Involvement of charybdotoxin-sensitive K+ channel in the relaxation of bovine tracheal smooth muscle by glyceryl trinitrate and sodium nitroprusside. To elucidate the involvement of K+ channels in the smooth muscle relaxation by glyceryl trinitrate (GTN) and sodium nitroprusside (SNP), effects of several K+ channel antagonists on the relaxant responses to GTN, SNP and 8-bromoguanosine 3',5'-cyclic monophosphate (8-Br-cGMP) were studied in bovine tracheal smooth muscle. Although an antagonist of large conductance Ca(++)-activated K+ channel, charybdotoxin, produced no definite effect on the relaxation induced by GTN, SNP and atriopeptin in the rabbit aortic ring preparation, this antagonist inhibited the relaxation by GTN, SNP, atriopeptin and 8-Br-cGMP in the bovine tracheal smooth muscle. Methylene blue, a soluble guanylate cyclase inhibitor, also had an inhibitory effect on the relaxation by GTN and SNP. Both apamin, a small conductance Ca(++)-activated K+ channel antagonist, and glibenclamide, an ATP-sensitive K+ channel antagonist, did not exhibit any inhibitory effect on the relaxant responses to GTN and SNP. GTN and SNP increased cGMP content. The increment was attenuated by methylene blue, whereas it was unaffected by charybdotoxin. These results indicate the involvement of large conductance Ca(++)-activated K+ channel in the relaxation of bovine tracheal smooth muscle by GTN, SNP and 8-Br-cGMP. The activation of K+ channel by GTN and SNP is thought to occur via increases in cGMP content.


A central nervous system action of nitric oxide in blood pressure regulation. We had reported that the systemic administration of N omega-methyl-L-arginine (L-NMA), a specific inhibitor of nitric oxide (NO) synthesis from L-arginine (ARG), raises arterial blood pressure (BP) while paradoxically enhancing central sympathetic outflow. Cervical spinal cord transection abolishes the increase in sympathetic outflow and attenuates the pressor effect of L-NMA. Thus, in addition to lowering BP by direct vasorelaxation, NO may also act in the central nervous system to reduce vascular sympathetic tone. To test this hypothesis we have injected L-NMA directly into the central nervous system in anesthetized rats. Intracisternally (i.c.), L-NMA elicited a small pressor response accompanied by a marked increase in sympathetic renal nerve activity (RNA). In contrast, the inactive stereoisomer N omega-methyl-D-arginine had neither pressor nor neural effects. The increases in RNA and BP elicited by i.c. L-NMA were abolished by spinal cord transection at C1 to C2 and by the i.v. administration of ARG. When administered i.c., ARG also abolished the increase in RNA elicited by i.v. L-NMA and significantly attenuated the pressor response. Thus, our findings indicate that L-NMA acts centrally by an ARG-reversible mechanism in the anesthetized rat to stimulate sympathetic nerve activity. Inasmuch as centrally synthesized NO has been postulated to play a second messenger and/or neurotransmitter role, our findings suggest that one such function would be the central regulation of sympathetic outflow and hence, BP.


Spinal interactions between opioid and noradrenergic agonists in mice: multiplicativity involves delta and alpha-2 receptors. The nature of the interaction between spinally administered opioid and alpha-2 agonists was investigated using the substance P behavioral test in mice. Morphine and agonists which more selectively activate mu or delta opioid receptors were co-administered intrathecally with direct and indirect acting adrenergic agonists norepinephrine, cocaine or clonidine and the behavioral responses to intrathecally coadministered substance P were evaluated. The ED50 values for agonists administered separately and concurrently were computed and drug interactions were evaluated using isobolographic analyses. After separate administration, all the opioid and adrenergic agonists inhibited the substance P-induced behavioral responses. Upon coadministration of opioid and adrenergic agonists, a multiplicative interaction was observed between morphine or the delta agonist D-Pen2-D-Pen-5-enkephalin and the adrenergic agonists. Additive or antagonistic interactions were found between the mu agonist Tyr-D-Ala-NMe-Phe-Gly(ol) and the same adrenergic agonists. The opioid antagonist naloxone and the alpha-2 adrenergic antagonist idazoxan were given as intrathecal pretreatments at doses chosen to shift the dose-response curves of their corresponding agonist (given alone) 4- to 10-fold to the right; this always resulted in a smaller, but significant (2- to 4-fold) shift in the dose-response curve of the other agonist given alone. Intrathecal pretreatment with naloxone or idazoxan altered some interactions between the opioids and clonidine. Although naloxone blocked completely the multiplicative interaction between morphine and clonidine, idazoxan did not. Both naloxone and idazoxan changed the antagonistic interaction between Tyr-D-Ala-NMe-Phe-Gly(ol) and clonidine to a multiplicative interaction. Neither antagonist blocked the multiplicative interaction between D-Pen2-D-Pen5-enkephalin and clonidine. These results suggest that: 1) interactions between opioid and adrenergic agonists in mouse spinal cord are mediated by delta and alpha-2 receptor subtypes; 2) the synergistic interaction between morphine and alpha-2 adrenergic agonists may involve action at delta opioid receptors; and 3) antagonist action on these drug interactions is complex.


FK 224, a novel cyclopeptide substance P antagonist with NK1 and NK2 receptor selectivity. We have discovered a novel cyclopeptide substance P (SP) antagonist, FK 224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2-pentylphenyl )- propionyl]-L-threonyl]tyrosyl-L-leucynyl]-D-phenylalanyl]-L-allo- threonyl]-L-asparaginyl]-L-serine-nu-lactone), which inhibited [3H]SP binding to guinea pig lung membranes in a dose-dependent manner. According to Rosenthal analysis, the inhibitory effect of FK 224 on [3H]SP binding appears to be competitive. In order to clarify the receptor subtype selectivity of FK 224, we have studied the interaction of FK 224 with three tachykinin receptors (NK1, NK2 and NK3) by using receptor binding techniques and in vitro bioassays, and have also compared FK 224 with the novel nonpeptide antagonist, (+/-)-CP-96,345. In binding experiments, FK 224 dose-dependently inhibited [3H]SP binding to rat cerebral cortical membranes (NK1) and [3H]neurokinin (NK) A (NKA) binding to rat duodenum smooth muscle membranes (NK2), but did not affect [3H]eledoisin binding to rat cerebral cortical membranes (NK3). In bioassay experiments, FK 224 inhibited SP-induced contraction of guinea pig ileum (NK1) and NKA-induced contraction of rat vas deferens (NK2) in a dose-dependent manner, but did not affect NKB-induced contraction of rat portal vein (NK3). In contrast, (+/-)-CP-96,345 inhibited SP-induced contraction of guinea pig ileum, but not NKA-induced contraction of rat vas deferens or NKB-induced contraction of rat portal vein. In the presence of FK 224, SP dose-response curves and NKA dose-response curves were shifted to the right in parallel with no depression of the maximal contraction.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of FK224, a novel compound NK1 and NK2 receptor antagonist, on airway constriction and airway edema induced by neurokinins and sensory nerve stimulation in guinea pigs. FK224 (N-[N2-[N-[N-[N-[2,3-didehydro-N-methyl-N-[N-[3-(2- penthylphenyl)-propionyl]-L-threonyl]tyrosyl]-L-leucynyl]-D- phenylalanyl]-L-allo-threonyl]-L-asparaginyl]-L-serine-nu-lactone) is a novel neurokinin (NK) antagonist that exhibits selectivity for NK1 and NK2 receptors. The effects of FK224 on airway constriction and airway edema induced by NKs and nerve stimulation have been investigated in guinea pigs. FK224 inhibited the contraction of isolated guinea pig trachea induced by substance P (SP, 10(-8) M), NKA (10(-9) M) and NKB (10(-8) M) in a concentration-dependent manner, and the IC50 values were 2.6 x 10(-6), 1.3 x 10(-6) and 2.3 x 10(-7) M, respectively. Tracheal contraction induced by histamine and acetylcholine was not affected by FK224, suggesting a specific effect on NK-mediated responses. FK224 also inhibited the atropine-resistant contraction of isolated guinea pig bronchi induced by electrical field stimulation with an IC50 value of 3.5 x 10(-6) M. In in vivo experiments, FK224 given i.v. inhibited SP (13.5 micrograms kg-1)-, NKA (1.1 micrograms kg-1)- and capsaicin (3.1 micrograms kg-1)-induced airway constriction in guinea pigs with ED50 values of 0.39 mg kg-1, 0.36 mg kg-1 and 1.1 mg kg-1, respectively. FK224 also inhibited SP (1.3 micrograms kg-1)-, NKA (11 micrograms kg-1)- and capsaicin (100 micrograms kg-1)-induced airway edema with ED50 values of 0.14 mg kg-1, 0.29 mg kg-1 and 0.30 mg kg-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative assessment of poly-L-aspartic and poly-L-glutamic acids as protectants against gentamicin-induced renal lysosomal phospholipidosis, phospholipiduria and cell proliferation in rats. Coadministration of poly-L-aspartic acid (poly-L-Asp) protects rats against all measured signs of aminoglycoside nephrotoxicity. Based on in vitro and acute in vivo models, previously we hypothesized that poly-L-Asp protects by forming complexes with the drug in lysomes of proximal tubular cells. However, another closely related peptide, poly-L-glutamic acid (poly-L-Glu), could not protect against gentamicin-induced phospholipidosis and nephrotoxicity, presumably because it is susceptible to rapid hydrolysis in sysosomes in vivo. The present study expands the in vivo comparison between these two polyanions to a subacute model of rats and examines in detail the influence of these polymers on the qualitative and quantitative morphological alterations of lysosomes, phospholipiduria and proliferation of cortical cells induced by gentamicin. Our results not only demonstrated that despite a significantly higher drug cortical accumulation, the coadministration of poly-L-Asp almost completely protects against the development of all these early renal alteration but also pointed to the possibility of a mild, albeit apparently nonlethal, lysosomal thesaurismosis to develop under these conditions. In contrast, poly-L-Glu could not protect against these early renal alterations, though cortical drug accumulation was not significantly higher; however, it induced a conspicuous proliferation of peritubular interstitial cells. Therefore, the present work, taken together with the earlier results of ours as well as that of others, tends to strengthen the hypothesis that the site of action of poly-L-Asp must be in lysosomes, which are also the organelles that sequester and accumulate the drug.


