiving MK-486. Proparnolol prevented the bradycardia caused by L-dopa but was without effect on the reflex facilitation. Both atropine and phentolamine had no effect on L-dopa bradycardia but prevented the facilitatory effect on reflexes. Inhibition of both peripheral and central dopa decarboxylase with Ro 4-4602 prevented all the effects of L-dopa. Infusions of dopamine which had obvious cardiovascular effects had no effect on reflex responses to norepinephrine. It is concluded that L-dopa, after decarboxylation, causes a centrally mediated enhancement of reflex vagal bradycardia. Pharmacological analysis of this enhancement suggests that this effect appears to be a result of central alpha receptor stimulation.


Central effect of beta adrenergic blocking agents on arterial blood pressure. dl-Sotalol, dl-pindolol, d-propranolol and dl-propranolol were evaluated for central hypotensive activity in chloralose-anesthetized vagotomized cats. Blood pressure and average evoked potentials recorded from one postganglionic renal nerve were measured during intraventricular (lateral ventricle) or intravenous (radial vein) infusion of each agent. Potentials were evoked in the sympathetic nerve by single shocks to the sciatic nerve. Three concentrations (1, 3, 5 mM) of each compound were infused consecutively for 20 minutes per concentration. The decrease in blood pressure after intraventricular infusion of 1 mM pindolol, 5 mM d-propranolol and 3 mM dl-propranolol was significantly greater than the decrease after intravenous infusion of the same concentrations of each agent. The decrease in the average evoked potential after intraventricular infusion of the 5 mM concentration was greater than the response after intravenous infusion. Consecutive (1, 3, 5 mM) intraventricular or intravenous infusions of sotalol did not significantly change either parameter. During intraventricular infusion of 3 mM dl-propranolol blood pressures was markedly decreased at a time when the average evoked potential was unchanged; however, parallel changes were observed during infusion of the drug in vagotomized cats in which the carotid sinus baroreceptors were also denervated. The results indicate a) that intraventricular administration of d-propranolol, dl-propranolol and dl-pindolol, but not of dl-sotalol, decreased blood pressure and discharge evoked in the postganglionic renal nerve by an action on central sympathetic structures, and b) that baroreceptor activity during hypotension can overcome the depressant effect of dl-propranolol on potentials evoked reflexly in the renal nerve.


The effects of quinidine and verapamil on electrically induced automaticity in the ventricular myocardium of guinea pig. The effects of 2 to 10 muM verapamil (1-5 mg/l) and 3.8 to 7.6 muM quinidine (2-4 mg/l) on automaticity in ventricular myocardial fibers were examined. Papillary muscles from guinea pigs were mounted in a sucrose gap chamber and transmembrane potential was recorded by standard microelectrode techniques. Automaticity was induced  with depolarizing currents of various strengths. Verapamil reduced phase 4 slope at all maximum diastolic membrane potentials. It also caused a selective reduction of the overshoot of action potentials arising from less negative maximum diastolic potentials. During exposure to verapamil, increased [Ca]0 partially restored action potential overshoot, but phase 4 slope was further reduced. Epinephrine caused a partial or complete reversal of verapamil-induced phase 4 slope depression but usually did not restore action potential overshoot. Quinidine reduced phase 4 slope at all maximum diastolic potentials. There was less marked reduction of action potential overshoot than in the case of verapamil. Epinephrine caused a partial reversal of the reduction of phase 4 slope produced by quinidine. It is concluded that although both verapamil and quinidine reduce automaticity in ventricular fibers, verapamil may be more effective in reducing the amplitude and occurrence of action potentials arising from low maximum diastolic potentials.


The effects of batrachotoxin on cat papillary muscle. The effects of batrachotoxin (BTX) upon the contraction and transmembrane potential of cat right ventricular papillary muscles were studied in vitro at 37 degrees C. BTX (2.0 x 10(-9) M) increased isometric contractile force by about 50% from control force, decreased the potential difference across the cell membrane to approximate -50 mV and produced spontaneous contractions of the papillary muscles. Each BTX-induced spontaneous contraction was accompanied by a spontaneous action potential which was generated when an oscillation in membrane potential reached threshold level. Spontaneous activity ovvurred only in muscles which were previously stimulated electrically. The positive inotropic effect of BTX was accompanied by an increase in the rate of force development. Papillary muscles from cats pretreated with reserpine did not differ from normal muscles in their responses to BTX treatment. Tetrodotoxin (2.0 x 10(-7) M) antagonized the effects of BTX, a finding which suggests that the actions of BTX are mediated by a selective increase in membrane permeability to sodium ions. The resultant BTX-elicited increase in the intracellular sodium ion concentration may increase the force of contraction through an augmentation of calcium influx via the sodium-calcium exchange system.


Effect of adenosine on myocardial oxygen balance. The present study was designed to determine the effect of adenosine on oxyhemoglobin equilibrium (P-50) and myocardial oxygen consumption (MVO2) in the isolated supported dog heart preparation perfused at a constant coronary blood flow. Heart rate was controlled at 150 beats/min. A-3-minute intracoronary infusion of adenosine (10, 50 and 100 mug/min) produced significant decreases in MVO2, whereas coronary venous P-50 did not change. Adenosine-5'-monophosphate (5'-AMP) infusion (70 and 140 mug/min) did not produce a significant change in MVO2. Both adenosine and 5'-AMP caused equivalent decreases in coronary artery perfusion pressure and peak left ventricular systolic pressure. Furthermore, adenosine (50 and 100 mug/min) produced a significant decrease in MVO2 of the isolated supported fibrillating heart. These results suggest that the reduction in MVO2 observed with adenosine is not related to coronary vasodilation or to a negative inotropic or chronotropic action. Theophylline (2.5 mg/kg) partially blocked the hemodynamic effects of adenosine while completely abolishing the decrease in MVO2. Neither inosine nor hypoxanthine (50 and 100 mug/min) changed MVO2, P-50 or myocardial hemodynamics. Thus, in addition to its proposed role in coronary blood flow regulation, adenosine appears to exert important effects on myocardial metabolism.


Active transport of phenol red by rat lung slices. 32S-phenol red was taken up by rat lung slices incubated in oxygenated Krebs-Ringer phosphate-glucose solution (pH 7.4) at 37 degrees C by a process showing the characteristics of active transport. Uptake against a concentration gradient occurred by a saturable process that was inhibited by low temperature, anaerobic conditions and certain metabolic inhibitors. Phenol red uptake was depressed in the presence of certain anionic dyes, such as chlorphenol red, bromphenol blue, bromthymol blue and bromcresol green, and by various other organic acids, including disodium cromoglycate, probenecid, cephalothin and benzylpenicillin. In contrast, isoniazid and p-aminohippuric acid had no effect on phenol red uptake, suggesting that a specificity exists in the rat lung for transport of anionic compounds. Interestingly, in the presence of paraquat, an organic cation,phenol red uptake was increased. The extent of uptake of phenol red by lung slices was dependent on levels of Na, K and Ca ion in the incubation medium as well as on the thickness of the tissue slice. Phenol red was bound to lung homogenates; however, the characteristics of the binding were such that binding alone could not account for accumulation by lung slices.


Effect of prolonged lithium ingestion on the response to mineralocorticoids in rats. The effect of long-term lithium administration on the response to mineralocorticoids was studied in rats which were adrenalectomized in order to avoid the effects of endogenous hormone. The hormone response was estimated from the changes in urinary excretion of sodium and potassium in rats on low and high sodium intake and from the consumption of a hypertonic NaCl solution by rats given a free choice between this and demineralized water. Lithium was found to lower the response to aldosterone and deoxycorticosterone acetate both in acute and chronic experiments. It was further found that in adrenalectomized rats given no hormone, those given lithium consumed significantly more NaCl solution than those given no lithium. The experiments therefore provide evidence that lithium induces a sodium requirement beyond that induced by the inhibition of the response to mineralocorticoids.


Studies on the binding of 5,5-diphenyl-hydantoin to nucleic acids in vitro and to rat brain subcellular fractions in vitro and in vivo. The binding of 5,5-diphenylhydantoin (DPH) to nucleic acids (bovine brain RNA, rat liver ribosomal and tRNA, Torula utilis RNA, and calf thymus and Escherichia coli DNA was studied using ultraviolet spectroscopy, gel chromatography and thermal transition profiles. Within the sensitivity of these methods, it was found that there is essentially little or no interaction between DPH and nucleic acids in vitro as has been reported previously. Little, if any evidence of DPH intercalation with DNA was noted during thermal transition studies. DPH does not interfere with DNA reassociation. Further studies into the nature of the in vivo subcellular distribution of 14C-DPH in rat brain revealed accumulation of the radioactivity primarily in the soluble fractions. The nuclear fraction and the microsomes, containing high DNA and RNA tissue ratios, demonstrated the greatest particulate association with radioactivity at 2 and 12 hours, respectively. This association with particulate fractions was not demonstrated after gel chromatography. These data do not support a hypothesis relating DPH binding to nucleic acids in vitro or in vivo to a possible mechanism of action of the drug.


The development of new iron-chelating drugs. 2,3-Dihydroxybenzoic acid has been identified as a potentially useful iron-chelating drug. Accordingly, we have evaluated a series of derivatives of hydroxylated benzoic acids for their ability to induce iron excretion in the iron-overloaded rat. In addition, we have examined a number of hydroxamic acids and some other naturally occurring iron-chelating agents. Of the 26 benzoic acid derivatives studied, none appeared to be more effective than 2,3-dihydroxybenzoic acid, for reasons which are discussed. Rhodotorulic acid, a hydroxamic acid produced by and isolated from cultures of Rhodotorula pilimanae, was the most effective of all the compounds studied in inducing iron excretion. When administered parenterally, rholotorulic acid induced iron excretion via both the urinary and the fecal routes and was more than twice as potent (on a weight basis) as desferrioxamine. Two ferrous chelators, alpha, alpha-dipyridyl ad 1,10-phenanthroline, induced a moderate amount of iron excretion, suggesting that a pool of ferrous iron may be available for chelation.


