according to the present invention , dicentrine was found to be the most potent vasorelaxant in rat thoracic aorta . it is an α 1 - adrenoceptor antagonist as revealed by its competitive antagonism of norepinephrine - or phenylephrine - induced vasoconstriction of rat aorta . these effects still persisted in denuded aorta . it did not affect the aortic contraction induced by thromboxane receptor agonist u - 46619 , angiotensin ii , high potassium or carbachol . contraction of guinea - pig trachea caused by histamine or carbachol was slightly inhibited , while β - adrenoceptor relaxation to isoprenaline in trachea was not affected . in anesthetized rats , i . v . bolus of dicentrine ( 0 . 1 - 1 . 0 mg / kg ) caused a dose - related reduce in mean arterial blood pressure , which reached a maximum within 5 to 10 min after injection and persisted throughout 2 hr observation period . the hypotensive activity of dicentrine was completely abolished after α 1 - adrenoceptor blockade . in conscious spontaneously hypertensive ( sh ) and normotensive ( nt ) rats , dicentrine also evoked dose - related decreases in mean arterial pressure which were greater magnitude in sh than in nt rats . oral administration to conscious sh rats , the hypotensive effect persisted over 15 hr . in rats fed with cholesterol - triglyceride - rich diet , the contractile force of aorta increased twice that of normal diet rats . dicentrine not only decreased the serum triglyceride level but also restored the contractile force of cholesterol - triglyceride - treated rat aorta back to normal values . in rat ventricular cells , the effects of dicentrine on action potential and membrane current were studied . at a stimulation frequency of 0 . 1 hz , dicentrine prolonged the action potential , increased the time to peak and reduced the initial upstroke amplitude . voltage clamp study revealed that the prolongation of action potential by discentrine was associated with a significant inhibition of both transient outward and steady state outward current . however , calcium current was less affected . the inhibition of the upstroke amplitude by dicentrine was correlated with its inhibition of fast sodium inward current . these results indicate that dicentrine may exert antiarrhythmic action . the active compounds of this invention can be administered by any conventional means available for use in conjunction with pharmaceuticals ; either as individual therapeutic active ingredient or in a combination of therapeutic active ingredients . ordinarily , 1 to 10 mg per day is effective to obtain desired results . the active ingredients can be admixed with pharmaceutically acceptable diluent and carrier , so that it can be administered orally in solid dosage forms , such as capsules , tablets , and powders , or in liquid dosage forms , such as elixirs , syrups , and suspensions , it can also be administered parenterally , in sterile liquid dosage forms . the following examples serve to demonstrate the pharmacological activities of the claimed compounds . these are not intended as limiting since numerous modifications and varieties wherein will be apparent to those skilled in the art . the dried , ground root material ( 500 g ) was extracted with 95 % ethanol , and the extract was concentrated in vacua and fractionated into ethanol - and ethylacetate - soluble fractions . the ethylacetate - soluble fraction was then applied to a column of silica gel and eight fractions were obtained . as shown in table 1 , many fractions possessed inhibitory effects on the platelet aggregation induced by arachidonic acid and collagen , and on the vasoconstriction induced by norepinephrine . from fractions 5 - 8 rechromatographed on silica gel column , several compounds were further purified . according to their spectral analysis and comparison with the physical constants in the literature ( lu et al ., yakugaku zasshi 92 : 910 - 917 , 1972 ), four compounds were identified as dicentrine , n - methylnandigerine , n - methylovigerine and dicentrinone . table 1__________________________________________________________________________platelet aggregation (%) aortic contraction (%) fractionarachidonic acid collagen ne - phasic ne - tonic__________________________________________________________________________control87 . 