In vivo and in vitro effects of the azidothymidine analog dideoxyinosine on the exocrine pancreas of the rat. Phase I clinical trials of the purine analog 2',3'-dideoxyinosine (ddl) revealed that 10% of the patients developed pancreatitis, yet there was no clear relationship between increasing doses of ddl and the development of pancreatitis. To test the effects of chronic ddl administration on the structure and function of the rat pancreas, male Wistar rats were given ddl at 100 mg/kg/day i.p. for 35 days or 1400 mg/kg/day for 30 days, in two divided doses. Serum amylase levels, pancreatic tissue water content (edema) and pancreatic morphology by light and electron microscopic examination of pancreata from ddl-treated rats were similar to those of rats receiving saline injections only (controls). 2',3'-Dideoxyinosine administration did not alter the subcellular distribution of the lysosomal enzyme cathepsin B, whose redistribution to a more dense zymogen granule-enriched subcellular fraction is an early indicator of acute pancreatitis. Dispersed pancreatic acini from rats receiving ddl (100 mg/kg/day for 30 days) were incubated in vitro for 15 min with either caerulein or carbamylcholine as secretory stimuli. There was no detectable difference in the stimulatable amylase secretion from ddl-treated animals compared to the control group. Based on these findings, we conclude that ddl has no direct toxic effect on the rat pancreas. 2',3'-Dideoxyinosine may be contributing to pancreatitis in acquired immunodeficiency syndrome patients by potentiating other pancreatotoxic agents or by its action on a pancreas that is already altered by the human immunodeficiency virus infection.


GABA-gated anion channels in intact crayfish opener muscle fibres and stretch-receptor neurons are neither activated nor desensitized by glutamate. The influence of glutamate on the GABA-activated Cl- conductance was studied in the slowly adapting stretch-receptor neuron and dactylopodite opener muscle fibre of the crayfish (Astacus astacus) using a two-microelectrode and a three-microelectrode voltage clamp, respectively. Glutamate (0.5-1.0 mM) had no effect on the GABA-activated conductance in either preparation. This indicates that the availability of the inhibitory channels for activation of GABA is not influenced by glutamate. The present results are in sharp contrast to those obtained by Franke et al. (J Comp Physiol A 159:591-609, 1986) in experiments on excised membrane patches, which suggested that glutamate is capable of both activating and desensitizing inhibitory postsynaptic channels in the crayfish opener muscle fibre.


Toad bladder amiloride-sensitive channels reconstituted into planar lipid bilayers. In the present study we used established methods to obtain apical membrane vesicles from the toad urinary bladder and incorporated these membrane fragments to solvent-free planar lipid bilayer membranes. This resulted in the appearance of a macroscopic conductance highly sensitive to the diuretic amiloride added to the cis side. The blockage is voltage dependent and well described by a model which assumes that the drug binds to sites in the channel lumen. This binding site is localized at about 15% of the electric field across the membrane. The apparent inhibition constant (K(0)) is equal to 0.98 microM. Ca2+, in the micromolar range on the cis side, is a potent blocker of this conductance. The effect of the divalent has a complex voltage dependence and is modulated by pH. At the unitary level we have found two distinct amiloride-blockable channels with conductances of 160 pS (more frequent) and 120 pS. In the absence of the drug the mean open time is around 0.5 sec for both channels and is not dependent on voltage. The channels are cation selective (PNa/PCl = 15) and poorly discriminate between Na+ and K+ (PNa/PK = 2). Amiloride decreases the lifetime in the open state of both channels and also the conductance of the 160-pS channel.


Multiple-channel conductance states and voltage regulation of embryonic chick cardiac gap junctions. We used the double whole-cell voltage-clamp technique on ventricle cell pairs isolated from 7-day chick heart to measure the conductance of their gap junctions (Gj) and junctional channels (gamma j) with a steady-state voltage difference (Vj) applied across the junction. Currents were recorded from single gap junction channels (ij) as symmetrical rectangular signals of equal size and opposite sign in the two cells, and gamma j was measured from ij/Vj. We observed channel openings at six reproducible conductance levels with means of 42.6, 80.7, 119.6, 157.7, 200.4 and 240.3 pS. More than half of all openings were to the 80- and 160-pS conductance levels. The probability that a high conductance event (e.g., 160 or 240 pS) results from the random simultaneous opening of several 40-pS channels is small, based on their frequency of occurrence and on the prevalence of shifts between small and large conductance states with no intervening 40-pS steps. Our results are consistent with three models of embryonic cardiac gap junction channel configuration: a homogeneous population of 40-pS channels that can open cooperatively in groups of up to six; a single population of large channels with a maximal conductance near 240 pS and five smaller substates; or several different channel types, each with its own conductance. Gj was determined from the junctional current (Ij) elicited by rectangular pulses of applied transjunctional voltage as Ij/Vj. It was highest near 0 Vj and was progressively reduced by application of Vj between 20 and 80 mV or -20 and -80 mV. In response to increases in Vj, Gj decayed in a voltage- and time-dependent fashion. After a 6-sec holding period at 0 Vj, the initial conductance (G(init) measured immediately after the onset of an 80-mV step in Vj was nearly the same as that measured by a 10-mV prepulse. However, during 6-sec pulses of Vj greater than +/- 20 mV, Gj declined over several seconds from G(init)to a steady-state value (Gss). At potentials greater than +/- 20 mV the current decay could be fit with biexponential curves with the slow decay time constant (tau 2) 5-20 times longer than tau 1. For the response to a step to 80 mV Vj, for example, tau 1 = 127 msec and tau 2 = 2.6 sec. The rate of current decay in response to smaller positive or negative steps in Vj was slower, the magnitude of the decline was smaller, and the ratio tau 2/tau 1 decreased.(ABSTRACT TRUNCATED AT 400 WORDS)


Staining sections of water-miscible resins. 2. Effects of staining-reagent lipophilicity on the staining of glycol-methacrylate-embedded tissues. Glycol methacrylate (GMA) sections of animal tissues were stained with a group of twenty-seven reagents of very varied chemical characteristics. The artefactual background staining of the resin was found to be dependent on the hydrophilic/lipophilic character of the staining reagent, as estimated from the logarithm of its octanol-water partition coefficient (log P). Intense background staining occurred with lipophilic stains, whose log P greater than 2. In keeping with this, use of GMA semi-permeable membranes for enzyme histochemistry failed to give staining when using a lipophilic substrate, probably because the substrate was trapped in the membrane. An analysis of other routine histochemical stains--in terms of the probable occurrence of high resin background staining and low tissue sensitivity--is made. A numerical guide is provided to help avoid artefacts resulting from hydrophobic and size effects. Note: small, hydrophilic reagents (log P less than 0; molecular weight less than 550 Da) are least likely to show either type of artefact. Conversely, reagents which are lipophilic, or/and of intermediate size (log P greater than 2; 550 less than ionic weight less than 1000 Da), give strong background staining.


Activation of protein kinase C pathway contributes to hydrogen peroxide-induced increase in endothelial permeability. We examined the effects of hydrogen peroxide (H2O2) on endothelial permeability and the possible role of protein kinase C (PKC) activation in mediating the response. Pulmonary microvessel endothelial cell monolayers were grown to confluency on gelatin- and fibronectin-coated microporous filters. Endothelial permeability was measured by determining the transendothelial clearance rate of [125I]albumin. The monolayers in all cases were challenged for 1 hour with H2O2. In some experiments, the monolayers were preincubated with PKC inhibitors H7 (an isoquinolinylsulphonamide derivative) (0.05 mM) or calphostin C (5 x 10(-6) mM) or with the inactive isoquinolinylsulphonamide analog, HA1004 (0.05 mM), before the H2O2 challenge. Addition of H2O2 (0 to 0.5 mM) to endothelial monolayers in the absence of PKC inhibitors resulted in a concentration-dependent increases in endothelial permeability and the response occurred without LDH release and morphologic evidence of cytolysis. The increase in permeability was significantly reduced by H7 and calphostin C, but not by HA1007. Immunocytochemical localization of PKC indicated that PKC isotype II was abundant in these cells and that it was distributed uniformly in the cytosol. H2O2 induced translocation of PKC to the cell membrane indicating enzyme activation. H7 and calphostin C prevented the H2O2-induced PKC translocation, whereas HA1004 had no effect. Both PKC inhibitors also prevented cell "rounding" and formation of interendothelial gaps, whereas HA1004 was ineffective. The results indicate that PKC activation is an important determinant of the H2O2-induced increase in endothelial permeability.


Differential distribution of tenascin and cellular fibronectins in acute and chronic renal allograft rejection. Acute and chronic renal allograft rejection injuries involve, albeit variably, all compartments of the organ and are associated with significant structural changes. We hoped to gain new insights into these phenomena by determining distribution of certain extracellular matrix proteins known to be involved in architectural remodeling processes. Frozen tissue samples from biopsies of acute (n = 14) and chronic (n = 12) human renal allograft rejections were studied to compare distribution of tenascin, the extradomains A and B (EDA, EDB), and oncofetal (Onc) isoforms of cellular fibronectin (cFn). Normal kidneys (n = 4) served as controls. Cryosections were immunostained by the avidin-biotin-complex method with monoclonal antibodies specific for those molecules. In acute rejection, reactivity for tenascin and EDA-cFn was increased slightly to moderately in glomerular mesangia and in most vessels while it was intensely and diffusely increased in the interstitium. Rarely were focal EDB-cFn and Onc-cFn reactions seen in lesions deemed to reflect acute injury. In chronic rejection, tenascin and EDA-cFn were strongly increased in most glomerular mesangia and in vascular walls but unevenly in the interstitium. In rare glomerular synechiae and vessels, enhanced staining for tenascin and EDA-cFn as well as EDB-cFn and Onc-cFn was noted while in obsolete glomeruli only EDB-cFn and Onc-cFn were detected. The enhanced distribution of tenascin and EDA-cFn partly reflected that noted during nephrogenesis, whereas staining patterns for EDB-cFn and Onc-cFn differed from their fetal counterparts. Tenascin and EDA-cFn are strongly and preferentially expressed in the interstitial and vascular compartments of acute and chronic renal rejection injury suggesting that, in these sites, active repair and remodeling occur during both phases of the rejection process irrespective of the changes seen by conventional microscopy. Tenascin, EDA-cFn as well as EDB-cFn and Onc-cFn are all involved, albeit variably, in the glomerular and vascular alterations of chronic rejection. The finding of tenascin and of the three isoforms of cFn in glomerular synechiae with actively proliferating epithelium suggests that certain epithelial cells might partake in the synthesis of these molecules.