Biliary excretion of 3,4-benzpyrene in nafenopin-treated rats. When rats treated for 2 days with nafenopin are injected i.v. with 3H-3,4-benzpyrene (BP), blood disappearance rates and liver levels of the carcinogen and the rate of biliary excretion of its metabolites are, in the main, similar to those of nontreated rats. This is in accord with the observation that nafenopin does not inhibit the metabolism of BP, which is the rate-limiting step in its biliary excretion. On the other hand, when 3H-BP metabolites are injected, nafenopin pretreatment slightly retards their rate of plasma disappearance and markedly inhibits their biliary excretion, as it does other organic anions. When rats are pretreated with 3-methylcholanthrene, the rate of metabolism of 3H-BP and consequently the biliary excretion of its metabolites is greatly stimulated. In this instance, metabolism may no longer be rate-limiting in the overall biliary excretion process and inhibition by nafenopin of liver-to-bile transport of metabolites can be observed. Since nafenopin pretreatment stimulates the synthesis of new liver tissue, it is presently a matter of conjecture as to whether or not the newly formed hepatocytes have the capacity to take up and excrete BP and its metabolites or whether nafenopin inhibits transport in all liver tissue.


The participation of 2-butanone in 2-butanol-induced potentiation of carbon tetrachloride hepatotoxicity. The role of alcohol metabolism in 2-butanol-induced potentiation of carbon tetrachloride (CCl4) hepatotoxicity was studied in rats. Animals were sacrificed at various times after the administration of 2-butanol (2.2 ml/kg p.o.) for the determination of blood 2-butanol and 2-butanone concentrations by gas chromatographic analysis. 2-butanol exhibited an apparent elimination half-life of 2.5 hours. With the decline of 2-butanol concentrations, there was a rise in 2-butanone blood concentrations with 43 mg/100 ml detected at 1 hour and a maximum of 105 mg/100 ml detected 4 hours after the administration of the alcohol. A 16-hour pretreatment with either 2-butanol (2.2 ml/kg p.o.) or 2-butanone (1.87 ml/kg p.o.) markedly enhanced the hepatotoxic response of CCl4 (0.1 ml/kg i.p.) as measured by serum glutamic pyruvic transaminase activity, hepatic glucose-6-phosphatase activity and triglyceride content. The enhanced hepatotoxicity produced by 2-butanol was not significantly different from that produced by 2-butanone. The potentiation of CCl4 hepatotoxicity by both agents was substantiated morphologically. The results indicate that 2-butanone production via the oxidation of 2-butanol appears to contribute to the marked response of 2-butanol.


Expiratory measurement of maximal amino-pyrine demethylation in vivo: effect of phenobarbital, partial hepatectomy, protacaval shunt and bile duct ligation in the rat. Current in vivo methods do not give information about the drug-metabolizing capacity (Vmax) and the affinity of the microsomal enzyme system for the drug i.e., the dose yielding Vmax/2 (Kd). To explore the possibility of estimating these variables from demethylation rates measured by 14CO2 exhalation, various doses of 14C-aminopyrine were injected i.v. to unanesthetized rats. Drug clearances based on 14CO2 exhalation agreed well with those derived from plasma disappearance rates. Evaluation of dose-response curves revealed saturation phenomena. In the normal rat, a Vmax of 173 nmol/min/100 g and Kd of 26 mumol/100 g could be calculated. Enzyme induction with phenobarbital increased Vmax to 745 nmol/min/100 g, whereas in the rat with portacaval shunt, it was reduced to 45 nmol/min/100 g. After 48-hour bile duct ligation, Vmax was not significantly different from the controls, but Kd increased to 36 mumol/100 g compatible with a competitive type of inhibition of aminopyrine demethylation. Two-thirds hepatectomy reduced Vmax by only 50% suggesting that a substantial portion of demethylation occurs extrahepatically. The approach presented appears to be a valid alternative to conventional plasma clearance methods allowing interpretation of some mechanisms affecting in vivo drug metabolism under various conditions.


The effect of acetazolamide on the movements of anions into the posterior chamber of the dog eye. The rate of entry of bicarbonate and chloride ions the posterior chamber of the dog, a species that has both HCO3- and Cl- concentrations in excess of plasma in this chamber, was measured in order to clarify the mechanisms involved in the produciton of aqueous humor. Four animals were given H14CO3- and 36Cl- intravenously first in a control series and then after pretreatment with acetazolamide, (50 mg/kg), a carbonci anhydrase inhibitor. Samples were taken from arterial blood and the posterior chamber. Acetazolamide did not affect chloride entry into the posterior chamber but bicarbonate entry was decreased about 50%. It is concluded that in this species, bicarbonate is the key anion for the decrease of aqueous humor production caused by the administration of acetazolamide.


Stereospecific radioimmunoassay for propranolol isomers. Antisera against propranolol were produced in rabbits immunized with propranolol conjugated to bovine serum albumin. The antiserum against dl-propranolol recognized both d- and l-propranolol to the same degree. However, antiserum against l-propranolol was able to discriminate the l-propranolol selectively. The antisera were used to develop radioimmunoassays for dl-propranolol and l-propranolol. The assay can detect as little as 10 pg of propranolol. Metabolites of propranolol do not interfere with the assay unless concentrations are very high. Serum and heart levels of l-propranolol and the d-isomer were determined in the rat after i.v. injection (1 mg/kg) of dl-propranolol. l-Propranolol declines rapidly in the blood after the injection. Concomitantly, there is a rapid accumulation of l-propranolol by the heart. The d-form of propranolol remains in the blood and is metabolized rapidly as reflected by a shorter half-life (23.8 minutes) than the one found for l-propranolol (5.20 minutes).


The effects of lithium and sodium on the potassium conductance of snail neurones. 1. The iontophoretic injection of lithium into snail neurones reversibly increased the resting relative potassium permeability (PK). 2. Long exposures to snail Ringer containing 25 mM-Li and correspondingly reduced Na also caused an increase in PK. This did not occur with Ringer in which the same reduction of Na was made by replacing it with Tris. 3. Replacement of part of the Ringer Na by either Li or Tris led to proportional decreases in internal Na. 4. Injecting large quantities of Na into ouabain-treated cells caused effects similar to those of Li injection. Without ouabain, Na injection stimulated the electrogenic Na pump. 5. A number of tests failed to produce any clear evidence that intracellular Ca was involved in the response to Li.


The contractile state of rabbit papillary muscle in relation to stimulation frequency. 1. The relationship between active force and stimulation frequency (0-25-5/sec) was studied at 36-37 degrees C in isolated papillary muscles of the rabbit. 2. The muscle's force producing capability at a given frequency was determined as the isometric twitch response to a test stimulus that was applied at various times after a priming period. The optimum contractile response was obtained at an interval of 0-8 sec between the test pulse and the last stimulus of the priming period. 3. The optimum contractile response exceeded the steady-state twitch amplitude at all stimulation frequencies higher than 1/sec. While the steady-state twitch resonse declined at frequencies higher than 4/sec, the optimum contractile response was steadily increased as the stimulation frequency was raised. 4. The optimum contractile response was also determined after priming the muscle with a sinusoidal a.c. pulse (field strength, 10 V (r.m.s.)/cm; frequency, 20 c/s; duration, 2-5 sec). The optimum contractile response obtained after a.c. stimulation was 2-2 times greater than the maximal steady-state response. Its absolute value was 67-3+/-6-1 mN/mm2 (mean +/-S.E. of mean, n = 6). 5. The twitch potentiation produced by priming the muscle at a given frequency decayed exponentially in two phases after optimum contractile response had been attained. The time constants of the two phases, determined after a.c. stimulation, were 2-6+/-0-8 (n = 4) and 92-0+/-13-3 sec (n = 7), respectively. 6. The optimum contractile response determined at various stimulation frequencies was linearly related to the fraction of time during which the cell membrane was depolarized (beyond -40 mV) by the action potentials. 7. The results are interpreted in terms of a two-component model of the metabolism of activator calcium in the excitation-contraction coupling.


Developmental aspects of potassium flux and permeability of the embryonic chick heart. 1. The rate coefficient of 42K efflux, the transmembrane potential, the intracellular concentrations of Na and K and the volume/surface area have been measured in embryonic chick hearts of different ages. 2. With respect to age, the rate coefficient for 42K efflux was minimal for preparations from 6-8 day old embryos, and distinctly higher values were obtained for the hearts of 3-5 and 18-20 days. With respect to the effect of external K concentration (Ko), all age groups showed a five- to sevenfold increase in rate coefficient between 2-5 and 140 mM-Ko. The effect of Ko was found to be indepedent of extracellular Na, except in the 18-20 day hearts bathed in K-free solution. 3. Intracellular concentrations of K and Na were found to decrease, membrane potential to increase with age. The volume/surface area measured by stereologic and morphometric techniques did not change with age. 4. The permeability coefficient for K (PK), calculated from the absolute K flux and the measured membrane potentials, was fairly constant for a given age between 2-5 and 20 mM-Ko. In K-free solution, PK was markedly reduced (factor 4). At a given Ko, PK increased twofold between 6-8 and 18-20 days while PNa remained relatively constant.


Effects of atropine, injected into a lateral cerebral ventricle of the rabbit, on fevers due to intravenous leucocyte pyrogen and hypothalamic and intraventricular injections of prostaglandin E1. 1. Cholinergic synapses in the hypothalamus may transmit information in those thermoregulatory pathways which function to raise body temperature. The effect of atropine, administered intracranially, on the febrile response to intravenous leucocyte pyrogen or intracranial prostaglandin E1 was therefore examined in conscious rabbits. 2. In rabbits exposed to a thermoneutral environment, micro-injections of PGE1, into the anterior hypothalamus, intraventricular injections of PGE1, and intravenous injection so leucocyte pyrogen all caused fever accompanied by vasoconstriction in the ears and reduced respiratory rate. Intraventricular injection of 200 mug atropine during such fevers attenuated their development. This was due to the activation of heat loss mechanisms through vasodilatation in the ears and an increase in the frequency of respiration. This suggests a similarity in the pattern of neuronal activity evoked by PGE1 and leucocyte pyrogen, at least at the site(s) where atropine directly or indirectly exerted its effect and in the efferent pathways from this site. 3. In rabbits exposed to a cold environment, intraventricular injection of PGE1 caused fever through the activation of shivering accompanied by increased O2 consumption. Intraventricular injection of atropine during the development of fever caused an inhibition of shivering accompanied by increased O2 consumption. Intraventricular injection of atropine during the development of fever caused an inhibition of shievering and a decrease in O2 consumption so that temperature ceased to rise and returned to normal. 4. During fever, reversal by atropine of the increased heat conservation of rabbits in a neutral environment, and of their increased heat production in a cold environment adds further support to the concept that cholinergic synapses provide an important link in central temperature-rasising pathways.