6 ± 1 . 6 88 . 9 ± 1 . 4 100 . 0 ± 16 . 8 100 . 0 ± 1 . 41 0 . 0 ± 0 . 0 *** 84 . 1 ± 1 . 9 132 . 7 ± 12 . 2 96 . 1 ± 2 . 72 spontaneous aggregation 130 . 6 ± 13 . 7 91 . 8 ± 1 . 6 * 3 74 . 0 ± 2 . 3 *** 83 . 5 ± 2 . 8 130 . 0 ± 21 . 2 94 . 7 ± 15 . 54 58 . 2 ± 6 . 2 *** 79 . 7 ± 5 . 0 * 186 . 6 ± 37 . 7 115 . 0 ± 14 . 35 0 . 0 ± 0 . 0 *** 0 . 0 ± 0 . 0 ** 25 . 0 ± 17 . 7 * 2 . 1 ± 1 . 5 *** 6 0 . 0 ± 0 . 0 *** 20 . 9 ± 8 . 4 *** 68 . 9 ± 10 . 2 24 . 0 ± 4 . 5 *** 7 0 . 0 ± 0 . 0 *** 0 . 0 ± 0 . 0 *** 5 . 0 ± 3 . 5 ** 1 . 9 ± 1 . 3 *** 8 0 . 0 ± 0 . 0 *** 0 . 0 ± 0 . 0 *** 0 . 0 ± 0 . 0 *** 0 . 0 ± 0 . 0 *** __________________________________________________________________________ means ± s . e . m . are presented . *: p & lt ; 0 . 05 , **: p & lt ; 0 . 01 , ***: p & lt ; 0 . 00 as compared with the respective control . concentration : arachidonic acid ( 100 μm ), collagen ( 10 μg / ml ), norepinephrine ( ne , 3 μm ), each fraction ( 100 μg / ml ). concentration - response curve analysis of norepinephrine - and phenylephrine - induced contraction of rat thoracic aortae was performed for the α1 - adrenoceptor antagonism by dicentrine in comparison with prazosin , yohimbine and phentolamine . as shown in table 2 , dicentrine was less potent than prazosin , but was much more potent than phentolamine or yohimbine . in all cases the schild slopes were not significantly different from 1 . 0 . table 2______________________________________agonist antagonist pa2 slope r______________________________________nore - dicentrine 8 . 19 ± 0 . 09 0 . 94 ( 0 . 85 - 1 . 2 ) 0 . 99pinephrinephenyl - dicentrine 9 . 01 ± 0 . 10 0 . 94 ( 0 . 95 - 1 . 32 ) 0 . 99ephrine prazosin 10 . 60 ± 0 . 10 0 . 95 ( 0 . 34 - 1 . 24 ) 0 . 99 yohimbine 6 . 20 ± 0 . 05 0 . 84 ( 0 . 65 - 1 . 03 ) 0 . 99 phentolamine 7 . 53 ± 0 . 10 0 . 72 ( 0 . 70 - 1 . 20 ) 0 . 99______________________________________ results are given as means ± s . e . m . or the mean with 95 % confidence limits in parentheses . in washed rabbit platelets , dicentrine inhibited the aggregation induced by arachidonic acid and collagen , but not that by thrombin , as shown in table 3 . at 6 min after the addition of inducer , indomethacin ( 50 μm ) and edta ( 2mm ) were added to stop the reaction , and thromboxane b 2 was assayed by ria kits . thromboxane formations caused by arachidonic acid , collagen and thrombin were all suppressed by dicentrine . table 3______________________________________ thromboxane b . sub . 2 aggregation (%) ( ng / 10 . sup . 8 platelets ) inducer control dicentrine control dicentrine______________________________________archidonic acid 92 ± 1 11 ± 7 *** 445 ± 44 19 ± 15 *** collagen 94 ± 1 51 ± 7 *** 478 ± 93 70 ± 5 ** thrombin 95 ± 2 92 ± 2 131 ± 25 44 ± 14 * ______________________________________ means ± s . e . m . are presented . *: p & lt ; 0 . 05 , **: p & lt ; 0 . 01 , ***: p & lt ; 0 . 00 as compared with the respective control . concentration : arachidonic acid ( 100 μm ), collagen ( 10 μg / ml ), thrombin ( 0 . 1 u / ml ), dicentrine ( 150 μm ). the effects of dicentrine and quinidine on action potential were compared and studied in rat ventricular cells . as shown in table 4 , cells bathed in ca ++ - tyrode , 3 to 5 min exposure to 3 μm dicentrine prolonged the action potential duration ( apd 50 ) from 59 . 9 ± 11 . 3 msec to 201 . 9 ± 28 . 7 msec . in addition to the prolongation of apd 50 , a depression of initial upstroke amplitude from 138 . 3 ± 2 . 6 mv to 125 . 5 ± 4 . 5 mv and prolongation of the time to peak amplitude from 5 . 0 ± 0 . 5 msec to 10 . 0 ± 1 . 9 msec were observed . for cells treated with 3 μm quinidine , similar effects were obtained . table 4______________________________________ap amplitude ( mv ) apd . sub . 50 ( msec ) t . sub . p ( msec ) ______________________________________a . control 138 . 3 ± 2 . 6 59 . 9 ± 11 . 3 5 . 0 ± 0 . 5dicentrine 125 . 5 ± 4 . 5 * 201 . 9 ± 28 . 