Comparison of enoximone and piroximone in patients after mitral valve operation: a prospective and controlled clinical study. Phosphodiesterase III (PDEII) inhibitors as so-called inodilators have previously proven a valuable alternative to positive inotropes in patients with cardiac insufficiency. In this study we compared patients receiving piroximone (P, n = 14, 0.5-mg/kg bolus in 30 min and then 3-6 micrograms/kg/min) with enoximone patients (E, n = 13, 1-mg/kg bolus and then 4-20 micrograms/kg/min) and with a third group (D, n = 14) receiving a combination of dopamine (4-10 micrograms/kg/min) and glyceroltrinitrate (0.5-5 micrograms/kg/min) for hemodynamic support. All three groups were comparable in terms of age, body surface area, and preoperative cardiac function [cardiac index (CI) less than or equal to 2.5 L/min/m2, LAP greater than 15 mm Hg]. Hemodynamic measurements (10) and Holter monitoring were performed until 18 h post MVR. In all groups, epinephrine was used for additional inotropic therapy if mean arterial pressure (MAP) was less than 60 mm Hg and/or CI was less than 2.5 L/min/m2. There was no early or late postoperative mortality in either group. Continuous support with epinephrine was necessary in 8 patients in group D, whereas initially 8 patients in group E and 6 patients in group P required epinephrine support. After PDE III inhibitor infusion, 2 patients in group E and 2 patients in group P remained epinephrine dependent (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative electrophysiologic effects of metabolites of quinidine and hydroquinidine. To evaluate whether the hydroxylated metabolites of quinidine (Q) and hydroquinidine (HQ): hydroxy-3S-quinidine (OH-Q) and hydroxy-3S-hydroquinidine (OH-HQ), exert electrophysiologic effects and participate in the therapeutic action of the parent drugs, we examined and compared the effects of the metabolites and the parent drugs on the electrical activity of guinea pig ventricular cells recorded by standard microelectrode technique. In addition, we investigated the potential arrhythmogenic properties of these compounds in rabbit Purkinje fibers in low K+ (2.7 mM) Tyrode's solution. The concentration [C]-, frequency-, and voltage-dependent effects of the drugs were investigated. Maximum upstroke velocity of phase 0 (Vmax) was [C]-dependently depressed by both OH-Q and OH-HQ but at a lesser degree than with Q and HQ, respectively: at the [C] of 50 microM, Vmax depression attained 26.7 +/- 2.6% with OH-Q versus 45.9 +/- 1.6% with Q and 32.3 +/- 1.9% with OH-HQ versus 54.6 +/- 1.4% with HQ. This effect was frequency and voltage dependent without significant differences between the four compounds. In the presence of equipotent [C], recovery kinetics of Vmax was significantly slower with metabolites than with respective parent drugs. In contrast, the effects of metabolites on action potential duration at 90% of repolarization (APD90) and effective refractory period (ERP) differed from those observed with parent drugs. With metabolites, APD90 and ERP were increased in a [C]-dependent manner, whereas the Q- and HQ-induced lengthening in APD90 and ERP was observed only at low concentration and low frequency. In addition, the OH-Q- and OH-HQ-induced APD90 lengthening was not altered by increasing pacing rate. In rabbit Purkinje fibers, increase in cycle length and prolonged exposure to either metabolites or parent drug caused early afterdepolarizations (EADs) and triggered activity. With all drugs tested, EADs arose more frequently at the plateau level than at the final repolarization of AP, but the incidence of EADs appeared to be much lower with metabolites than with parent drugs. The present results demonstrate that OH-Q and OH-HQ exert qualitatively similar but quantitatively less potent depressant effects on Vmax than Q and HQ, respectively, but differ in the lengthening effect on APD. We suggest that metabolites may participate in class I antiarrhythmic action of their respective parent drug and contribute to their arrhythmogenicity.


Effects of captopril on metabolic and hemodynamic alterations in global ischemia and reperfusion in the isolated working rat heart. In the isolated working rat heart model, we studied metabolic and hemodynamic effects of 5- and 30-min global ischemia followed by reperfusion and assessed the potentially beneficial effect of captopril 80 micrograms/ml added throughout the experiment. Creatine kinase (CK) and catecholamines were measured in coronary effluent. De novo eicosanoids (prostaglandin E2) synthesis was assessed in endocardial explants. Hemodynamic alterations occurred after 30-min ischemia and were reflected most dramatically by a reduction in cardiac output (CO 72 +/- 10% of baseline values in captopril vs. 68 +/- 16% in controls) without significant differences as a result of treatment. Captopril shortened reperfusion ventricular fibrillation (VF) duration (6.9 +/- 1.2 vs. 13.6 +/- 8.7 min, p less than 0.05) but had no effect on VF incidence. No differences occurred in norepinephrine (NE) outflow, whereas total CK release was greater in controls. Five controls versus none of the treated hearts (p less than 0.05) released trace amounts of epinephrine during reperfusion. Increased de novo PGE2 synthesis was demonstrated after 5-min I (465 +/- 168 vs. 238 +/- 75 pg/100 mg tissue per hour, p less than 0.01). Captopril stimulated production of PGE2 in normoxic hearts (p less than 0.02), but the difference was no more apparent in ischemic hearts. We conclude that captopril produces some biochemical and electrophysiologic evidence of myocardial salvage, but these effects are not sufficient to induce hemodynamic improvement after global ischemia and reperfusion.


Importance of the flow perfusion deficit in the response to captopril in experimental myocardial infarction. Previous results on the effects of angiotensin-converting enzyme (ACE) inhibition in myocardial ischemia are conflicting. To determine whether acute ACE inhibition may influence myocardial perfusion deficit during ischemia and reduce ischemia-reperfusion injury, anesthetized open-chest dogs underwent 2-h left anterior descending coronary artery (LAD) occlusion followed by 6-h reperfusion. After 1-h coronary occlusion, each dog was randomized to receive either captopril [5 mg/kg intravenous (i.v.) bolus and 0.25/kg/h infusion for 7 h] or saline. Whereas arterial pressure was reduced (p = 0.001), captopril did not influence myocardial perfusion deficit: Blood flow in the central ischemic zone represented 17.1 +/- 2.8% of the flow in the nonischemic zone versus 20.5 +/- 3.8% before treatment (NS). The values of the control group were 17.8 +/- 2.5 and 16.7 +/- 2.4%, respectively. In addition, there was no difference in infarct size: 35.9 +/- 3.3% of the area at risk in captopril-treated dogs versus 40.0 +/- 3.6% in controls. Analysis of subgroups based on the level of the collateral flow indicated, however, that ACE inhibition had an adverse effect on infarct size in dogs with high collateral flow: 31.9 +/- 4.6% in captopril dogs versus 17.6 +/- 4.7 (p = 0.048). This effect was related to a decrease in collateral flow because animals exhibiting the highest increase in perfusion deficit presented the greatest increase in infarct size (r = -0.92, p = 0.003). Although in dogs with low collateral flow, ACE inhibition appeared to exert a slight beneficial effect on infarct size, we conclude that at least in this dog model, acute ACE inhibition could exacerbate myocardial injury.


Antioxidant effects of angiotensin-converting enzyme (ACE) inhibitors: free radical and oxidant scavenging are sulfhydryl dependent, but lipid peroxidation is inhibited by both sulfhydryl- and nonsulfhydryl-containing ACE inhibitors. With an assay that generates free radicals (FR) through photooxidation of dianisidine sensitized by riboflavin, 4 x 10(-5) M captopril, epicaptopril (SQ 14,534, captopril's stereoisomer), zofenopril, and fentiapril [all sulfhydryl (-SH)-containing angiotensin-converting enzyme (ACE) inhibitors] were shown effective scavengers of nonsuperoxide free radicals whereas non-SH ACE inhibitors were not. Captopril was a more effective FR scavenger at pH 5.0 than at pH 7.5. Captopril (2 x 10(-5) M) also scavenged the other toxic oxygen species hydrogen peroxide and singlet oxygen and inhibited microsomal lipid peroxidation. Finally, captopril reduced the amount of superoxide anion-radical detected after neutrophils in whole blood were activated with zymosan, probably by inhibiting leukocyte superoxide production.


Mechanism of antiarrhythmic efficacy of propafenone as assessed by programmed electrical stimulation in conscious dogs. Programmed electrical stimulation (PES) was performed in 18 conscious, chronically instrumented mongrel dogs 6-21 days after a 4-h occlusion of the left anterior descending coronary artery (LAD). At baseline, 8 of 10 animals responded with sustained ventricular tachycardia (SVT) and 2 of 10 responded with ventricular fibrillation (VF). Cumulative administration of 2 and 4 mg/kg propafenone intravenously (i.v.) prevented induction of the baseline arrhythmia in 7 of 10 (p less than 0.05) and 5 of 10 (p = 0.1) animals, respectively. Cumulative administration of two doses of saline to 8 control animals with SVT inducible at baseline did not affect subsequent inducibility. QRS duration was only slightly prolonged after 2 mg/kg propafenone (+3.5 +/- 1.1 ms, p less than 0.05). Administration of 4 mg/kg was associated with a further increase in QRS duration (+8.0 +/- 2.3 ms, p less than 0.01) and a decrease in sinus cycle length (-60.0 +/- 17.2 ms, p less than 0.05). Propafenone consistently and significantly prolonged ventricular refractoriness only in responders. Furthermore, at both dosages, there was a negative correlation between drug-induced increases in ventricular refractoriness and baseline refractoriness (r = -0.72, p = 0.02; r = -0.81, p = 0.005 with 2 mg/kg and 4 mg/kg propafenone, respectively). Thus, the lesser antiarrhythmic efficacy of 4 mg/kg as compared with 2 mg/kg may result from excessive increases in intraventricular conduction time and/or unfavorable hemodynamic effects of this dose. Furthermore, our study confirms an association of the antiarrhythmic efficacy of propafenone with increases in ventricular refractoriness. In addition, the present investigation demonstrated that such increases in refractoriness are most likely to occur at short baseline values.


New sustained-release nifedipine formulation in treatment of essential hypertension. Unidipin Cooperative Study Group. Sustained-release nifedipine (SR) (developed by Elan, Athlone, Ireland; Unidipin is the tradename of Nifedipine SR, registered by Farmitalia Carlo Erba SpA, Milano, Italy) is a new nifedipine formulation suitable for once-daily administration. In a double-blind, randomized study of 269 hypertensive subjects, nifedipine SR efficacy and tolerability were investigated in comparison with the conventional twice-daily nifedipine tablet formulation. After a 3-week placebo phase, patients were titrated to 50-100 mg once daily nifedipine SR or 20-40 mg twice daily (b.i.d.) of the reference treatment. Significant and comparable reductions in systolic and diastolic blood pressures (SBP, DBP) during supine rest and on standing were observed in the two groups during and at the end of 3-month treatment. At the last visit, supine BP reductions of 17 +/- 17.7/14.8 +/- 8.8 mm Hg 24 h after nifedipine SR and of 21.7 +/- 19/16.1 +/- 9 mm Hg 12 h after the conventional tablet were measured. The numbers of patients achieving the goal BP reduction were comparable. There were no significant differences between treatments in the nature and severity of adverse events. Long-term efficacy and safety of the new formulation were investigated in patients receiving treatment for 12 months. After the initial significant reduction, the patients' BP showed a trend to a further less pronounced decrease for the remainder of the study. In only two patients was the dose readjusted during long-term administration. No serious side effects or alterations of laboratory tests occurred. Nifedipine SR is effective and safe therapy for elevated BP, with advantages in terms of patient acceptability.