The effects of ouabain and ethacrynic acid on the intracellular sodium and potassium concentrations in renal medullary slices incubated in cold potassium-free ringer solution and re-incubated at 37 degrees C in the presence of external potassium. 1. The cells in slices cut from the renal outer medulla of normally hydrated adult rats were loaded with Na and depleted of K by incubation for up to 100 min in cold iso-osmolal K-free Ringer containing 180 mM-Na. There was a continuous net cellular water loss during this time; an inverse linear relationship existed between water content and intracellular Na concentration. 2. The original intracellular Na and K concentration were restored following 60 min re-incubation in warm Ringer (37 degrees C) containing 5-9 mM-K. Restoration of cellular water content was incomplete after re-incubation for up to 120 min. 3. During incubation in cold K-free Ringer the presence of 1 mM ouabain did not affect cellular Na uptake or K and water loss. Ethacrynic acid, 1 mM, completely blocked cellular Na uptake and water loss, without affecting the intracellular K concentration at 100 min. When ouabain and ethacrynic acid were present together water loss was also prevented but intracellular Na concentration rose slightly by 100 min. 4. During re-incubation in warm K-containing Ringer 1 mM ouabain inhibited Na extrusion completely for up to 60 min while only partially preventing K uptake and further depressing the level of cellular hydration. Ouabain in the presence of 1 mM ethacrynic acid had similar effects on intracellular Na and K concentrations, but raised the level of intracellular water above that of cells in control slices. 5. Ethacrynic acid alone, 1 mM, did not interfere with Na extrusion or K uptake, but also raised intracellular water above control values. 6. The results obtained are discussed in relation to (a) the nature of the preparation used, (b) the possible membrane transport processes occurring and their known or suggested sensitivity to ouabain and ethacrynic acid, (c) the mechanisms which may be responsible for cell volume maintenance in the medulla.


Isolation of rod and cone contributions to cat ganglion cells by a method of light exchange. 1. The great majority of cat retinal ganglion cells are known to receive signals from rods and from a single (green) cone type. The centre region of the receptive fields of these cells was stimulated by a spot that changed back and forth from orange to white. By adjusting the intensity of the white spot relative to that of the orange a condition could be established at which the photon-catch rate of the rods remained unchanged during the orange-white exchange. At this intensity setting, termed the rod isolept, rods are thus unstimulated by the exchange, however intense, and the ganglion-cell response was found to be due entirely to the green cones. At another intensity setting of the white spot relative to the orange (cone isolept), the photon catch of the green cones remained unchanged during the exchange and ganglion-cell responses were found to arise entirely from the rods. 2. A neutral wedge in the combined exchange beam (but not in the steady background that covered the whole receptive field) regulated the size of the exchange stimulus and thus the magnitude of the ganglion-cell discharge heard from a loud speaker to the exchange. Exchange threshold was the wedge setting at which this change in firing rate could only just be heard. 3. At the cone isolept, cones remain unstimulated however intense the exchange stimulus, and the rod increment threshold curve was determined over its full range from absolute threshold up to saturation. Likewise, at the rod isolept, the cone increment threshold curve was determined over the same intensity range as for the rods. Rod saturation was found to occur at the point where the cone increment threshold curve began to rise from its absolute threshold level toward its Weber region. 4. The exchange approach also enabled both rod and cone dark-adaptation curves following a strong bleaching exposure to be obtained in the same experiment by moving successively between the cone and rod isolepts. At the cone isolept the time course of early rod dark adaptation could thus be determined when the rod threshold to flashing spots lay well above that of the cones.


Cancellation of rod signals by cones, and cone signals by rods in the cat retina. 1. The interaction of rod and cone signals at the level of cat retinal ganglion cells was studied by a method of light exchange. Two spectrally distinct lights were exchanged in such a manner that the rate of photon catch by rods increased in a stepwise manner at the same moment that the cone rate decreased in the same manner, and vice versa. 2. Under any conditions of adaptation, where both rods and cones contributed to the ganglion-cell discharge, it was always possible to adjust the ratio of the magnitudes of the rod and cone stimuli so that no change in ganglion-cell discharge could be detected by listening to the recorded activity via a loudspeaker. We term this condition a silent exchange. 3. On the face of it, the condition of silent exchange arises when rod and cone signals are able to cancel one another, when made opposite in phase by the exchange situation. But was this silence due to a true cancellation of the signals from one photoreceptor type by those of the other type, or was it due to our failure to stimulate the photoreceptors adequately? In order to test whether rod signals can cancel those of cones we bleached both visual pigments and set our exchange apparatus to stimulate the two photoreceptors in the antagonistic manner described above. At first no response could be heard on exchange, for the thresholds of both rods and cones lay above that of our apparatus. But the cones soon recovered and a strong response was heard on exchange. With no change in our stimulating situation, this response diminished with time and silence was again restored. This restoration of silence could not be due to the cones alone, for with time their sensitivity could only further increase. It could only be the increasing sensitivity of the rods that quietened the cone signals. In agreement with this conculsion, the dark-adaptation curve of the rods showed that they became sensitive to our stimulus at the time that the cones began to be silenced. 4. By means of coloured backgrounds we have also shown the converse, namely that rods signals can be cancelled by those of cones.


The effect of zinc on the late displacement current in squid giant axons. 1. Displacement currents produced by single depolarizing or hyperpolarizing voltage-clamp pulses (Idepol and Ihyperpol) were recorded from intracellularly perfused squid giant axons treated with tetrodotoxin and tetraethylammonium chloride. The effect of internal Zn on the slow part of the displacement current was studied at different holding potentials. 2. Internal Zn in a concentration of 3-3 mM markedly reduced the slow charge displacement associated with depolarizing and hyperpolarizing pulses. 3. At a holding potential more negative than -60 mV Idepol is normally larger than Ihyperpol if measured with pulses of equal height. The asymmetry Idepol greater than Ihyperpol (which possibly reflects the movement of gating charges) was abolished by Zn. 4. The reversed asymmetry Ihyperpol greater than Idepol which is normally seen at holding potentials less negative than -60 mV was not blocked by Zn. This suggests that the underlying mechanism is different from that of the asymmetry Idepol greater than Ihyperpol. 5. The Zn-sensitive slow charge displacement during single depolarizing pulses was strongly reduced by lowering the holding potential from about -90 to about -30 mV. 6. The observations with single clamp pulses were confirmed by averaging and summing the currents associated with an equal number of depolarizing and hyperpolarizing pulses. 7. The effect of internal Zn on the charge displacement is thought to be due to a reaction with mobile charges in the membrane dielectric. Internal Zn in a concentration of 0-5-1 mM did not significantly shift the Na inactivation curve, indicating that it does not react with surface charges at the inner side of the membrane.


The effect of acetzolamide on Ion transport across isolated sheep rumen epithelium. 1. The net fluxes of sodium and chloride from the lumen to the blood side of isolated sheep rumen epithelium were reduced by treatment of both sides of the epithelium with acetazolamide. 2. The changes in the net fluxes of sodium and chloride were significantly correlated and showed recovery after removal of acetazolamide. 3. The net flux of potassium from blood to lumen side of the epithelim was not affected by treatment with acetazolamide. 4. It is suggested that acetazolamide blocks coupled sodium and chloride transport which may be mediated through 'low-activity' carbonic anhydrase enzymes.


Secretin-like choleretic effect of prostaglandins E1 and E2 in cats. 1. The effects of intraportal and hepatic arterial infusion of prostaglandins E1 and E2 on liver function and circulation was studied in fasting chloralose anaesthetized cats. 2. Infusion of the prostaglandins at rates of 0-1, 1-0 and 5-0 mug/kg.min caused a 35-40% increase in bile flow. This may be explained by a decrease in the reabsorption or a secretion of sodium ions by  the ductular cells. The canalicular bile production and bile flow. This may be explained by a decrease in the reabsorption or a secretion of sodium ions by the ductular cells. The canalicular bile production and bile acid excretion was not affected by the prostaglandins. 3. Infused at rates of 1-0 and 5-0 mug/kg.min the prostaglandins caused a transient decrease in mean arterial blood pressure and mesenteric vascular resistance. The resistance in the intrahepatic arterioles and low-pressure vessels was not affected. 4. The prostaglandins did not influence the splanchnic uptake of oxygen and ethanol, whereas a slight increase in the splanchnic glucose output occurred. 5. The effects of the two prostaglandins were identical and not related to the route of administration.


Frequency-related inhibitory mechanisms controlling rhythmical activity in the septal area. 1. The response patterns of identified neurones in the medical and lateral septal regions to varying rates of repetitive stimulation of the fimbria were investigated in rats anaesthetized with urethane. 2. Neurones in the lateral septum which characteristically respond to single pulse stimulation of the fimbria with an activation-inhibition sequence, exhibited a reduction or complete elimination of the inhibitory component both during and following tetanic volleys delivered at 7-12 HZ. Stimulation at lower frequencies did not alter the response. 3. Concurrently with this effect on the inhibitory component of the response exhibited by lateral septal cells, repetitive volleys eliminate the small amplitude burst discharges which are correlated with the onset of the inhibitory period and are considered to indicate the firing of inhibitory interneurones. 4. Tetanic stimulation of the fimbria at rates which eliminate this interneuronal response in the lateral septum, produce an irregular pattern of firing in medial septal neurones which previously exhibited a synchronized bursting discharge to single pulses. 5. Ipsilateral section of the fimbrial input to the septum resulted in the elimination of the burst discharge pattern exhibited by medial septal neurones. 6. The results suggest that a frequency gating mechanism in the lateral septum, activation of which is dependent upon the level of hippocampal output, is responsible for controlling the firing pattern of medical septal neurones.