7 * 10 . 0 ± 1 . 9 * b . control 135 . 2 ± 2 . 2 62 . 6 ± 3 . 9 5 . 3 ± 0 . 5quinidine 121 . 2 ± 2 . 3 * 276 . 0 ± 18 . 6 * 10 . 8 ± 2 . 4 * ______________________________________ means ± s . e . m . are presented , *: p & lt ; 0 . 05 as compared with the respective control . apd . sub . 50 : action potential duration measured at 50 % repolarization fro the peak amplitude . t . sub . p : time to peak measured from the start of depolarization to the peak of the action potential . concentration : dicentrine ( 3 μm ), quinidine ( 3 μm ). effects of dicentrine and prasozin on systemic hemodynamic parameters of pentobarbital - anesthetized rats were compared and shown in table 5 . dicentrine is resemble to prazosin , another α1 - adrenoceptor blocker , both drugs produce similar hemodynamic changes : a decrease in mean arterial pressure ( map ), a reduction in total peripheral resistance by increasing blood flow , little or no change in cardiac output ( co ). however , dicentrine produces no change in heart rate ( hr ), or stroke volume ( sv ) in comparison with prazosin . table 5______________________________________hemo - dynamic dicentrine ( 1 . 0 mg / kg ) prazosin ( 0 . 1 mg / kg ) parameters before after before after______________________________________map 122 ± 5 62 ± 5 *** 120 ± 4 68 ± 6 ***( mm hg ) hr ( bpm ) 353 ± 10 348 ± 8 367 ± 9 337 ± 10 * co ( ml / min ) 21 ± 2 25 ± 4 27 ± 3 32 ± 3sv 50 ± 3 55 ± 9 64 ± 4 79 ± 7 *( μ / min / beat ) blood flow 7 ± 4 200 ± 27 ** 7 ± 4 171 ± 14 ** ______________________________________ *: p & lt ; 0 . 05 ; **: p & lt ; 0 . 01 , ***: p & lt ; 0 . 001 before vs . after . if rats fed with high cholesterol and high fat diet for three weeks , the blood level of cholesterol increased to two folds and triglyceride 3 . 5 folds , as shown in table 6 . if dicentrine was administered orally twice a day ( 10 mg / kg ) in the last week , triglyceride level was restored to normal value , while cholesterol level was unchanged . prazosin had similar effect at a dose of 5 mg / kg . table 6______________________________________ cholesterol triglyceridetreatment ( mg / dl ) ( mg / dl ) ______________________________________1 . normal diet 62 ± 4 . 5a 84 ± 5 . 4 . sup . b2 . high cholesterol & amp ; fat diet 120 ± 7 . 1 . sup . a 305 ± 11 . 1 . sup . bcd3 . high cholesterol & amp ; fat diet + 112 ± 4 . 6 108 ± 4 . 3 . sup . cdicentrine ( 10 mg / kg ) 4 . high cholesterol & amp ; fat diet + 112 ± 3 . 9 114 ± 9 . 2 . sup . dprazosin ( 5 mg / kg ) ______________________________________ . sup . a , b , c , d : data in pair show significant difference ( p & lt ; 0 . 001 ). if rats fed with high cholesterol and high fat diet for three weeks , the maximal contractile force of isolated thoracic aorta increased two folds , as shown in table 7 . if dicentrine was administered orally twice a day ( 10 mg / kg ) in the last week , the maximal contractile force of isolated thoracic aorta was restored to normal range . prazosin had similar effect at a dose of 5 mg / kg . table 7__________________________________________________________________________ concentration of phenylephrine ( m ) treatment 3 × 10 . sup .- 8 10 . sup .- 7 3 × 10 . sup .- 7 10 . sup .- 6 3 × 10 . sup .- 6__________________________________________________________________________1 . normal diet 0 . 2 ± 0 . 04a 0 . 48 ± 0 . 05 0 . 69 ± 0 . 10 0 . 86 ± 0 . 15 0 . 94 ± 0 . 182 . high cholesterol & amp ; 0 . 71 ± 0 . 10 1 . 14 ± 0 . 10 1 . 55 ± 0 . 10 1 . 73 ± 0 . 10 1 . 87 ± 0 . 10fat diet3 . high cholesterol & amp ; 0 . 22 ± 0 . 05 0 . 55 ± 0 . 07 0 . 55 ± 0 . 07 0 . 67 ± 0 . 11 0 . 75 ± 0 . 12fat diet + dicentrine4 . high cholesterol & amp ; 0 . 30 ± 0 . 05 0 . 51 ± 0 . 08 0 . 70 ± 0 . 09 0 . 80 ± 0 . 12 0 . 87 ± 0 . 12fat diet + prazosin__________________________________________________________________________ a : contractile force ( g ); dosage : dicentrine ( 10 mg / kg ), prazosin ( 5 mg / kg )
a method for the treatment of hypertension , arrhythmia , thrombosis or / and atherosclerosis with an effective amount of dicentrine or other alkaloids extracted from lindera oldhammii hemsl .