Endothelin dilates bovine pulmonary circulation and reverses hypoxic pulmonary vasoconstriction. To assess the effects of endothelin 1 (ET) on the pulmonary and systemic vascular beds simultaneously, we examined the hemodynamic responses to ET in awake calves implanted with a Jarvik total artificial heart (TAH), a device that maintains constant cardiac output (CO). During basal conditions, successive incremental intravenous (i.v.) injections of 1, 3, and 10 micrograms ET caused a dose-dependent decrease in pulmonary arterial pressure (PAP), (from 24 +/- 3 to 15 +/- 1 mm Hg, p less than 0.05) while having no effect on systemic arterial (SAP), left atrial (LAP), and right atrial (RAP) pressures. Administration of 30 micrograms ET i.v. also decreased PAP, had no effect on LAP and RAP, but increased SAP from 100 +/- 6 to 118 +/- 4 mm Hg (p less than 0.05). The decrease in PAP was rapid, occurring within seconds and lasting 10 min, whereas the increase in SAP occurred after 2-5 min and was prolonged for greater than or equal to 20 min. As compared with injection in the right atrium, administration of 30 micrograms ET into the left atrium reduced PAP to a similar extent, but induced a greater increase in SAP (+32.5 +/- 4 vs +17.5 +/- 2 mm Hg, p less than 0.05). ET also dose-dependently reversed the acute pulmonary vasoconstriction induced by inhalation of an hypoxic gas mixture. In all cases, pulmonary vasodilation occurred without evidence of short-term tolerance. The results demonstrate that ET is a potent in vivo pulmonary vasodilator. In calves, the predominant hemodynamic response to ET is pulmonary vasodilation, with systemic vasoconstriction apparent only at higher concentrations of the peptide.


Long-term diuretic therapy: effects of dose reduction on antihypertensive efficacy and counterregulatory systems. In the present study, the effects of a dose reduction on antihypertensive efficacy and metabolic side effects of diuretic therapy were investigated in 36 hypertensive patients. During the first treatment period of 1 year, the patients were treated with 25 mg of the thiazide diuretic bemetizide (n = 18) or 25 mg bemetizide plus 50 mg of the potassium-sparing agent triamterene (n = 18). Mean blood pressure (BP) values decreased significantly (p less than 0.01) during the first year of the trial. Thereafter, doses were reduced to 10 mg bemetizide or 10 mg bemetizide plus 20 mg triamterene in patients whose BP became normal during the first year (n = 16 in both groups). At the end of the second year, equal BP control was achieved with doses more than twice smaller than those used during the first year. During the second year of the trial, activation of the renin-angiotensin system (RAS) was significantly less pronounced as compared with the first year and the percentage of patients with hypokalemia (less than 3.5 mM) decreased from 62.5 to 25% in the bemetizide group. Thus, this long-term study provides additional evidence that diuretics have a flat dose-response curve with respect to their antihypertensive efficacy, whereas lower doses might cause less pronounced activation of counter-regulatory systems. Furthermore, our results indicate that long-term studies might be necessary to assess the full antihypertensive potential of low doses of antihypertensive agents.


Effect of oral dilevalol on forearm circulation in essential hypertension. In 7 patients with untreated mild essential hypertension, a single 200-mg dilevalol dose was administered orally. Blood pressure (BP, left brachial artery catheter), heart rate (HR), and left and right forearm blood flows were measured and left and right forearm vascular resistances were calculated before and for approximately 3 h after drug administration. Dilevalol administration was followed by a sustained reduction in BP, little change in HR, and a similar pronounced and sustained increase in left and right forearm blood flows and reduction in left and right forearm vascular resistances. At the end of the observation period, the changes in left forearm circulation were unaffected by left brachial artery infusion of saline but markedly reduced by left brachial artery infusion of propranolol at doses that had no effect on BP, HR, and contralateral forearm vasodilatation. Thus, at an oral dose exerting an antihypertensive effect, dilevalol induces a marked and persistent vasodilation due largely to the beta-adrenoceptor agonism of the drug.


Effects of ibopamine on exercise-induced increase in norepinephrine in normal men. The effects of 100 mg ibopamine, an orally active aselective dopamine (DA) agonist, on plasma catecholamines was evaluated in 8 healthy men during sympathetic stimulation by graded exercise in a single-blind, placebo-controlled cross-over study. The exercise consisted of progressive cycling activity less than or equal to 90% of the previously determined VO2max. Graded exercise resulted in an increase in systolic and mean blood pressure (SBP, MBP), heart rate, norepinephrine (NE) and epinephrine level, with a decrease in diastolic BP (DBP). The increase in NE was significantly blunted by ibopamine as compared with placebo. No differences for BP, heart rate (HR), or epinephrine between placebo- and ibopamine study day were noted. In previous studies, ibopamine decreased resting plasma NE in patients with congestive heart failure (CHF), whereas plasma NE was not altered by ibopamine in healthy volunteers. This different outcome in both categories might therefore be explained by the absence of substantial sympathetic stimulation in normal humans at rest. Because it is reasonable to assume that the effect of ibopamine on systemic and local hemodynamics is negligible as compared with the effect of exercise in the healthy volunteers, the plasma decrease caused by ibopamine is probably related to stimulation of DA2-receptors. In conclusion, ibopamine blunts the increase of plasma NE during graded exercise in healthy men.


Effect of spirapril on left ventricular hypertrophy due to volume overload in rats. The effect of the angiotensin-converting enzyme (ACE) inhibitor spirapril on structural and functional parameters of volume-overloaded rat hearts was evaluated in a time-course study. Left ventricular hypertrophy (LVH) was induced by graded disruption of the aortic valve in male Wistar rats. Four weeks later, structural (LV mass and LV wall thickness) as well as functional parameters [LV end-systolic and end-diastolic volumes, stroke volume (SV), ejection fraction (EF)] were determined in anesthetized animals by magnetic resonance imaging (MRI). The rats were then divided into two groups, one of them receiving spirapril (10 mg/kg/day) in food. LV parameters were evaluated by MRI at 4, 18, 25, and 32 days after treatment was started. MRI analysis before the start of treatment showed that both groups had developed a similar degree of eccentric LV hypertrophy. Similarly, LV wall thickness, end-systolic and end-diastolic volumes, SV, and EF did not differ between the groups. Treatment with spirapril resulted in stable LV weight during the follow-up period of 32 days, whereas the untreated group showed a significant steady increase in heart weight. LV end-diastolic volume, LV end-systolic volume, and SV were smaller in the spirapril group when measured after 25 and 32 days, but only the difference in end-diastolic volume reached statistical significance. LV wall thickness and EF were not affected by spirapril. After the last MRI determinations, blood pressure (BP) and the response to angiotensin I (ANGI) were measured in conscious animals. Systolic BP (SBP) and mean arterial pressure (MAP) were significantly lower in spirapril-treated rats, and the dose-response curve to ANGI was shifted to the right.(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of dopamine receptor and alpha 2-adrenoceptor agonists and antagonists on muscarinic receptor stimulation in cardiac sympathetic ganglia of the dog. The effects of dopamine (DA)-receptor and alpha 2-adrenoceptor agonists and antagonists on ganglionic muscarinic stimulation were examined in anesthetized dogs. All drugs were injected or infused intra-arterially into the blood supply of the cardiac sympathetic ganglia. The muscarinic agonists McN-A-343 (10, 20, and 30 micrograms) and muscarine (1, 2, and 3 micrograms) increased heart rate. The muscarinic receptor stimulation elicited by McN-A-343 or muscarine was significantly inhibited by infusion of the DA2-receptor agonist quinpirole (3 and 10 micrograms/min) but not by the DA1-receptor agonist SK&F 38393 (10 and 30 micrograms/min). The alpha 2-adrenoceptor agonist BHT 933 (3 and 10 micrograms/min) also inhibited muscarinic receptor stimulation. The DA2-receptor antagonist domperidone (10 micrograms/min) and the alpha 2-adrenoceptor antagonist yohimbine (1 micrograms/min) had no effects on muscarinic receptor stimulation, but they antagonized the inhibitory effects of quinpirole and BHT 933, respectively. The nicotinic transmission elicited by preganglionic cardiac sympathetic nerve stimulation (1 and 2 Hz) was also inhibited by DA-receptor and alpha 2-adrenoceptor agonists and antagonists. These results suggest that DA2-receptors and alpha 2-adrenoceptors suppress muscarinic transmission as well as nicotinic transmission in the cardiac sympathetic ganglia of the dog.


Mechanisms of action of cicletanine in human and guinea pig resistance arteries. Human subcutaneous (s.c.) arteries and guinea pig mesenteric vessels (internal diameter 150-570 microns) were isolated and mounted on a microvascular myograph. Cicletanine-induced relaxation curves were constructed after preconstriction with either depolarising potassium (KPSS) or norepinephrine (NE) and in the presence and absence of indomethacin, glibenclamide, or tetraethylammonium chloride (TEA). Using only guinea pig vessels, cicletanine relaxation curves were constructed with and without charybdotoxin. In human vessels, there was no significant difference between cicletanine-induced relaxation in vessels preconstricted with either NE or KPSS, and neither ATP-sensitive or Ca(2+)-activated K channels were involved. However, with indomethacin added, in human vessels the maximal response to cicletanine (30 microM) was reduced by 51% (p less than 0.05). In guinea pig mesenteric arteries, cicletanine (30 microM) produced a 95% relaxation of the NE-constricted vessel and only 30% relaxation of the KPSS-constricted vessel (p less than 0.001). There was no evidence for any involvement of the ATP-sensitive K channel or the eicosanoid system. The relaxation to cicletanine (less than 3 microM) in with TEA added was greatly reduced (p less than 0.001) and with charybdotoxin added the concentration response curve to cicletanine was shifted approximately 3 log units to the right (p less than 0.001), suggesting an involvement of Ca(2+)-activated K channels. The acute vasodilator action of cicletanine is complex, with multiple mechanisms of action, and the relative importance of these varies in different species or at least in different vascular beds.