The ionic basis of the resting potential and a slow depolarizing response in Rohon-Beard neurones of Xenopus tadpoles. 1. Rohon-Beard cells in the spinal cord of Xenopus laevis tadpoles have been studied in animals 4-days to 2-weeks-old (Nieuwkoop & Faber, 1956, stages 45-49). These neurones have an unusually large resting membrane potential of -88 mV, in Ringer solution containing 3-0 mM K+. 2. Their resting potential (R..) depends on the concentration gradient of K+ across the cell membrane. These cells follow the prediction of the Nernst equation for a K+-selective electrode, down to external K+ concentrations as low as 1-0 mM (R.P. -118 mV). 3. The resting potentials of muscle cells in these animals exhibit the same dependence on external [K+], as has been shown previously. 4. Rohon-Beard cells can be driven antidromically, bu stimulation of the anterior end of the spinal cord with brief current pulses through a suction electrode. Antidromic action potentials fail to invade the cell body with repeated stimulation at 1Hz. 5. Even when impulses fail to invade Rohon-Beard somata, slow depolarizations can be produced by single shocks or trains of shocks which cause impulse activity in other neurones. The response can be observed to a single stimulus or to a train of stimuli. The magnitude of the depolarization is graded, depending on the number of stimuli and the frequency of stimulation. 6. Support is presented for the hypothesis that the slow depolarization in Rohon-Beard cells is mediated by the release of K+ into their environment by the impulse activity of neighbouring neurones. The slow depolarization increases in solutions containing 1-5 mM-K+, and decreases in solutions containing 6-0 mM-K+. The changes are in quantitative agreement with those anticipated by theory. 7. The slow depolarization is unlikely to be due to a conductance change produced by a synaptic transmitter, since hyperpolarization and depolarization of the Rohon-Beard cell with injected current do not change the amplitude of the response. Further, low Ca-high Mg solutions which block neuromuscular transmission do not block the response. 8. The possible role of the slow depolarizing response in the physiological activity of these neurones is discussed.


Centrifugal actions on amacrine and ganglion cells in the retina of the turtle. 1. An electrophysiological investigation of efferent synapses in the retina of the turtle was conducted by recording intracellularly from amacrine cells. These cells have been selected because in birds they have been shown to have direct anatomical connexions with centrifugal fibre terminals. 2. Amacrine cells could be easily distinguished from most other retinal cells, except ganglion cells, by their different photo-responses. Because both amacrine and ganglion cells may generate action potentials they were distinguished by their responses to optic nerve stimulation. 3. The response of ganglion cells to single shock stimulation of the optic nerve consists of an antidromic action potential followed by a late synaptic potential. 4. Cells which did not show antidromic responses but were electrically excitable, by passing direct current through the recording electrode, were considered to be amacrine cells. 5. Amacrine cells generate an e.p.s.p. in response to optic nerve stimulation. An analysis of the e.p.s.p. suggests that it may be due to a single afferent fibre terminating in the proximity of the cell soma. By analogy to the bird, it is concluded that the amacrine cells e.p.s.p.s result from the activation of centrifugal fibres.


The temporal and steady-state relationships between activation of the sodium conductance and movement of the gating particles in the squid giant axon. 1. Comparisons were made between the kinetics and steady-state properties of the sodium conductance changes and of the sodium gating currents, in the squid giant axon perfused with caesium fluoride and maintained at a high membrane holding potential. The conductance measurements were made with reduced external sodium and as much electrical compensation as possible, in order to minimize errors caused by the series resistance. 2. After an initial delay of 10-150 musec whose size was a function of the holding potential and pulse amplitude, the conductance rise on depolarization followed cube law kinetics. 3. Values of the time constant taum, as defined by Hodgkin & Huxley (1952b), were determined for membrane potentials ranging between -140 and +70 mV. They lay on a nearly symmetrical bell-shaped curve with maximum (at 6-3 degrees C) of just under 500 musec at -36 mV. 4. Values of the gating current time constant tau(V) were determined over the same potential range, and found to lie on a very similar bell-shaped curve. A computed least-squares best fit gave the maximum as 460 musec, also falling at about -36 mV. 5. The midpoint of the minfinity curve lay at -34 mV, and its slope at this point was 0-0139 mV-1. Another series of measurements on intact axons gave a midpotential of -25 mV. In the perfused axons the state of the membrane was better described by the constant field equation than by gNa. Recalculation of minfinity from PNa shifted the curve about 15 mV in a positive direction.


Low resistance junctions between mesoderm cells during development of trunk muscles. 1. Electrical connexions between mesoderm cells have been examined during the formation of somites in Xenopus laevis, Bombina orientalis and Ambystoma mexicanum. 2. In Xenopus the resting potentials of presumptive myotome cells (-65 + 2 mV, S.E. of mean) and somite muscle cells (-65 +/- 0-6 mV S.E. of mean) were 40 mV, greater than dermatome cells (-25 +/- 0-6 mV, S.E. of mean). Similar differences were found in Bombina and Ambystoma. 3. In all three species cells of the dermatome layer of the mesoderm were electrically coupled to each other. Cells of the presumptive myotome layer in the unsegmented region of the mesoderm were also electrically coupled. 4. In Xenopus dermatome and myotome layers of the mesoderm were not electrically coupled to each other either before or after somite formation. In the other two species dermatome and myotome layers were uncoupled once the somites had formed. 5. In all three species the position of the intersomite border in the unsegmented mesoderm region is marked by the breaking of electrical contracts between those cells destined to form the next somite and the rest of the unsegmented mesoderm. 6. In the axolotl each somite remains electrically insulated from its neighbour. In Xenopus and Bombina electrical connexions are re-established between somite muscle cells once the morphogenetic movements underlying somite formation are complete. 7. Presumptive myotome cells in Xenopus and Ambystoma acquire the membrane property of inward-going rectification before incorporation into a somite. 8. Once Xenopus and Bombina embryos show spontaneous movements large end-plate potentials are recorded from the head somites. Excitation spreads from somite to somite along the low resistance intercellular pathway allowing simultaneous contraction of several somites before extensive somite innervation. 9. The structure of developing somite muscle of Xenopus has been studied with the electron microscope. 10. Close membrane contacts of the gap junction type have been seen between undifferentiated presumptive myotome cells, muscle cells in the same somite and between muscle cells in adjacent somites. 11. Myofilament organization first begins in mesoderm cells when they are forming a new somite. Complete sarcomeres appear in the head somites when the embryo begins spontaneous flexion movements.


Alterations in resting membrane properties during neural plate stages of development of the nervous system. 1. The mean resting membrane potential of cells in the neural plate of axolotl embryos increases from -25 to -45 mV (maximum values from -35 to -60 mV) when the embryos move from early to mid-neural plate stages of development. 2. Increasing the extracellular [K] to 20 mM shortly before the spontaneous increase in resting potential occurs causes neural plate cells to hyperpolarize. 3. A moderate increase in [K]omicron does not hyperpolarize the membrane of neural plate cells at earlier stages or at late neural fold stages. 4. Both the hyperpolarization produced by K and the normal increase in resting potential are blocked by cardiac glycosides. 5. Cells of the ventral ectoderm do not display an increase in resting potential during the neural fold stages of development and do not hyperpolarize in response to a moderate increase in [K]omicron. 6. The results suggest that activation of the Na pump may be an early consequence of neural induction. They are discussed in the light of this suggestion.


Cortical suppression of the ritino-collicular pathway in the monocularly deprived cat. 1. In nine cats monocularly deprived from birth, the responses of single neurones in the superior colliculus contralateral to the deprived eye were studied. 2. In six animals most units could be driven by visual stimuli only through the ipsilateral (experienced) eye despite the fact that this colliculus receives a major input from the contralateral (deprived) retina. 3. Immediately following removal of visual cortex, including areas 17, 18 and 19, the collicular units could be driven by the deprived eye. 4. We conclude that the cortex must exert a powerful suppression of the retino-collicular input, and we argue that this suppression occurs in normal as well as in monocularly deprived animals. 5. In three animals the retinal input from the deprived eye was not suppressed but instead dominated many collicular celld, apparently to the exclusion of the cortical input from the experienced eye.


Intercellular coupling in the atrioventricular node and other tissues of the rabbit heart. 1. A fluorescent tracer dye, sodium fluorescein (mol.wt. 332), was used to assess the relative degree of intercellular coupling in various tissues of the rabbit heart. 2. Dye was injected intracellularly by micro-iontophoresis. Subsequent movement into contiguous cells was monitored by video microscopy. From these data the permeability of the intercellular boundaries was computed. 3. The values of boundary permeability were consistent with those expected from previous studies with tracers whose molecular weights bracketed that of fluorescein. 4. In the atrium, ventricle, Purkinje strands and His bundle, the relative magnitude of the boundary permeability correlated reasonably well with the relative profusity of gap junctional area on the intercalated disk, the latter estimated from published data. 5. The rate of passage of dye between N cells of the atrioventricular, AV, node was at least three orders of magnitude lower than between cells of the other tissues studied; this result is consistent with published reports indicating few gap junctions between cells within the region of slow conduction. 6. Quantitative considerations based on these data indicate that N cells may not be sufficiently well coupled to permit impulse propagation through the AV node by intercellular current flow, alone.


Mode of stimulation by aldosterone of the sodium efflux in barnacle muscle fibres: effects of ouabain, ethacrynic acid, diphenylhydantoin, (ATPMg)(2-), adenine translocase inhibitors, pyruvate and oxythiamine. 1. A study has been made of the nature of the delayed stimulation caused by external aldosterone in barnacle fibres pre-exposed to aldosterone. 2. (i) Microinjection of 0-5 M-ATPMg2- caused only a small but prompt rise in the Na efflux. (ii) Microinjection of 0-5 M-ATPMg2- followed by external application of 10(-5)M aldosterone greatly augmented the magnitude of the delayed stimulation. The response was dose-dependent, as well as dependent on the concentration of external K+ and H+, but not Na+, Ca2+ or Mg2+. (iii) External application of 10(-5) M aldosterone for 30 min followed by its withdrawal from the bathing medium failed to bring about delayed stimulation. By contrast, fibres into which ATP had been injected showed delayed stimulation under these conditions. 3. Microinjection of actinomycin-D or spironolactone SC-14266 into fibres into which ATP had been injected followed by external application of aldosterone resulted in complete abolition of the delayed stimulation. 4. Delayed stimulation was reduced whether ATP had been injected or not by prior external application of 10(-4)M ouabain or internal application of 8 x 10(-2)M ethacrynic acid. It was completely abolished by prior application of ouabain externally and ethacrynic acid internally, or only 10(-4)M diphenylhydantoin externally. 5. (i) Microinjection of atractyloside or bongkrekic acid caused a substantial fall in the resting Na efflux. Bonkrekic acid proved more powerful than atractyloside. Microinjection of 0-05 M-ATPMg2- into fibres poisoned with 2-0 x 10(-2)M bongkrekic acid completely restored the Na efflux.


Lateral geniculate relay of slowly conducting retinal afferents to cat visual cortex. 1. Lateral geniculate neurones of the cat were studied in terms of the latency for activation by local electrical stimulation of the retina, the latency of electrical activation from the visual cortex and properties of receptive fields. Most of the units were relay cells (antidromic activation from visual cortex) but a small proportion were trans-synaptically activated from the cortex. The latter group included units with on-off, on-centre or off-centra receptive fields. 2. Direct activation of lateral geniculate neurones from local electrical stimulation of retinal ganglion cells or their axons in the retina was identified by the sharpness of timing of the elicited impulses. This procedure revealed the existence of slowly conducting axons relaying in the lateral geniculate nucleus. 3. The distribution of latencies for direct activation from the retina was bimodal with an extended tail of long values. It is similar to the distribution of antidromic latencies of retinal ganglion cells following stimulation of the optic tract. 4. There was a tendency for geniculate neurones with fast input from the retina to have fast axons to the visual cortex and correspondingly for medium-speed and slow input. 5. The previous classification of geniculate receptive fields into sustained and transient types was extended to include commonly encountered 'brisk' and uncommonly encountered 'sluggish' varieties of each. The extension was based on visual properties and latency for direct electrical activation from the retina. Units with receptive fields differing from the familiar on-centre or off-centre concentric pattern were encountered rarely; they included colour-coded fields, local-edge-detectors and one edge-inhibitory off-centre type.


Effect of renin-angiotensin system on sodium intake. 1. Water and saline intake was measured in rats depleted of Na by I.P. dialysis. Na intake was prevented 180 min but not 60-90 min after bilateral nephrectomy. Unilateral nephrectomy as well as ureteral ligature had no effect on Na intake. 2. Renin (3u.) injected I.P. re-established the Na appetite abolished by nephrectomy. 3. Angiotensin I (5 ng) or II (5-40 ng) injected into the 3rd ventricle, also restored the Na intake and this effect was dose-dependent. 4. The angiotensin converting-enzyme inhibitor Sq 20,881 (1 mg/kg) inhibited the effect of AI but not that of AII in restoring Na intake. 5. It is concluded that the kidneys might play a role in the regulation of Na intake through the renin-angiotensin system.


The physiology and anatomy of long ranging afferent fibres within the spinal cord. The caudal extent of the terminal arborizations of dorsal root afferents was determined in adult cats. The method used micro-electrode stimulation within the dorsal horn and the recording on a distant dorsal root filament of the antidromic action potentials evoked by the stimulation of axons within the spinal cord. 2. It was found that all filaments examined in the L2, 3 and 4 dorsal roots contained axons which projected at least as far as the S1 segment. The axons descended in or near the dorsal columns and from there penetrated into the grey matter. 3. The course of single fibres was followed to their apparent terminals. Thresholds, latencies and relative and absolute refractory periods were measured for single axons. These measurements confirmed that continuous axons ran from dorsal roots to distant segments and that the action potentials recorded were not dorsal root reflexes. 4. The majority of fibres with long range central arborizations were shown to have normal receptive fields in the dermatome of their parent dorsal root. They were not aberrant fibres leaving the spinal cord. 5. The long range afferents exist in substantial numbers since fifteen of eighty axons isolated by micro-electrode recording in the L2 dorsal root sent their axons as far as the S1 segment. The presence of these afferents from five segments away does not fit the data published on the inhibitory and excitatory receptive fields or dorsal horn cells which appear adequately explained by afferents arriving over nearby dorsal roots up to two segments away.


Directional differences of impulse spread in trabecular muscle from mammalian heart. Trabecular bundles from the right ventricle of calf hearts were used. Electrical properties measured by the application of longitudinal current were compared to those measured by the application of transverse current. 2. The following data were obtained on the basis of classical cable analysis: (i) a ratio of 3-0 for longitudinal to transverse conduction velocity, (ii) a ratio of 3-6 for intra- to extracellular longitudinal resistance, (iii) a ratio of 12-6 for intra- to extracellular transverse resistance, (iv) a ratio of 9-4 for intracellular transverse to intracellular longitudinal resistance, (v) a ratio of 2-7 for the extracellular transverse to the extracellular longitudinal resistance. 3. The disparity in conduction velocity could be explained on the sole grounds of differences in the resistivity of the intracellular and extracellular paths for current flow in the two directions, confirming theoretical predictions. 4. The value of the transverse internal resistance can be accounted for on the ground of frequent branching in a three-dimensional network. There is no need to make the additional assumption of current flow through lateral low resistance pathways between parallel fibres.


Ionic currents in the guinea-pig taenia coli. Short segments of portions of taenia coli of the guinea-pig averaging 54 mum X 219 mum X ca. 200 mum have been studied by a double sucrose-gap voltage-clamp technique. 2. The average total capacitance was 0-4 muF, corresponding to approximately 10(4) cells, if a specific membrane capacitance of 3 muF/cm2 were assumed. 3. A significant resistance, averaging 11-4omega, was in series with the membrane, and seriously limited the accuracy of the voltage control possible. 4. On depolarization, an early transient inward current was followed by a late maintained outwary current. 5. The late current was carried mainly by K+, because its direction could be reversed if the preparation were first depolarized in isotonic K2SO4 and held back to the original resting potential. 6. After appropriate corrections for residual capacitative and leakage currents, a reversal potential for the late current (Eb) was determined to be 15-20 mV more negative than the natural resting potential. It was not affected by the amplitude or the duration of the activating voltage step, but could be changed by prolonged applications of holding current. 7. At rest, the ratio of PNa:PK was 0-16:1; for Eb it was 0-05:1. 8. The reversal potential for the transient early inward current (Ea) averaged 22 mV in Krebs-bicarbonate solution, but was shifted to about 35 mV when the late current was first suppressed with tetraethylammonium ion. The shift suggested that there was some overlap of the early and late currents. 9. Reduction of [Na+]o to 50% of normal, or replacement of all Na+ with dimethyldiethanol ammonium ion and choline ion, failed to cause any significant shifts in the reversal potential of the early current or reduce the magnitude of the early current. 10. Reduction of [Ca2+]o to 0-25 or 0-1 of the normal caused shifts of the Ea toward the negative and reductions in the early current. These changes can occur without changes in the maximum chord conductance of the early current, such as might happen in ordinary Krebs-bicarbonate solution, or in preparations which had been depolarized by prior treatment with isotonic K2SO4 and then held back to the original membrane voltage. 11. Increase of [Ca2+]o to 5 times normal increased the early inward current, and the maximum chord conductances of the early and late currents, but did not shift the Ea. 12. In preparations pretreated with TEA, increasing [Ca2+]o to 5 times normal shifted Ea toward 45 mV. 13. The various observations are interpreted to mean that the early current in the taenia coli is carried principally by influx of Ca2+, and not by Na+.


Characteristics of the rectifying properties of the sino-atrial node cell of the rabbit. After confirming the region of the sino-atrial (S-A) node by its characteristic action potential, man-made strands including the pacemaker region of the rabbit heart were prepared and simple cable theory analysis performed. The estimated gamma was 828 mum in Tyrode. 2. The single sucrose gap method was employed to conduct both the current-clamp experiment and the voltage-clamp experiment. In both methods outward-going and inward-going rectification were observed. 3. The existence of a positive after-potential in the case of the current-clamp experiment and of an outward current tail in the case of the voltage-clamp experiment after cessation of cathodal pulses suggests that the outward-going rectification is due to the increase of K conductance. 4. The slowly developed inward-going rectification was always accompanied with a decrease of membrane resistance. It is unlikely that change in K conductance is solely responsible for this rectification. Discussion was made of the possibility that changes in both Na and Cl conductance together with K conductance might be involved.


Lactate metabolism in the isolated perfused rat kidney: relations to renal function and gluconeogenesis. In the intact dog, decreases in both glomerular filtration rate and net renal Na+ reabsorption due to raised ureteral pressure were not associated with a decrease in renal lactate oxidation rate, although total renal CO2 production decreased in proportion to the changes in net renal reabsorption of Na+ and glomerular filtration rate. 2. In order to determine whether, in the absence of other added substrates, the metabolism of lactate supports only the 'basal' renal metabolism or can enhance renal function as well, the rate of lactate utilization and decarboxylation by the isolated perfused rat kidney have been quantified in relation to renal function and one measure of renal basal metabolism, glucose production. 3. The perfusate was Krebs-Ringer bicarbonate (pH 7-35-7-48) with Fraction V bovine serum albumin, 6g/100 ml. L-(+)-lactate was added to raise the lactate concentration from endogenous levels to 2-5, 5-0 or 10 mM. 4. We determined: net lactate utilization rate, lactate decarboxylation rate (14CO2 produced from L-(+)-[U-14C]lactate), net glucose production rate, and net re-absorptive rate of Na+. 5. The apparent Km and Vmax for lactate oxidation were 2-1 mM and 1-29 mumole.g-1.min-1 respectively. There was no apparent maximum for total lactate utilization rate due to continuing increases in glucose production rate as lactate concentration was raised. At ca. 10 mM lactate, glucose production accounted for about half of the total lactate utilized. Therefore the basal energy requirements of the kidney need not be constant since glucose production increases as lactate concentration is raised. 6. Both lactate oxidation rate and lactate utilization rate were significantly correlated with the net reabsorption of Na+ by the renal tubules, with the percentage of filtered Na+ reabsorbed and with the glomerular filtration rate. The major fraction of the net renal reabsorption of Na+ was probably supported by the metabolism of substrates either bound to albumin or derived from renal tissue since the percentage of filtered Na+ reabsorbed increased from ca. 78%, when no lactate was added, to 97% when initial lactate concentration was 10 mM. Therefore, addition of lactate increased both the basal mebabolism and tubular function. However, these observations do not permit us to conclude whether it was the presence of lactate, or its utilization by oxidative or by other pathways which enhanced net renal reabsorption of Na+ and the glomerular filtration rate.