Cilazapril and captopril accelerate recovery from hypoxia in myocardial cell aggregates in culture. We wished to determine whether angiotensin-converting enzyme (ACE) inhibition alters the effect of hypoxia and reoxygenation directly on the cardiac myocyte; to compare two different ACE inhibitors, one with and one without a sulfhydryl group (i.e., captopril and cilazapril), and to examine the potential interaction of these ACE inhibitors with agents that purportedly prevent the deleterious action of oxygen-derived free radicals. Ventricular myocytes were obtained from 7-day-old chick embryo hearts and were maintained in culture for 96 h before study. Hypoxia produced a significant (p less than 0.05) and marked reduction in cardiac contractile frequency that was not influenced by captopril 10(-6) and 10(-7) M or cilazapril 10(-6) or 10(-7) M. During the reoxygenation period, cardiac contractile frequency gradually returned to normal. Both ACE inhibitors, captopril and cilazapril, were associated with a similar significant (p less than 0.05) enhancement of restoration of contractile frequency. Angiotensin II (ANGII) reversed the effect of these ACE inhibitors. Two agents that reduce reoxygenation-induced myocardial damage, perhaps through alteration in production or degradation of oxygen-derived free radicals, i.e., allopurinol and superoxide dismutase (SOD), significantly (p less than 0.05) accelerated recovery of cardiac myocytes during reoxygenation. There was no additive effect with either captopril or cilazapril plus allopurinol or SOD. Conclusions about the actions of these ACE inhibitors must be tempered by the evidence that substrates other than ANGI, particularly bradykinin, are processed by the enzyme and inhibited by ACE inhibitors so that some of the observed effects may have been due to accumulation of other substrates.(ABSTRACT TRUNCATED AT 250 WORDS)


Pretreatment with captopril improves myocardial recovery after cardioplegic arrest. Among the interventions designed to limit postischemic oxidative injury, those that enhance the myocardial content of thiol groups are attractive because thiols are powerful antioxidant. Indeed, part of the protection afforded by the angiotensin-converting enzyme (ACE) inhibitor captopril in regional myocardial ischemia is attributed to its thiol group. This study assesses the effects of captopril in a surgically relevant model of global ischemic arrest. Thirty rats were implanted subcutaneously (s.c.) with osmotic pumps that allowed continuous delivery of captopril (total dose 75 mg), enalapril (a nonthiol-containing ACE inhibitor, total dose 7.5 mg) or saline in 48 h. Drug concentrations were equipotent in their effect on angiotensin I (ANGI) pressor response. Hearts were then excised, perfused under isovolumic conditions, and subjected to 90-min cardioplegic arrest at 30 degrees C followed by 1-h reperfusion. Pre- and postischemic coronary flows were significantly higher to a similar extent in the two drug-pretreated groups than in controls. However, captopril-pretreated hearts had the best recovery of contractility (dP/dtmax; 3,590 +/- 74 versus 2915 +/- 64 mm Hg s-1 in the enalapril group, p less than 0.001), and diastolic pressure (13.7 +/- 0.9 mm Hg vs. 20.0 +/- 1.6 mm Hg in the enalapril group, p less than 0.05). We conclude that pretreatment with ACE inhibitors improves myocardial recovery after cardioplegic arrest and that captopril is more effective than enalapril. The additional protection afforded by captopril was not flow mediated, suggesting that the cardioprotective effects of this drug not only involve an ACE inhibition-dependent coronary vasodilation but could be related to a thiol-dependent limitation of oxidative injury.


Effects of early angiotensin-converting enzyme inhibition in a pig model of myocardial ischemia and reperfusion. In a blind, randomized study, the effects of perindopril, a nonsulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitor, were compared with those of placebo in a closed-chest pig model of myocardial infarction. In anesthetized pigs, myocardial ischemia and reperfusion were induced by inflation and deflation of a catheter balloon in the left anterior descending coronary artery (LAD), respectively. Thirty minutes after induction of ischemia and 15 min before reperfusion, a bolus injection of 0.06 mg/kg perindoprilat (n = 12), the active compound of perindopril, or placebo (n = 12) was administered in the pulmonary artery of these animals. After the acute phase of myocardial infarction, treatment with 12 mg/day perindopril or placebo was continued orally for 2 weeks. During the entire treatment period, 7 of 12 animals died in the placebo group versus 2 of 12 animals in the perindopril group (Fisher's exact test p less than 0.04). This beneficial effect of perindopril on mortality could not be attributed to salvage of myocardial tissue because the increases in creatine phosphokinase and coronary venous purine levels were similar in perindopril- and placebo-treated animals. Neither were there any significant between-treatment differences in the hemodynamic and (neuro)humoral parameters during the acute phase of myocardial infarction. The difference in mortality was observed within 24 h after myocardial infarction. Prevention of acute pump failure and, especially, life-threatening ventricular arrhythmias may explain this improvement in survival by perindopril. Retrospectively, logistic regression analysis showed that, irrespective of treatment, survival was inversely correlated to plasma renin activity (PRA) before induction of ischemia (r = -0.33; p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)


Effects of SUN-1165, N-(2,6-dimethylphenyl)-8-pyrrolizidine acetamide hydrochloride hemihydrate, a new class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the refractory period in canine myocardial infarction. Effects of SUN-1165, a class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the effective refractory period (ERP) were examined in a canine model of myocardial infarction and compared with those of lidocaine. The antiarrhythmic effects were examined on the arrhythmias developed 24 h after left anterior descending coronary artery (LAD) ligation and ventricular premature stimulation-induced arrhythmias 5-7 days after LAD ligation. Effects on intraventricular conduction and ERP were also examined in animals 5-7 days after LAD ligation. The intraventricular conduction time (CT) was determined by excitation induced by a ventricular stimulation at various coupling intervals from 200 to 1,000 ms. SUN-1165 (1 and 3 mg/kg) showed a marked reduction in the frequency of ventricular ectopic beats 24 h after LAD ligation and was more potent than lidocaine. SUN-1165 (1 and 3 mg/kg) prolonged CT in the infarcted zones over a wide range of the coupling intervals and produced block of severely delayed conduction. In contrast, lidocaine prolonged CT only at short coupling intervals. Ventricular premature stimulation produced ventricular arrhythmias, which were prevented by pretreatment with SUN-1165 (3 mg/kg). ERP was prolonged by SUN-1165 (3 mg/kg). In conclusion, SUN-1165 showed antiarrhythmic effects in a canine model of myocardial infarction. A selective depression of delayed conduction in the infarcted zone and a prolongation of ERP probably contribute to this antiarrhythmic effect.


Efficacy and safety of deferoxamine conjugated to hydroxyethyl starch. The efficacy and safety of deferoxamine conjugated to hydroxyethyl starch (HES-DFO) was evaluated in an in vitro rat cardiac membrane lipid peroxidation (CMLP) assay and in a swine model of regional myocardial ischemia/reperfusion injury in comparison to DFO. The rat CMLP results demonstrate that HES-DFO is at least as potent as DFO (IC50 = 10 and 13 microM, respectively). HES-DFO given intravenously (i.v.) at the equivalence of 25 mg/kg and 100 mg/kg DFO in a swine model of regional myocardial ischemia [20-min left anterior descending coronary artery (LAD) occlusion followed by 60-min reperfusion] showed no significant changes in hemodynamics as compared with DFO at 25 mg/kg i.v. In addition, HES-DFO was at least as potent as DFO with regard to recovery of regional segment shortening function (%SS). Furthermore, both HES-DFO and DFO significantly reduced tissue water content (edema) in the area at risk (AAR). We conclude that conjugation of DFO to HES improves the safety without any interference in the efficacy of DFO.


Quinaprilat increases total body vascular compliance in rats with myocardial infarction. To test whether quinaprilat, a new angiotensin-converting enzyme (ACE) inhibitor, has any venous effect, we measured its immediate effects on mean circulatory filling pressure (MCFP), intravascular volume, and total body vascular (i.e., venous) compliance in conscious rats with healed myocardial infarction induced by coronary artery ligation. MCFP was determined by inflating a right atrial balloon to arrest the circulation instantly and temporarily. Total body vascular compliance was derived from total circulatory pressure-volume relationships as determined by series measurements of MCFP with different intravascular volume status. In 8 rats with mean infarct size of 26 +/- 4%, 30-min infusion of quinaprilat (0.1 mg/kg/min) decreased both mean arterial and central venous pressures (MAP, CVP) by 8 and 0.7 mm Hg, respectively (p less than 0.02); heart rate (HR), MCFP, hematocrit, and blood volume remained unchanged. As compared with control vehicle infusion, quinaprilat increased total body vascular compliance (2.09 +/- 0.12 vs. 2.69 +/- 0.23 ml/kg/mm Hg; p less than 0.05) and decreased extrapolated unstressed circulating volume (34.96 +/- 1.10 vs. 28.53 +/- 2.55 ml/kg; p less than 0.02). These data suggest that quinaprilat produces possible venodilation through improved total body vascular compliance, thereby reducing cardiac preload in this rat model of myocardial infarction.


Comparative hemodynamic effects of Org 7797, flecainide, and propafenone in anesthetized pigs with developing myocardial infarcts. The hemodynamic effects of a new Ic antiarrhythmic agent (Org 7797) were compared with those of flecainide and propafenone in anesthetized pigs with developing myocardial infarcts. One hour after acute coronary artery occlusion, the only significant hemodynamic effect of an intravenous (i.v.) dose of Org 7797 (0.5 mg/kg) known to prevent ischemia-induced ventricular fibrillation (VF) in dogs was a decrease in heart rate (HR) (of 3%) while cardiac output (CO), stroke volume (SV), and left ventricular (LV) dP/dtP-1 were unchanged. At four times this dose, the only sustained and significant responses to Org 7797 were decreased CO and bradycardia, whereas decreases in arterial and LV pressures (BP and LVP) and LVdP/dtP-1 were transient. In contrast, a therapeutic dose of flecainide (2 mg/kg) induced sustained reductions in CO, SV, LVdP/dtP-1, and LVP whereas a similar (therapeutic) dose of propafenone decreased LVP, reduced CO partly as a result of bradycardia and decreased LVdP/dtP-1 but not sufficiently to decrease SV. Two electrical deaths occurred in each of the propafenone (n = 6) and flecainide (n = 7) groups, but arrhythmic deaths did not occur in Org 7797- or saline-treated animals. We conclude that Org 7797 in therapeutic doses, unlike propafenone and especially flecainide, is not cardiodepressant in animals whose cardiac function is already compromised. In addition, there was no evidence of proarrhythmogenicity at the doses of Org 7797 used.


Combined effect of dietary calcium and calcium antagonists on blood pressure reduction in spontaneously hypertensive rats. Calcium supplementation and calcium channel blockers are known to have antihypertensive effects in similar subsets of hypertensive patients, as well as in spontaneously hypertensive rats (SHR). To investigate this apparent paradox, we placed 12-week-old SHR on one of three dietary levels of calcium (0.2, 0.4, or 0.8%), as well as on one of four doses of nifedipine (0, 50, 150, or 300 mg/kg food) for 8 weeks. We performed a similar experiment using four verapamil doses (0, 300, 900, or 1,800 mg/kg food). In the nifedipine experiment, two-way analysis of variance showed significant independent antihypertensive effects of both nifedipine (p less than or equal to 0.0001) and calcium (p less than 0.0001) and significant interaction (p = 0.0034), the latter suggesting a synergistic effect. In the verapamil experiment, both calcium and verapamil again had significant independent antihypertensive effects (p = 0.006 and p = 0.004, respectively), but there was no significant interaction. Although the effects of the calcium supplement or calcium antagonist alone were significant, such hypotensive responses were not optimal or predictable or clearly dose-dependent. However, the combination of a calcium supplement and calcium antagonist resulted in predictable or dose-dependent effects, and the optimal effect was reflected in the reduction of the SHR pressure to normal range for Wistar-Kyoto (WKY) rats. These results appear to indicate that supplementary calcium and calcium channel blockers act by different mechanisms in lowering blood pressure (BP), and that the combination of those differing mechanisms of action may have potential therapeutic benefit.