Visual cells in the pontine nuclei of the cat. Two hundred and thirty-two visually activated neurones were recorded in a small area of the rostral pontine nuclei of cats. The location of visually activated neurones was coextensive with the input from visual areas of cat's cortex as determined by degeneration studies. 2. Pontine visual cells could only be driven by visual stimuli. Cells responsive to somatosensory or auditory stimuli were also found in different regions in rostral pontine nuclei. They too responded to only one modality. 3. 96% of the cells were directionally selective. 4. Pontine visual cells were responsive to a wide range of stimulus speeds. Some cells responded to targets moving as fast as 1000 degrees/sec without losing directional selectivity. No pontine visual cells gave a clearly sustained response to a stationary stimulus. 5. Exact stimulus configurations were not critical. Large fields containing many spots were the most effective stimuli for 50% of the cells. Inhibition of responses depending upon stimulus dimensions, direction of movement, or location in the visual field was found for many cells. 6. Receptive field dimensions were large, ranging in size from 3 degrees X 4 degrees to more than an entire hemifield. 7. 94% of the cells had receptive fields which were centred in the contralateral hemifield. 8. 98% of the cells could be driven from both eyes. 9. The properties of the pontine visual cells suggest a corticopontocerebellar pathway sensitive to a wide range of speeds and directions of movement, but not sensitive to precise form.


Two types of extrajunctional L-glutamate receptors in locust muscle fibres. L-glutamate applied iontophoretically to the extrajunctional membrane of locust muscle produced a biphasic response, depolarization followed by hyperpolarization (i.e. DH-response). Applying L-glutamate and DL-ibotenate from multibarrel micropipettes allowed comparison of their extrajunctional responses. While glutamate produced a two component response, ibotenate produced a single component H-response. 2. The equilibrium values for the H-responses to L-glutamate and DL-ibotenate applied at the same extrajunctional site were very similar. The equilibrium value was 59-5 +/- 5-4 mV indicating an increased Cl- conductance. The H-response was reversed and abolished in Cl- free medium. Picrotoxin 10(-3) M selectively blocked the H-component of the DH-response in a reversible manner. 3. The possibility that the D- and H-responses arose from the activation of two distinct types of extrajunctional glutamate receptors was investigated. Desensitization of the glutamate H-response by ibotenate and vice versa indicated the presence of an extrajunctional H-receptor sensitive to glutamate and ibotenate and an extrajunctional D-receptor sensitive to glutamate and insensitive to ibotenate. The junctional depolarizing response to glutamate was insensitive to ibotenate. 4. The presence of junctionally occurring H-receptors could not be discounted, although, if present, they were not measurably activated by the excitatory transmitter. 5. Double logarithmic plots (coulomb dose vs. response) for the actions of glutamate and ibotenate on H-receptors had values of 0-75, indicating that both drugs act on the same receptors with similar mechanisms. The value for the action of glutamate on the D-receptors was 1-5. 6. While the extrajunctional D-receptors show analogies to the extrajunctional ACh receptors in vertebrate muscle, the significance of the extrajunctional H-receptors remains speculative.


Evidence for carrier-mediated uptake and efflux of sugars at the serosal side of the rat intestinal mucosa in vitro. A modification of the everted sac technique is described which allows several sacs to be prepared rapidly and simultaneously from the same segment of rat intestine. 2. A method has been developed for comparing the transport of two sugars by measuring changes in the ratios of their concentrations as they pass across the intestinal wall. 3. With this method significant differences were observed between the D-[3H]galactose and L-[14C]glucose ratios in the mucosal epithelium, the serosal tissue and the serosal compartment. These results indicate that both the efflux of galactose from the serosal side of the mucosal epithelium and the uptake of the sugar into the mucosa are carrier-mediated processes. 4. The mediated efflux of galactose at the serosal side of the epithelial layer is inhibited by the presence of phlorizin on the mucosal side and to some extent by any reduction in the mucosal Na+ concentration. Both of these treatments inhibited galactose uptake at the brush border. Serosal efflux of the sugar appeared to be saturated at high concentrations of D-galactose. 5. Pre-treatment of the sacs with mercuric chloride considerably reduced D-galactose uptake from the luminal side, but did not affect its efflux relative to L-glucose at the serosal side of the mucosal epithelium. 6. Carrier-mediated sugar uptake into the mucosal epithelium from the serosal side was also examined. The role of the bidirectional, carrier-mediated sugar transport processes at the serosal pole of the mucosal epithelial cell in transintestinal transport is discussed.


Comparison of vasoactive intestinal peptide and secretin in stimulation of pancreatic secretion. Pancreatic volume flow as well as bicarbonate and protein secretion have been measured in chronic pancreatic fistula cats and dogs in response to I.V. infusion of VIP and secretin or duodenal perfusion of sodium oleate and HCl solution. 2. VIP and secretin infused I.V. in cats produced superimposable pancreatic dose-response curves for volume flow and bicarbonate secretion, reaching almost identical observed and maximal calculated outputs with both peptides. In dogs, VIP was shown previously to be a much less effective stimulant of pancreatic secretion than secretin and the maximal observed bicarbonate output in response to VIP was only about 17% of that to secretin (Konturek, Thor, Dembinski & Król, 1975). It is condluded that VIP in cats is a secretin-like full agonist, whereas in dogs it is a partial agonist of pancreatic bicarbonate secretion. 3. In cats, secretin and VIP showed equal efficacy and their combination exhibited an augmentatory action on pancreatic bicarbonate secretion with additive kinetics, whereas in dogs, VIP was found to have a lower efficacy than secretin and to inhibit competitively secretin-induced pancreatic secretion. These results might be explained by the interaction of VIP and secretin, two chemically related peptides, on a common receptor site of the exocrine pancreas. 4. Caerulein, an analogue of CCK-PZ, infused I.V. in cats and dogs caused a negligible pancreatic bicarbonate secretion and a potent dose-dependent protein secretion. The combination of graded doses of VIP or secretin with a background dose of caerulein resulted in significantly higher bicarbonate and protein outputs than those induced by VIP or secretin alone. 5. Duodenal perfusion of sodium oleate soap in cats and dogs produced pancreatic dose-response curves for volume flow and bicarbonate output similar to those evoked by VIP in these species. Pancreatic protein secretion in response to luminal oleate was slightly higher than could be accounted for by the action of VIP alone. This might be attributed to the release by oleate not only of endogenous VIP but also CCK-PZ or to the vago-vagal reflexes from gut to pancreas. The results of our combined study on cats and dogs suggest the possibility that oleate releases VIP from the gut and that this peptide may play a physiological role in the stimulation of pancreatic secretion.


Visual cortical cells: their developmental properties in normal and dark reared kittens. 582 units were recorded in area 17 in twenty-one normally reared kittens, and fourteen dark reared ones, aged between 8 and 42 days. 2. Four classes of neurones were defined: (a) non-activable cells that cannot be excited by any peripheral stimulation; (b) non-specific cells that are sensitive to a visual stimulus moving in any direction; (c) immature cells that are preferentially excited by a rectilinear stimulus but are unselective for its precise orientation; (d) specific cells that appear to be as selective for orientation as the simple or complex cells of the adult cat. 3. 23% of the cells presenting adult characteristics of specificity in terms of directionality and orientation are present in both the normally reared and in the dark reared kittens as soon as the first visual response (12 days) appears. 4. In normally reared kittens the proportion of specific cells increases with age, while that of the non-specific cells decreases. 5. Up to 3 weeks of age there is no significant difference in the proportion of the different types of cells in the dark reared from the normal kittens. But thereafter in the dark reared kittens the specific cells tend to disappear while the non-specific cells increase in number. 6. This confirms the view that cells with some highly specific response properties of the adult visual cortical neurones, especially in relation to orientation specificity, are present in the earliest stages in the absence of all visual experience. However, visual experience is necessary to maintain and develop these specific cells after the third week of post-natal life.


Absorption from a mixture of seventeen free amino acids by the isolated small intestine of the rat. Absorption and secretion from a mixture of seventeen free amino acids has been measured in isolated perfused rat small intestine. 2. The absorption rate of an amino acid from this mixture is proportional to its concentration in the perfusate and independent of its chemical constitution. The constant of proportionality is the same as that previously observed when the perfusate contained peptides as well as amino acids. 3. Amino acids are concentrated, on average, sixfold during passage across the mucosa, and the free amino acid composition of the secretion into the tissue fluid is very similar to that of the luminal perfusate. 4. Peptides do not appear to be added to the tissue fluid during absorption of free amino acids. 5. It is concluded that the mechanisms for absorption of free amino acids are in general independent of those for absorption of peptides.


A Markovian model of adult gaze behavior. This study was designed to test a proposed Markov chain model of adult gaze behaviors. Hypotheses for an individual's gaze behavior, dyadic visual interaction, and dyadic gaze states within an independent decision model were examined. Subjects were assigned to a same- or mixed-sex dyad and instructed to converse for approximately 5 min about life at the university. Video tapes of the conversations were unobtrusively obtained and scored by an observer of gaze behaviors for 4 1/2 min in 24 pairs of subjects: eight male, eight female, and eight mixed-sex dyads. The results indicate that the occurrence of a gaze behavior is dependent on a 0.6-sec history, but infrequently prolonged Looking behaviors were found to occur slightly more often than Markovian formulations predicted. The mathematical properties of gaze behavior demonstrated in this experiment are congruent with those of dialogic time patterns, suggesting a regularity in the gross temporal organization of nonverbal communications.


[Double contrast radiography in the study of the gastric posterior wall (author's transl)]. The authors report their experience about 2,422 examinations with double contrast radiography in the study of the gastric posterior wall. This technique is of great value in the detection, analysis and follow-up of gastric ulcerations. In 54 per cent of cases,  the double contrast radiography showed endoscopically proven ulcerations, which where not recognized by standard barium meal technique. The diagnosis of the benign tumours of the posterior wall of the stomach has been also increased bay double contrast radiography. Thus, this technique is recommended for routine examination of the stomach.