Desensitization of beta-adrenoceptor- and prostaglandin E1 receptor-mediated human vascular smooth muscle relaxation. Regulation of beta-adrenoceptors in animal tissues and human cell cultures has been extensively described; on the other hand, relatively little is known about regulation of beta-adrenoceptors in human tissues in vivo. Both beta-adrenoceptors and the prostaglandin E1 (PGE1) receptors stimulate vasodilation. We wondered if prolonged infusion of isoproterenol or PGE1 would cause desensitization of smooth muscle relaxation and used the dorsal hand-vein compliance technique to investigate this question. After constructing a dose-response curve to either the beta-agonist isoproterenol or to PGE1 in a phenylephrine preconstricted vein, isoproterenol (271 ng/min), PGE1 (956 pg/min), or saline was infused for 4 h in separate experiments. There was no change in the ED50 or Emax for either isoproterenol or PGE1 after saline infusion. After a 4-h infusion of isoproterenol, the maximal vasodilator response to isoproterenol was significantly (p less than 0.01) attenuated from 61 +/- 33% to 19 +/- 10%, while the ED50 significantly increased (p less than 0.01) from a geometric mean of 37 to 197 ng/min. After infusion of isoproterenol, the mean maximum PGE1-induced venorelaxation of 129 +/- 29% was modestly but significantly (p less than 0.05) blunted to 96 +/- 35%, while the ED50 of PGE1 increased significantly (p less than 0.01) from a geometric mean of 81 to 398 pg/min. A 4-h infusion of PGE1 significantly (p less than 0.01) attenuated the maximum response to PGE1 from 73 +/- 35 to 28 +/- 16%. The maximal vasodilatory response to isoproterenol was also significantly blunted (p less than 0.05) from 62 +/- 35 to 42 +/- 41%, with no change in ED50.(ABSTRACT TRUNCATED AT 250 WORDS)


Heart rate dynamics after acute cocaine administration. We examined heart rate (HR) patterns after a bolus intravenous (i.v.) administration of a high (10 mg/kg) dose of cocaine in unrestrained cats. Mean R-R intervals, SD, and other measures of variability were assessed in three periods: waking baseline, early postcocaine administration, and later recovery periods. Cocaine resulted in initial tachycardia and reduced HR variability. This reduction in variability was independent of changes in the average rate: during the recovery period, HR returned to baseline values, but the reduced variability persisted. Nonlinear methods of assessment yielded additional results: Cocaine introduces a high correlation between one beat and the next and a tendency for cardiac accelerations to be followed immediately by decelerations and vice versa. The overall effect of the drug is to restrict deviation from a fixed rate.


Selective adenosine-2 agonist produces both direct and reflex tachycardia in normotensive rats. Hemodynamic responses to intravenous (i.v.) injection of DPMA [N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl] adenosine); PD 125,944], a potent adenosine agonist with a 32-fold selectivity for the adenosine-2 (A2) receptor subtype, were characterized in conscious and anesthetized rats. In conscious rats instrumented with miniaturized pulsed-Doppler flow probes, i.v. injection of increasing doses of DPMA (3-30 micrograms/kg) had little effect on mean arterial pressure (MAP, maximal decrease -8 +/- 4 mm Hg) or renal and mesenteric resistance (maximal change 8 +/- 14 and 0 +/- 15%, respectively). In contrast, DPMA markedly reduced MAP (maximal decrease -61 +/- 8 mm Hg) in a dose-dependent (1-30 micrograms/kg) fashion in pentobarbital-anesthetized rats. The A2 agonist also caused a sustained, dose-dependent increase in heart rate (HR, maximal increase 75 +/- 12 beats/min) in conscious rats. The tachycardia and decrease in arterial pressure were completely reversed by i.v. administration of CGS 15943 (250 micrograms/kg), a selective adenosine receptor antagonist. Pretreatment with propranolol or hexamethonium significantly reduced but did not abolish the tachycardia, suggesting that the increase in HR was mediated only partially through reflex increases in sympathetic tone. These data indicate that (a) anesthesia potentiates the depressor actions of DPMA and (b) stimulation of A2 receptors increases HR through both direct and indirect mechanisms of action.


Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF/Mcc-cp rats. Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.


Beta-blocking agents with vasodilating action. beta-Adrenoceptor-blocking drugs in current use can be separated into two main groups: those nonselective and those selective for beta 1-receptors. Members of each group reduce cardiac output and lead to an increase in peripheral resistance with a concomitant reduction in blood flow. beta-Blocking drugs not only may occupy the receptor preventing stimulation but also may have intrinsic sympathomimetic activity. Those with marked partial agonist activity at the beta 2-receptor giving some beta 2-mediated vasodilation can be regarded as the first multiple-action beta-blocking drugs. Subsequently, drugs have been developed that in addition to blocking the beta-receptor have an important peripheral vasodilator activity. Labetalol was the first drug of this group to be developed; prizidolol followed but has been withdrawn because of toxicity. Several other agents have been described, including bucindolol, carvedilol, celiprolol, dilevalol (one of the isomers of labetalol), and medroxolol. Three mechanisms have been reported to be responsible for peripheral vasodilation: alpha-receptor blockade, beta 2-agonism, and a dilator action independent of either the alpha- or beta-receptors. Evidence for these various mechanisms is more readily obtainable from animal experiments, but some confirmatory evidence has been obtained in humans. Inhibition of alpha-stimulation had been found with labetalol, medroxalol, and carvedilol and suggested with celiprolol. beta 2-Mediated vasodilation has been demonstrated by, for example, celiprolol and dilevalol; evidence of a vasodilation independent of alpha-blockade or beta 2-stimulation has been reported with celiprolol and carvedilol.


Pharmacokinetics and efficacy of carvedilol in hypertensive patients with chronic renal failure and hemodialysis patients. The efficacy, safety, and pharmacokinetics of carvedilol were investigated in an open trial performed on 13 hypertensive patients with chronic renal failure and six additional patients requiring hemodialysis. In hypertensive renal failure patients, treatment with carvedilol (5 mg/day) for 1 week produced a significant decrease in blood pressure (from 172/101 to 146/84 mm Hg) but did not change the heart rate. The pharmacokinetics of carvedilol did not change with repeated administration, and there was no accumulation of this drug. In hemodialysis patients with hypertension, the pharmacokinetics of carvedilol after a single dose of 10 mg did not vary between dialysis and nondialysis days, and blood pressure decreased significantly on both days. In addition, there was no accumulation of carvedilol during a 4-week trial of therapy, and blood pressure was decreased significantly from 170/93 to 145/83 mm Hg. There were no side effects and no abnormal laboratory findings noted during the trial. These results indicate that carvedilol is an effective and safe agent for hypertensive patients with chronic renal failure and for hemodialysis patients with hypertension and that dosage adjustments are probably not required in these clinical situations.


Effects of carvedilol during exercise.

Effects of carvedilol during exercise. The effect of carvedilol on cardiovascular and physical performance parameters at rest and during exercise was evaluated in an open, uncontrolled study. Assessments were made at rest, at one-half anaerobic threshold (1/2AT), at AT, and at maximal work load (WLmax) before and after 3 weeks of treatment with 12.5 mg carvedilol once daily for 1 week, followed by 25 mg carvedilol once daily for 2 weeks. Ten well-conditioned healthy male volunteers maintained their regular training program during the study, and all completed the study. End-of-study measures of physical performance (time to WLmax, WLmax, and VO2/kg) and behavioral measures (Borg scale) of perceived exertion were unchanged from prestudy values. End-of-study diastolic BP (DBP) at rest and at WLmax was unchanged compared with prestudy values (mean +/- SD; 81.0 +/- 7.38 and 84.4 +/- 4.95 mm Hg, respectively, compared with 82.0 +/- 8.88 and 85.0 +/- 7.07 mm Hg, respectively). Mean +/- SD change from prestudy to end-of-study baseline resting systolic BP (SBP) was a reduction of 11.5 +/- 8.83 mm Hg, and mean +/- SD change from prestudy to end-of-study SBP at WLmax was a reduction of 20.0 +/- 12.25 mm Hg. Mean +/- SD change from prestudy to end-of-study resting heart rate (HR) a reduction of 7.8 +/- 18.45 beats/min, and mean +/- SD change from prestudy to end-of-study HR at WLmax was a reduction of 19.7 +/- 9.24 beats/min. The effect of carvedilol thus represents a combination of reduction in resting systolic BP and HR and attenuation of the exercise-induced changes in these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)


A comparison of carvedilol with a combination of propranolol and isosorbide dinitrate in the chronic treatment of stable angina. The beta-blocking and vasodilating agent carvedilol was compared with a combination of propranolol and isosorbide dinitrate (ISDN) in a double-blind, parallel-group study. After two baseline sitting bicycle exercise tests on placebo, 31 patients with chronic stable angina were asymmetrically randomized to treatment with carvedilol (25 mg b.i.d.) or propranolol-ISDN (80 mg/20 mg b.i.d.) for a period of 6 months. Further exercise tests were performed 2 h after the first dose as well as after 1, 3, and 6 months of treatment. Twenty-seven patients were considered evaluable for efficacy. Differences between the two groups were observed with emphasis on total exercise time and time to 1-mm ST-segment depression. In contrast to a greater peak effect of the first propranolol/ISDN dose, the chronic antianginal and anti-ischemic effects of carvedilol at trough were found to be more marked than those of the combination.


Effects of carvedilol on ventricular arrhythmias. Carvedilol is a nonselective beta-blocker with alpha-mediated vasodilating properties that has been shown to be effective in systemic hypertension, stable angina, and congestive heart failure (CHF). In this study, we studied the effects of carvedilol on premature ventricular contractions (PVCs) in 65 patients undergoing treatment with carvedilol (12.5-50 mg b.i.d.) for 4-8 weeks. Twelve patients had hypertension, 41 had stable angina, and 12 had CHF. Holter monitoring for 24 h was performed before and after active carvedilol therapy. Median PVCs per 24 h decreased from 25.5 to 6.0 (p less than 0.001, n = 52). Reduction in PVC activity occurred in 77% of patients, and 23% of patients with multifocal PVCs changed their morphology to unifocal. Nonsustained ventricular tachycardia was present in four patients before treatment; this was abolished in all patients. R-on-T PVC was present in six patients; it decreased in five and increased in one. New ventricular tachycardia (less than 8 beats) occurred in two patients, but QT prolongation was not noted in these patients. An improvement in Lown's classification occurred in 50% of patients. However, in the CHF group, the improvement in Lown's criteria was observed in 73% of patients. Carvedilol does not appear to possess proarrhythmic effects, and chronic therapy reduces PVC activity in a wide range of patients. This property of carvedilol is complementary to its hypotensive and anti-ischemic effects. In the CHF group, the beneficial effects of carvedilol on left ventricular function and hemodynamics may combine with the improvement in PVC activity to produce a significant improvement in mortality.


Constriction of human dorsal hand veins in vivo with several vasoconstrictors and the influence of oral administration of carvedilol. In vivo measurements of human dorsal hand vein diameters have become a valuable tool in investigating vasoactive agents. This study in 13 healthy volunteers was performed to establish the influence of locally infused clonidine, angiotensin II, norepinephrine, and prostaglandin F2 alpha (PGF2 alpha) on hand vein diameter in a nonsystemically active dose range. The study was intended to select agents suitable for venous preconstriction before and after oral administration of 50 mg carvedilol to obtain information on the mechanisms of vasodilation of this combined alpha- and beta-blocker. Infusions of norepinephrine (ED50, 20-40 ng/min) and PGF2 alpha (ED50, 480-1,170 ng/min) into the hand vein under investigation led to nearly complete constriction of the vessel. Infusions with clonidine and angiotensin II led to approximately 35% diameter reduction under the same conditions. A wide interindividual variety of hand vein dose response was observed for all vasoconstrictors. Oral administration of 50 mg carvedilol led to a rightward shift in the dose-response curves of angiotensin II, norepinephrine, and PGF2 alpha. On a 5% significance level, the venoconstrictive effects of norepinephrine and PGF2 alpha were attenuated by carvedilol compared with placebo. We conclude that a mechanism of vasodilation by carvedilol in addition to alpha-adrenoceptor antagonism could be responsible for the attenuation of venoconstriction induced by PGF2 alpha.


Efficacy and safety of carvedilol in comparison with nifedipine sustained-release in chronic stable angina. In patients with chronic stable exertional angina pectoris, the antianginal and anti-ischemic efficacies and the safety of 25 mg carvedilol b.i.d. were compared with those of 20 mg nifedipine sustained-release (SR) in a double-blind, randomized, multicenter study. In 22 centers, 166 patients were enrolled. After washout and run-in phases with two symptom-limited seated bicycle exercise tests on placebo, eligible patients were allocated to one of the two parallel treatment groups. After 4 weeks of active treatment, an additional exercise test was performed 12 h after the preceding dose. The patients were issued diary cards to document the daily number of anginal attacks and glyceryl trinitrate applications. Symptom-limited total exercise time, time to onset of angina, and time to 1-mm ST-segment depression increased with both treatments vs. placebo baseline values. The changes were more distinct in the carvedilol group, but the between-group differences were not statistically significant. Angina symptomatology during daily life and glyceryl trinitrate consumption were markedly improved by each treatment. Adverse events on treatment, particularly those correlated to vasodilation, were less frequent in the carvedilol group.


The once-daily dose regimen of carvedilol: a meta-analysis approach. Establishing the overall efficacy or safety of a drug requires a unified methodological approach and analysis of all clinical trials that are intended to be summarized. As an example, this article presents the aggregated dose-response relationship and a subgroup analysis (by age) over all studies of the antihypertensive drug carvedilol. The clinical end points were change from baseline of blood pressure and pulse after 2-4 weeks of treatment with a once-daily dose regimen. All antihypertensive trials were reanalyzed using an intent-to-treat principle. Aggregated data (mean, standard deviation, sample size) for each random group within each study were then combined by means of meta-analysis. The results show that the main patient population can be treated adequately with 25 mg of carvedilol q.d. The dose-response curve shows a typical sigmoid shape: a steeper increase from 12.5 to 25 mg of carvedilol and a following flat part (25, 50, and 100 mg of carvedilol q.d.). There is a considerable variation of the results between studies, which is much bigger than the dose-response effect. Most of this variation is due to monocentric trials.


Safety of the coadministration of carvedilol and nifedipine sustained-release in the treatment of essential hypertension. A single-center, randomized, double-blind study in 14 hypertensive patients was conducted to investigate the acute and short-term safety of the addition of carvedilol to pre-existent nifedipine sustained-release (SR) therapy as well as on the addition of nifedipine SR to pre-existent carvedilol therapy when treatment with the initial monotherapy did not adequately control blood pressure. Mean supine blood pressure at study entry was 171/106 mm Hg. Acute reductions in blood pressure were greater with combination treatment than with either monotherapy. Dosing with 25 mg carvedilol once daily or 20 mg nifedipine SR twice daily resulted in mean peak reductions in supine blood pressure of 21/11 and 20/16 mm Hg, respectively, after 1 week of treatment with each respective monotherapy. With combination treatment, mean peak reductions (after dosing on days 1, 3, and 10) ranged from 26 to 40 mm Hg in supine systolic blood pressure and from 14 to 23 mm Hg in supine diastolic blood pressure. Acute changes in mean standing systolic and diastolic pressures were comparable to those in the supine position. Combination treatment resulted in an additive acute antihypertensive response without synergistic potentiation. Neither monotherapy nor the coadministration of the two agents in the doses used resulted in a significant antihypertensive response at the time of trough plasma levels of study medication, perhaps due to the short-term nature of the trial which did not allow the full antihypertensive effect of either agent to be realized. Before dosing with study medication, heart rates were minimally changed from study entry levels with either monotherapy or combination treatment.(ABSTRACT TRUNCATED AT 250 WORDS)


Myocardial protection with carvedilol.

Myocardial protection with carvedilol. Carvedilol is a multiple-action cardiovascular agent that is both a beta-adrenoceptor antagonist and a vasodilator and has recently been made available for the treatment of mild-to-moderate hypertension. Clinical trials are ongoing to establish the efficacy of carvedilol in angina and congestive heart failure. beta-Adrenoceptor antagonists are known to reduce myocardial work secondary to reductions in heart rate and contractility; accordingly, they have been shown to be cardioprotective in animals and in humans. Because carvedilol has beta-adrenoceptor antagonist activity, it also should provide significant cardioprotection. The additional vasodilating activity of carvedilol, which will further reduce myocardial work by decreasing afterload and myocardial wall tension, should provide more salvage of ischemic myocardium than that afforded by a pure beta-adrenoceptor antagonist, such as propranolol. We investigated the ability of carvedilol and propranolol to reduce infarct size in experimental models of acute myocardial infarction in the rat, pig, and dog. The left anterior descending coronary artery was occluded for 30 (rat) or 45 min (pig) and then reperfused for 24 h (rat) or 4 h (pig). In the dog, the left circumflex coronary artery was occluded for 60 min and reperfused for 24 h. Vehicle, carvedilol, or propranolol was administered intravenously 15 min before ischemia (and, in the rat only, repeated 4 h after ischemia). An additional group of dogs was subjected to permanent left anterior descending coronary artery occlusion for 6 h, and carvedilol or propranolol was given 15 min after occlusion. Infarct size was examined on stained tissue sections using quantitative image analysis.(ABSTRACT TRUNCATED AT 250 WORDS)


Disposition of carvedilol enantiomers in patients with liver cirrhosis: evidence for disappearance of stereoselective first-pass extraction. The racemic drug carvedilol exerts its antihypertensive action through vasodilation and nonselective beta-blockade. The R(+)-enantiomer has twice (31.1%) the absolute bioavailability than the S(-) form (15.1%). The pharmacokinetics of the enantiomers were investigated after intravenous (i.v.) (12.5 mg in 1 h) and p.o. (25 mg) administration of racemic carvedilol in six patients with cirrhosis of the liver according to a randomized crossover design. Although the difference between areas under the curve of R(+) and S(-) were of borderline significance after i.v. administration but significant after oral administration, no difference existed between the absolute bioavailabilities of R(+) (83.7%) and S(-) (71.3%). The enantiomer ratio is similar after i.v. (1.3) and p.o. administration (1.6). In contrast to healthy subjects, the apparent volume of distribution of S(-) is about 90% greater than that of R(+) in patients. The renal excretion of carvedilol and of one of its major metabolites, carvedilol glucuronide, also exhibited stereoselective behavior, but in opposite directions. In patients with liver cirrhosis, stereoselective metabolism of carvedilol is still operative. However, probably because of portocaval shunts, the hepatic first-pass extraction is markedly reduced, eliminating the difference in bioavailability between the two enantiomers.


Alpha 1-blocking properties of carvedilol during acute and chronic administration. Carvedilol is a beta-adrenergic-blocking drug with vasodilating properties. This vasodilation has been ascribed to alpha 1-adrenergic blockade, but it has never been shown in the clinical setting. We addressed this issue by studying eight patients with mild essential hypertension who were given prazosin, 2 mg or carvedilol, 25 mg p.o. following a 2-week washout from previous treatment, according to a randomized double-blind, crossover experimental design. Before and 2 h after the administration of either prazosin or carvedilol, the patients were infused i.v. with increasing doses of phenylephrine (0.2-1.2 microgram/kg/min) and isoproterenol (0.01-0.05 microgram/kg/min). The patients were thereafter maintained on carvedilol 25 mg daily for 3 weeks, and the i.v. phenylephrine and isoproterenol infusions were repeated 2 h after the last tablet administration. The results showed that the single dose of carvedilol and prazosin lowered blood pressure (beat-to-beat finger pressure measurement) to a similar extent, but that heart rate was unaffected by prazosin and reduced by carvedilol. The tachycardic response to isoproterenol was abolished by carvedilol and unaffected by prazosin, whereas the pressor response to phenylephrine was reduced by carvedilol and virtually abolished by prazosin. The antihypertensive, beta-blocking and alpha 1-adrenergic-blocking effects of carvedilol were unchanged following prolonged administration of the drug. Thus, at a clinically effective dose, carvedilol not only has beta- but also sizeable alpha 1-blocking effects. These effects are preserved during prolonged administration of the drug. For a comparable antihypertensive action, however, the alpha 1-blocking effect is less pronounced than that of an alpha 1-blocker such as prazosin.


Different vasodilating mechanisms--different peripheral effects? Many factors, both local and systemic, are known to influence the caliber of peripheral vessels and regional blood flow. Methods of studying limb blood flow and its alteration by disease and drugs present considerable problems. We compared the effects of a series of antihypertensive drugs on limb blood flow and their functional effects in patients with hypertension and peripheral vascular disease. Results from studies with new antihypertensive drugs such as carvedilol are awaited.


Carvedilol in hypertension: effects on hemodynamics and 24-hour blood pressure. Nineteen men (mean age, 44 years) with moderately severe essential hypertension were studied invasively at rest and during exercise. After initial predrug recordings, patients received 25 mg carvedilol orally, and central hemodynamics at rest and during exercise were recorded 1 and 2 h after tablet intake to evaluate the immediate effects of carvedilol. Blood pressure decreased by 11% within 1 h, and the hemodynamic results indicated a combination beta-blocking and vasodilating effect. After 6-9 months of treatment (dose, 25-100 mg), supine hemodynamics were recorded, first 12-24 h after the last dose and then 1 and 2 h after an additional 25-mg dose. During chronic treatment (2 h after the last dose with the patient at rest and in the supine position), mean arterial pressure was reduced by 17% (p less than 0.001) and total peripheral resistance index was reduced by 6% (NS), whereas heart rate and cardiac index were reduced by 12%. Exercise hemodynamics demonstrated a decrease in blood pressure of 17% (p less than 0.001). Exercise stroke index increased by 5% (NS), in part compensating for the reduction in heart rate of 17%. Total peripheral resistance index was reduced by 5% (NS). Twenty-four-hour blood pressure monitoring (Accutracker II) demonstrated significant blood pressure reductions in awake as well as in asleep patients. Blood pressures decreased from 163/102 to 141/84 mm Hg in from 135/78 to 122/68 mm Hg in awake and asleep patients; respectively. Carvedilol is an effective antihypertensive agent, and the hemodynamic mode of action reflects alpha 1- and beta 1-blocking activities.