[Endovascular extraction of catheters after accidental migration into the cardiac cavities (author's transl)]. The authors describe a technique which permits the extraction of intra-vascular foreign bodies by the intermediary of femoral catheterization. By this method it was possible to extract a catheter below Holter's valve, after accidental migration into the cardiac cavities, in four cases.


[Presentation of a simple apparatus enabling easier tomography in Hirtz's position (author's transl)]. By means of a smiple and hardly burdensome apparatus, owing to a tomograph with hypocycloidal or better spiral scanning a detailed study of the boney structures of the base of the skull can be obtained in a position which up to now has been reputed to be difficult.


[Radiological exploration of alveolar echinococcosis. Concerning two cases with hepatic and splenic localization (author's transl)]. Two cases of alveolar echinococcosis were observed, the first in a 30 year old man, suffering from a hepatic localization, of the classical icteric and tumoral form, the second in a 26 year old patient, with an exclusively splenic localization, a very exceptional possibility. In both cases, coeliac arteriography showed vascular lesions which led one to suspect the diagnosis. To our knowledge, this is the first case of alveolar echinococcosis explored by arteriography. Furthermore, in the first patient, retrograde catheterization of the biliary tract was carried out, which showed very marked changes of the biliary tract. Inspite of the amount of information provided by the radiological investigations, the diagnosis was not made until the surgical intervention.


[Paget's disease with osseous demineralization (author's transl)]. Radiological diagnosis of Paget's disease which is based on hypertrophy of the osseous cortex, osteocondensation and a fibrillary appearance of the cancellous bone, can be rendered difficult when there is superadded demineralization. This is usual in the initial phase of the condition and take on the form of circumscribed osteoporosis. Such an appearance can however be misleading owing to its wide extent or to the number of localizations, as was the case in two of our cases; the diagnosis of Paget's disease must then be established from histological criteria. Besides this demineralization which is directly related to the morbid process in Paget's disease, calcium deficiency is known to modify the clinical and radiological symptomatology of Paget's disease. Our first two cases illustrate this fact and the remarkable effectiveness of "remineralization" therapy in such cases.


[A technique of physical modification in mammography (author's transl)]. The authors propose a technique for use in association with mammography involving aspiration with traction which complements the standard procedure. Traction of the breast makes possible a dynamic study of the organ and its coverings. It may be used in association with radiography, xerography, thermography and transillumination. The changes in the pictures obtained should be compared to other techniques and may be of assistance to the radiologist in their interpretation. An image which does not move is suspicious. An area of translucence around a dense zone, appearing more clearly with traction, is suspicious. Images which do not converge towards the nipple are suspicious. In the light of the information obtained from these new techniques, further examinations may be requested. This simple technique poses no problems for the radiologist and is well accepted by the patient. It provides valuable information contributing to a better approach to diagnosis.


[The parietal band. Normal angiographic appearance and its importance in the angiographic investigation of certain congenital cardiac malformations (author's transl)]. The angiographic study of the parietal band (distal conus) is an important part of the investigation of certain cardiac malformations. In this presentation we have tried to determine the angiographic appearance of the normal parietal band as well as the angiographic aspect of certain conal malformations. Different anomalies of the parietal band may be distinguished: --1) An abnormally developped parietal band may be hypertrophied. 2) The parietal band may be underdevelopped. 3) A well developped parietal band may be in an abnormal position in relation to the interventricular septum. In determining an angiographic relationship between the parietal band, be it normal or abnormal, and the ventricular septal defect, we have tried to establish an angiographic classification of ventricular septal defects.


[Usefulness of renal scinitigraphic scanning in the prognosis of acute renal failure (author's transl)]. The authors present their first results concerning the use of renal scintigraphic scanning using hippuran in acute renal failure (A.R.F.). The tubular stages of hippuran, extraction and secretion then excretion correspond to phenomena which are normally apparent within the first 10 minutes following the injection of hippuran, also it seemed interesting to study the changes which occur in A.R.F. 18 hospital in-patients with A.R.F. were studied, 10 of them suffering from tubulointerstitial nephropathy (T.I.N.) 4 with acute glomerulonephritis (A.G.N.), 2 with obstruction of the urinary pathways and 2 with tubular necrosis on underlying chronic renal failure. In the 10 cases of T.I.N. the phenomenon of extraction was evident without any sign of secretion appearing during the 24 minutes of the investigation. No relationship could be found between the scintigram and the rapidity of recovery from A.R.F., but 8/10 recovered satisfactory renal function, the two others died from their disease, the A.R.F. being only secondary. Two of the 4 cases of A.G.N. had normal or slightly lowered extraction and minimal or absent secretion, and they recovered, in the 2 others no image of extraction appeared within 24 mn. and in these 2 cases the course was unfavorable. Finally, the last four had evident extraction and for 3 of them the course was favorable, the death of the fourth being consecutive to the primary disease. It therefore seems that the presence of an extraction phenomenon, whatever the aetiology of the A.R.F., is a parameter which authorizes the prognosis of a favorable course whereas its absence during the 24 mn. of the investigation permits one to envisage an unfavorable course.


[Angiographic findings in primary miliary hepatic tuberculosis (author's transl)]. The authors describe the hepatic angiographic findings in two patients with primary miliary hepatic tuberculosis. The main angiographic features are abnormalities of the distal arterioles, with small, nodular and irregular formations. The hepatic and portal veins are normal. To our knowledge, it is the first report of angiographic abnormalities in miliary tuberculosis of the liver. The diagnostic and pronostic interest of these findings are discussed.


[A rare cause of antro-pyloric stenosis in the child: septic granulomatosis. Concerning one case (author's transl)]. Presentation of a case of pyloric stenosis in a five year old boy due to a granuloma during the course of septic granulomatosis. The discussion must enable one to evoke the diagnosis when it is a known case of granulomatous disease, and consequently to treat it medically with antibiotics. In the opposite case where the disease is not known, it is a question of etiological discussion of pyloric stenosis. It is now worth thinking of septic granulomatosis routinely with the more classical causes of pyloric stenosis in the order boy.


[Osseous and pulmonary sarcoidosis in a 12 year old girl. Radiological study (author's transl)]. The authors present a rather rare case of sarcoidosis in a 12 year old child. Boney involvement constitutes the first manifestation of the condition, with micro-cystic radiological appearance of the second phalanges of both third fingers. The chest X-ray demonstrated glandular and parenchymatous involvement. The diagnosis was histologically confirmed by osseous biopsy. The authors compare their case with other previously published cases.


The paediatric training required by the general practitioner. A report by a Joint Working Party of the British Paediatric Association and the Royal College of General Practitioners. This report has been written because special programmes of training for general practice are being developed in many parts of the country and there are questions about the paediatric component of training which need to be discussed nationally.An important part of this report is devoted to listing educational objectives which should be attained in paediatrics by the general practitioner at the end of his training.


Psychotherapy services outside the National Health Service. With the help of an Upjohn Travelling Fellowship, I visited 15 units providing services for people under stress. There were nine residential units and six non-residential units, all were Christian charitable organisations and in all there was close co-operation with the medical profession.All these organisations accept referrals from general practitioners and deserve to be more widely known.


A general-practice study of the commonest presenting symptoms of alcoholism. In general practice alcoholism should be considered when the doctor detects marital disharmony, repeated sickness absenteeism, repeated aggressive behaviour, patients who are in debt, patients in trouble with the Law, patients with frequent upset stomachs for no obvious reason, patients presenting with anxiety and depression, and those who smell of drink.


Medical records, medical audit, and community hospitals. A survey of community hospitals suggests a need for improving medical records and communications and introducing review procedures. A new and extended system based on an A4 size unit record is described. The benefits of a medical audit procedure in which all general practitioners and senior nurses participate are discussed.


Pregnancy in women using intra-uterine contraceptive devices. Among 1,041 women fitted with intra-uterine contraceptive devices during a period of 21,445 months there were 51 pregnancies: a rate of 2.9 per hundred women years. Pregnancy occurred most commonly in the young and nulliparous. The importance of the patient checking her device is stressed. Pregnancy occurs most commonly soon after fitting, but may occur at any time. In more than half the cases pregnancy occurred with the device in the uterus. Though most pregnancies were uterine there was a high incidence of ectopic pregnancies. Many pregnancies ended in vaginal delivery, but since the Abortion Act 1967 fewer probably now go to term.


Social work and general practice. A report of a three-year attachment. Much has been written about social worker/general-practitioner collaboration, particularly about conflict of roles, differing functions, avenues of accountability, and problems of distributing scarce resources.We suggest that if the two professions are to work more comfortably together, then it is imperative that both also share the despair, hopelessness, anxiety, and anger that are the occupational hazards of each. We suggest ways in which doctors and social workers can look at the pain their patients are suffering to the benefit of the patient and their own working relationship.


Effect of HCG on the interstitial cells and androgen production in the immature rat testis. The effect on the interstitial cells in the immature rat testis of administration of HCG for different periods was correlated with testosterone plasma levels. Significant and progressive stimulation of mitosis was observed after 3 days of HCG treatment but stabilization occurred after 5 days. The numbers of precursor fibroblasts had increased by the 5th day and were still increasing by the 10th day of treatment. Numbers of Leydig cells were significantly greater at 5 and 10 days of treatment. Plasma testosterone showed a progressive and continuous increase in all groups. The increase in Leydig cell number is considered to be due to a combination of increased stimulation of mitoses in Leydig cells and differentiation of precursor fibroblasts. Mitosis seems to precede fibroblastic differentiation, but the latter continues when mitotic changes have stabilized. The elevation of plasma testosterone concentrations is probably due firstly to the stimulation of the existing Leydig cells and then to the increase in the number of hormone-secreting cells.