Hemodynamic effects of carvedilol after acute oral administration in hypertensive and normal subjects. Forearm hemodynamics using pulsed Doppler flowmetry were studied in nine healthy volunteers and 12 patients with mild-to-moderate hypertension before and after acute oral administration of the beta-blocking and vasodilating agent carvedilol. Both the 25- and the 50-mg dose produced a significant blood pressure reduction by comparison with placebo in normotensive and hypertensive subjects. Only the 50-mg dose caused a decrease in forearm vascular resistance in hypertensive subjects. The decrease disappeared after wrist occlusion. Although brachial artery diameter did not change, a significant decrease in tangential tension was observed. This study provides evidence that carvedilol produced arteriolar dilation within the forearm of hypertensive subjects in association with a decrease in brachial artery tangential tension.


Blood pressure lowering and cerebral blood flow: a comparison of the effects of carvedilol and propranolol on the cerebral circulation in hypertensive patients. The first part of this article concerns the general relation between blood pressure lowering and cerebral blood flow. Factors known to affect cerebral blood flow are reviewed, and recent advances in the field of innervation of cerebral blood vessels are outlined. Special emphasis is placed on the importance of the phenomenon of autoregulation and how this is disturbed in patients with hypertension. Not all antihypertensive drugs exert the same action on the cerebral circulation to produce the same blood pressure-lowering effect. In addition, the actions exerted by common antihypertensive drugs on the cerebral circulation are described. The second part of the article provides a comparison between the effect of carvedilol and that of propranolol on blood pressure reduction and cerebral blood flow. In a double-blind, crossover study involving 14 patients with mild-to-moderate hypertension, carvedilol was shown to have no effect on cerebral blood flow, whereas there was a slight tendency for lower flows to occur with the use of propranolol. Because of the small sample size, statistical significance was not reached. These results are consistent with other recently published findings.


Use of multiple-action agents on the heart: pathophysiological and therapeutic considerations. The introduction of beta-adrenoreceptor antagonists into clinical practice has resulted in major progress in the treatment of hypertension, angina pectoris, and congestive heart failure. However, the first and second (beta 1 selective) generations of beta-blockers induce a series of unwanted functional and metabolic effects, suggesting the search for a third generation of beta-antagonists. The new multiple-action beta-blockers, which have important peripheral vasodilator properties, appear to be promising with regard to clinical efficacy and side effects. In hypertensive patients, the vasodilation could add a more pathophysiological mechanism and therefore could induce a better preservation of systolic function. The global cardioprotection may be further improved by the absence of long-term metabolic effects. By virtue of their peripheral and coronary vasodilating properties, multiple-action beta-blockers could exert more favorable anti-ischemic effects in patients with angina pectoris than the traditional beta-blockers. In congestive heart failure, afterload reduction, and possibly myocardial beta 2-activation induced by multiple-action beta-blockers can minimize the negative inotropic effects, leading to better toleration at the beginning of treatment. The potential benefits of multiple-action beta-blockers have been assessed by preliminary studies and should be confirmed by trials in progress.


Vasodilatory action of carvedilol.

Vasodilatory action of carvedilol. Carvedilol is a dual-acting drug designed to produce two complementary effects: beta-blockade and vasodilation. These effects are induced in the same dose range, a prerequisite for utilizing both properties in an appropriate manner. The vasodilation is mediated predominantly by specific alpha 1-adrenoceptor blockade. At markedly higher concentrations, additional vasodilating actions besides alpha 1-blockade can be observed. These effects resemble those of Ca(2+)-antagonistic properties. However, they do not contribute to the acute blood pressure-lowering activity of carvedilol but may be responsible for the increased blood flow to specific organs. At beta-blocking doses, carvedilol reduces the regional and systemic vascular resistance in various experimental models, healthy volunteers, and in patients with cardiovascular diseases such as hypertension, coronary artery disease, and heart failure. The profile of carvedilol thus insures beneficial treatment of hemodynamic disorders characterized by increased sympathetic tone and increased vascular resistance.


Effect of carvedilol on left ventricular function and mass in hypertension. The effects of carvedilol, a nonselective beta-blocker with peripheral vasodilator action, on left ventricular function and mass in essential hypertension were studied in 14 patients with diastolic filling abnormalities. Treatment produced significant decreases in blood pressure (systolic: 168.4 +/- 10.5 to 154 +/- 17.2 mm Hg, p less than 0.005; diastolic: 101.6 +/- 8.6 to 95.3 +/- 11.6 mm Hg, p less than 0.025), left ventricular mass (316.7 +/- 85.8 to 276.8 +/- 84.9 g, p less than 0.05), and left ventricular mass index (157.9 +/- 42.4 to 131.6 +/- 34.6 g.m-2, p less than 0.025). There were coincident improvements in the parameters of diastolic left ventricular filling (E/A ratio: 0.66 +/- 0.14 to 0.80 +/- 0.26, p less than 0.025; mean E descent velocity: 245 +/- 130 to 264 +/- 70 cm.s-2, p less than 0.05). No significant alterations in systolic function were observed, although three patients with systolic impairment improved to normal during treatment. Two other patients, however, were withdrawn from the study because of hypotension and cardiac failure. In conclusion, carvedilol is effective in the treatment of hypertension and produces adequate blood pressure control with a percentage reduction in left ventricular mass. The associated changes in diastolic function may be due in part to the mass reduction, but no direct relation has been established, and the effect of afterload reduction on diastolic left ventricular filling remains important.


Regression of left ventricular hypertrophy. Since our first studies on hypertrophy regression, this parameter has achieved an increasing interest in the treatment of hypertension. During the past 8 years we studied different groups of antihypertensive drugs with the use of magnetic resonance imaging (MRI). This article discusses the antihypertensive drug carvedilol. We examined 17 patients with diastolic blood pressure of at least 95 mm Hg and left ventricular wall thickness of at least 15 mm. Measurements were carried out before and after treatment with 25 mg/day carvedilol for 6 months. We demonstrated a significant regression of septal thickness from 17.7 to 16.3 mm. At each wall, three measurements at different points were performed by MRI and the means were calculated. Left ventricular ejection fraction and wall motion did not show any significant changes in radionuclide ventriculography after treatment. The diastolic blood pressure was reduced from 98.0 to 88.7 mm Hg. All differences are significant (p less than 0.05). There was no significant correlation between the extent of regression of septal hypertrophy and the degree of pretherapeutic hypertrophy, the age of patients, or the dimension of blood pressure reduction.


Can intravenous beta-blockade predict long-term hemodynamic benefit in chronic congestive heart failure secondary to ischemic heart disease? A comparison of intravenous with oral carvedilol. Several studies have demonstrated the long-term beneficial effects of beta-blockers in the treatment of congestive heart failure. Despite interest in this mode of therapy, clinical application of beta-blockers has been limited due to their negative inotropic effect. A subset of the heart failure patients do not show improvements with standard beta-blocker therapy. Carvedilol, a new nonselective beta-blocking agent with concurrent alpha-blocking properties, was evaluated in 17 patients with chronic heart failure secondary to ischemic heart disease. All had resting left ventricular ejection fraction less than or equal to 45% and were maintained on diuretic therapy. Acute hemodynamic measurements were made after administration of intravenous carvedilol (2.5-7.5 mg) and after chronic therapy for 8 weeks (12.5 to 50 mg b.i.d.). Radionuclide ventriculography, ambulatory intra-arterial blood pressure monitoring, and right heart catheterization were performed before and after 8 weeks of chronic therapy. Twelve patients completed the study (five were withdrawn). Symptomatic and hemodynamic improvements were demonstrated in 11 of the 12 patients after 8 weeks of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


Receptor pharmacology of carvedilol in the human heart. The beta-blocker and vasodilator carvedilol was examined in preparations of human ventricular myocardium. Carvedilol is a high-affinity, slightly beta 1-selective competitive beta-blocking agent, with a KD for beta 1-receptors of approximately 4-5 nM and a selectivity of sixfold to 39-fold for beta 1-receptors rather than beta 2-receptors, depending on the method used to assess subtype potency. Carvedilol also is a potent alpha 1-blocking agent, with a beta 1: alpha 1-blocking relative potency of 1.7-fold. In human lymphocytes containing beta 2-receptors and human myocardial membranes containing both beta 1- and beta 2-receptors, carvedilol exhibited the unique property of guanine nucleotide-modulatable binding. This is a property shared with bucindolol, another beta-blocker and vasodilator that is structurally similar to carvedilol. Despite the presence of guanine nucleotide-modulatable binding, no intrinsic activity of carvedilol was detected in preparations of isolated human heart or in myocardial membranes.


A comparison of carvedilol with atenolol in the treatment of mild-to-moderate essential hypertension. INT-CAR-07 (U.K.) Study Group. The efficacy and safety of carvedilol, a beta-blocker with vasodilating properties, were compared at a dosage of 25 to 50 mg once daily with those of atenolol at a dosage of 50-100 mg once daily in a double-blind, randomized, parallel-group, multicenter study. After a single-blind placebo phase of 3 to 6 weeks, 47 patients (median age, 59 years) were randomized to receive carvedilol and 52 patients (median age, 57 years) were randomized to receive atenolol for an 8-week study period. Patients on carvedilol received 12.5 mg for the first 2 days and then 25 mg as a once-daily dosage. The initial dosage of atenolol was 50 mg once daily. The dosage of each treatment could be doubled (to 50 and 100 mg once daily, respectively) at week 4 if the response was inadequate. Sitting and standing blood pressures and heart rates were recorded 24 h after the dose at weeks 4 and 8. Data from 90 of 98 patients who completed the study were eligible for per-protocol analysis. Approximately one-third of the patients in each group required upward dose titration at week 4 because of inadequate response. At week 8, 84% patients receiving carvedilol and 91% receiving atenolol had sitting diastolic blood pressure less than or equal to 90 mm Hg or decreased their blood pressure by greater than or equal to 10 mm Hg (95% confidence intervals for difference between carvedilol and atenolol, +7% and -21%). Safety profiles were similar between treatments. One patient withdrew; a skin rash developed during the fourth week of treatment with atenolol.(ABSTRACT TRUNCATED AT 250 WORDS)