Effect of gonadotrophins and testosterone on the seminiferous tubules of the immature rat. The actions of HCG and PMSG for different periods and of testosterone of the immature rat testis were studied. Short-term administration of HCG (1-3 days) induced an early meiotic and postmeiotic stimulatory effect but a decrease in spermatogonial numbers. Administration of HCG for longer periods (10 days) caused a reduction in numbers of all cell types. Treatment with HCG + PMSG reduced the amount of inhibition, while PMSG alone resulted in histological and humoral signs of stimulation of the interstitial tissue and the meiotic and postmeiotic stages; the numbers of spermatogonia were not affected. Testosterone caused stimulation of the meiotic and postmeiotic stages and a reduced number of spermatogonia. It is concluded that while PMSG directly stimulates spermatogonia, HCG acts through testosterone secretion at the meiotic and postmeiotic stages. The early inhibitory effects of HCG and testosterone on spermatogonial numbers could be ascribed to the inhibition of endogenous FSH by androgens.


Inhibition of bull and rabbit sperm enzymes by alpha-chlorohydrin. High concentrations of alpha-chlorohydrin were found to inhibit hyaluronidase, beta-glucuronidase, and aryl sulphatases in bull and rabbit spermatozoa, but not acrosin and neuraminidase. Preincubation of the enzyme and alpha-chlorohydrin was essential to achieve the maximum inhibition which was irreversible.


The development and proliferation of the trophoblast from ectopic mouse embryo allografts of increasing gestational age. The development and proliferation of trophoblast from ectopic mouse embryo allografts and isografts of increasing gestational age in nonimmune and specifically preimmunized hosts was studied. Specific preimmunization of recipients significantly inhibited haemorrhagic nodule development from 3-3 1/2 and 4-4 1/2 day post coitum homozygous blastocysts and from 5-5 1/2 day homozygous egg cylinders. Preimmunization had no effect on the percentage of haemorrhagic nodules which developed from 6-6 1/2 day homozygous egg cylinders. Haemorrhagic nodule development was significantly increased for F1 hybrid allografts compared to homozygous allografts to preimmunized recipients. Coincident with the immune inhibition of haemorrhagic nodule formation was the microscopic finding that in some cases trophoblast cells developed without subsequent proliferation in preimmunized hosts. The results are discussed in relation to the expression of transplantation antigens by the developing conceptus, the continued differentiation of the embryo after transplantation, and the inductive influences of the inner cell mass on trophoblast ontogeny.


Progesterone and 20 alpha-dihydroprogesterone in sheep: a model of their distribution and metabolism. The rates of metabolism of progesterone and 20alpha-dihydroprogesterone (20alpha-diHP) in sheep have been measured during and after the infusion of tracer amounts of [3H]progesterone. There were significant differences in the blood concentration of [3H]progesterone between experiments, but these were not attributable to the stage of gestation or to the difference between pregnant and non-pregnant animals. The mean (+/- S.E.M.) metabolic clearance rate of progesterone was 3-277 +/- 0-239 litres blood/min. The simplest model of the distribution of progesterone was one containing two pools, V1[P] and V2[P], where [p] is the blood concentration of progesterone, and in 23 experiments on 7 sheep the mean pool dimensions were 7-8[P] mug and 70[P] mug, respectively. This model was developed to include the formation of 20alpha-diHP from progesterone. Progesterone appeared to be the major source of 20alpha-diHP, though this did not seem to be an obligatory metabolite. The parameters obtained gave comparably low residual deviations for both labelled steroids and were consistent with other observations made on progesterone clearance.


The influence of photoperiod on growth and sexual function in male and female collared lemmings (Dicrostonyx groenlandicus). The effect of photoperiod on sexual function and growth in weanling male and female collared lemmings (Dicrostonyx groenlandicus) was studied. Males and females maintained in 6 hr light:18 hr dark after weaning were larger at the end of 70 days than their siblings kept in 20L:4D. Males in 6L:18D were longer and overall body growth was greater. Males in 6L:18D had heavier adrenals but there were no differences in the weights of testes, preputial glands or seminal vesicles or in the mean testosterone levels of the two groups. Females in 6L:18D had heavier preputial glands than the 20L:4D females. There were no differences between the two groups in uterine, ovarian or adrenal weights or in the number or mean size of atretic or healthy Graafian follicles. Adult males kept in 6L:18D increased more in body weight than those in 20L:4D, but there was no detectable influence of the short photoperiod on reproductive function.


Fertility in cows after treatment with a prostaglandin analogue with or without progesterone. Two infections each of 500 mug Cloprostenol (ICI-80,996), a synthetic analogue of PGF-2alpha, 11 or 12 days apart or pretreatment for 7 days with progesterone from an intravaginal silastic coil and one injection of 500 mug Cloprostenol were both effective in synchronizing oestrus in heifers or nursing beef cows. After two inseminations at 72 and 96 hr after the end of treatment, the calving rate for cows observed in oestrus after both treatments or for cows that had oestrous-like mucus after the progesterone+Cloprostenol treatment did not differ from that of control cows, but was significantly (P less than 0-025) lower for cows diagnosed as ready for insemination by the characteristics of mucus after the two injections of Cloprostenol. Treated cows disgnosed per rectum as having inactive ovaries had a significantly (P less than 0-005) lower calving rate than those diagnosed as having active ovaries at the start of treatment. Significantly (P less than 0-005) more treated than control cows were inseminated and became pregnant in the first 15 days of the treatment period, but the overall level of reproductive efficiency was low.


The distribution of blood flow to the reproductive organs of rats near term. The rate of ovarian and utero-placental blood flow through vessels of less than 25 mum diameter was examined with radioactive microspheres in 5 non-pregnant rats and 19 rats at Day 22 of pregnancy. Total blood flow to the reproductive organs was 0-559 ml/min in the non-pregnant animals and 13-2 ml/min in those near term, a 23-fold difference. The mean ovarian blood flow was high and increased from 0-202 ml/min to 0-845 ml/min. Myometrial and endometrial blood flow increased from 0-156 to 2-24 ml/min. The mean maternal placental blood flow at Day 22 of pregnancy was 0-76 ml/min or 121 ml.,min-1 .100 g-1. Litter size was negatively correlated with mean fetal weight but showed little relationship to mean placental weight or to mean maternal placental blood flow.


Distribution and development of embryos in the pig. The distribution and development of pig embryos were determined in relation to the number of embryos and their positions within the uterine horn between Days 14 and 34 after mating. The observed distribution of 1-11 embryos within a uterine horn was highly correlated (r = 0-96) with the theoretical expected distribution. Embryo spacing was uniform regardless of the number of embryos within the horn. Nitrogen content of the embryo in relation to its position within the uterine horn indicated that development was similar for embryos located at the utero-tubal end or cervical end and comparable to those located in the middle portion of the horm. Placental development, as indicated by nitrogen content, was similar regardless of location within the horn.


Effect of indomethacin on egg transport and pregnancy in the rabbit. Treatment of rabbits with indomethacin (10 mg/kg/day) 48 hr before mating, and with 20 mg/kg at 12 hr followed by 8 mg/kg at 48, 72 or 96 hr after mating did not affect the rate of egg transport through the oviduct. Indomethacin treatment at the time of implantation interfered with pregnancy and caused degeneration and resorption of embryos. These results suggest that inhibition of prostaglandin synthesis does not directly affect egg transport, but that prostaglandin appears to be required for the retention of implanted embryos.


Fertilizing ability in vivo and in vitro of spermatozoa of rats and mice treated with alpha-chlorohydrin. The fertilizing ability of epididymal spermatozoa from rats and mice treated for 3 or 4 or 9 or 10 days with various doses of alpha-chlorohydrin was tested in vitro, and in vivo by intrauterine insemination. The minimum doses (per kg/day) needed to affect fertilization significantly were: rat, in vitro, 8-8 mg for 3 or 4 days, 4-4 mg for 4 days and 2-7 mg for 9 or 10 days; in vivo, 4-4 mg for 3 or 4 days and 2-7 mg for 9 or 10 days: mouse, in vitro, 4-4 mg for 3 days and 13-3 mg for 9 days; in vivo, 44-2 mg for 3 days and 26-5 for 9 days. Rats were infertile for at least 18 days after receiving 44-2 mg alpha-chlorohydrin/kg/day for 3 days, but fertilizing ability, tested in vivo and in vitro, was restored 10-11 days and 15-18 days, respectively, after daily treatment with 11-1 mg alpha-chlorohydrin/kg for 3 days.


Acceleration of sexual maturation in female rats by male stimulation. In comparison to controls reared in isolation, female rats reared in the presence of an adult male from weaning attained puberty 5 days earlier when living in groups or almost 9 days earlier when living singly with a male. Accelerated sexual development occurred in the absence of accelerated physical growth.


Monoamine oxidase in rat placenta, human placenta, and cultured choriocarcinoma. The activity of monoamine oxidase (MAO), an enzyme which metabolized catecholamines and indoleamines, was determined in rat placenta at various stages of gestation, in human term placenta, and in choriocarcinoma grown in culture. From Day 15 to Day 20 of gestation the specific activity (units/mg protein) of MAO in rat placenta increased at least 3-fold; from Day 20 to the time of parturition, it decreased about 50%. The specific activity of MAO in human placenta at term was about 50%. The specific activity of MAO in human placenta at term was about 8 times higher than that of rat placenta at term. No MAO activity was found in choriocarcinoma grown in culture.


Seasonal changes in the pineal gland related to the reproductive cycle in the male hare, Lepus europaeus. During the autumn months, the gonads and reproductive tract of adult male hares (Lepus europaeus) are regressed and circulating gonadotrophin levels are low. At this time the pineal glands are most active as judged by the organ size, and the nuclear and cytoplasmic size of the pinealocytes. There was an inverse relationship between the size of the pineal gland and the weight of the testis, the plasma and testicular testosterone levels, and possibly also the plasma LH levels.


Patient acceptance of nurse-midwife in a private group practice. Forty private obstetrical patients cared for by a group practice employing a nurse-midwife were interviewed. Half of the study group accepted the nurse-midwife for delivery. The other 20 were delivered by an obstetrician. Acceptance of prenatal care by the nurse-midwife was found to be favorable. Patients reported feeling more comfortable with the nurse-midwife and perceived her as more understanding, sympathetic and available to answer questions than the physicians. The initial encounter with the nurse-midwife differed significantly between those in the two delivery groups. Patients accepting the nurse-midwife for delivery were more likely to have first met her alone while those who chose to be delivered by an obstetrician-gynecologist were more likely to have been introduced to the nurse-midwife by the physician. The implications of this initial "imprinting experience" on the acceptance of the nurse-midwife for delivery are discussed.