[Herpes zoster of the right cervical region associated with right facial nerve palsy and hoarseness].

A 69-year-old man was suffering from herpes zoster on his 2nd and 3rd right cervical spinal segments and 3rd branch of the trigeminal nerve. He came to our hospital on his 10th illness day and was treated with continuous cervical epidural block, intravenous infusion of acyclovir for five days, and oral paramethasone and Vitamin B12. Oh his 18th illness day, right facial nerve palsy and hoarseness became clear. His cerebrospinal fluid showed no abnormality except cell count 23 x 3 mm-2. No clear paralysis of vocal cords was detected on laryngoscopy. He was also treated with right stellate ganglion block starting on his 21st illness day. His pain and facial nerve palsy recovered completely by his 68th illness day, but hoarseness continued about two months. The hoarseness might be a result of spread of the disease 1) by cerebrospinal fluid, 2) by contact with the 3rd cervical nerve and vagal nerve via accessory nerve, and 3) direct effect on the vocal cords and the muscles controlling them. Herpes zoster on the head and neck region shows various complications and we should follow its course cautiously.

[Endocrine effects of induced hypotension by ketanserin in anesthetized dogs].

Plasma levels of catecholamines, aldosterone and cortisol as well as plasma renin activity during hypotension by ketanserin were studied in 9 mongrel dogs under 0.87% halothane in oxygen (1MAC). Mean arterial pressure was reduced and maintained at 60 mmHg for 60 minutes by the infusion of 0.1% ketanserin solution. Plasma norepinephrine decreased progressively during hypotension to 35% of the control value after induced hypotension. In contrast, plasma epinephrine increased three-four folds compared with the control value during and after induced hypotension, but this change was not statistically significant. Plasma renin activity and plasma aldosterone showed a slight increase during hypotension but returned toward the control value after discontinuing the infusion of ketanserin. Plasma cortisol remained unchanged throughout the experiment. In conclusion, our data show that hypotension by ketanserin is not accompanied by the activation of the renin-angiotensin-sympathetic system or adrenocortical system.

[Hemodynamic effects of induced hypotension by ketanserin in anesthetized dogs].

Hemodynamic effects of hypotension induced by ketanserin were investigated in 18 mongrel dogs under 0.87% halothane in oxygen (1 MAC). They were randomly allocated to one of two groups. Group C (n = 9) received no vasodilator therapy and served as a control and group K (n = 9) received 0.1% ketanserin solution. Mean arterial pressure decreased and was maintained at 60 mmHg for 60 minutes in group K. No change was noted in hemodynamic variables measured in group C throughout the experiment. During and after induced hypotension in group K, stroke volume index increased significantly compared with the control value. On the other hand, systemic vascular resistance was significantly reduced, reaching 50% of the control value at the end of the hypotensive period. Left ventricular maximum dp/dt showed a significant reduction during hypotension but then increased gradually to the control value. In addition, heart rate decreased significantly during and after induced hypotension, therefore these vasodilator effects were not accompanied by reflex tachycardia. Cardiac index remained unchanged throughout the experiment. Further, no changes in central venous pressure, mean pulmonary artery pressure, pulmonary capillary wedge pressure and pulmonary vascular resistance were observed. In conclusion, the data indicate that ketanserin is a potent systemic vasodilator producing stable hemodynamics. It also reduces systemic vascular resistance without reflex tachycardia and this is a favorable effect of ketanserin.

[Endocrine effects of hypotension induced by diltiazem in rabbits].

Endocrine effects of hypotension induced by diltiazem, a calcium antagonist, were studied in 16 male rabbits under the inhalation of 0.7% halothane in oxygen. They were randomly allocated to one of two groups. Group C (n = 8) received no vasodilator therapy and served as control and group D (n = 8) received infusion of diltiazem. Mean arterial pressure was decreased and was maintained at 60 mmHg for 60 minutes in group D. No change was noted in plasma catecholamines measured in group C throughout the experiment but plasma renin activity decreased progressively. During and after induced hypotension in group D plasma epinephrine showed a dramatic rise compared with the control value. The maximum increase occurred 30 minutes after induction of hypotension but this change was not statistically significant. Plasma norepinephrine in group D was significantly higher than the control value. Compared with the control value (0.19 +/- 0.04 ng.ml-1), plasma norepinephrine was activated 30 and 60 minutes after induction of hypotension (0.71 +/- 0.16 ng.ml-1, P less than 0.05, 0.82 +/- 0.20 ng.ml-1, P less than 0.05, respectively). Plasma renin activity in group D was significantly higher than the control value. The highest level of plasma renin activity was three times the control value 30 minutes after induction of hypotension. In conclusion, our data show that induced hypotension by diltiazem activates the renin-angiotensin-sympathetic nervous system.

[A comparison of the endocrine effects of hypotension induced by nicardipine with those by sodium nitroprusside in dogs].

Plasma catecholamines, plasma renin activity, plasma aldosterone and plasma cortisol during hypotension induced by sodium nitroprusside and nicardipine were studied in 27 mongrel dogs under 0.87% halothane in oxygen. They were randomly divided into three groups: sodium nitroprusside (group S: n = 8), nicardipine (group N: n = 8) and controls (group C: n = 9). Group C received no vasodilator therapy and served as a control. Mean arterial pressure was reduced and maintained at 60 mmHg for 60 minutes in hypotensive groups. No changes were noted in plasma catecholamines and plasma cortisol in group C throughout the experiment, but plasma renin activity and plasma aldosterone decreased progressively. During hypotension induced by sodium nitroprusside and nicardipine, plasma epinephrine was significantly higher than the control value. However, after the hypotensive drugs were discontinued, plasma epinephrine decreased slightly. During and after induced hypotension, plasma renin activity of group N and group S were significantly higher than the control values. The highest levels of plasma renin activity 36.7 ng.ml-1.hr-1 in group N and 23.2 ng.ml-1.hr-1 in group S were observed. Plasma aldosterone concentration was significantly higher than the control value in group N. The maximum increase occurred 30 minutes after discontinuation of the nicardipine and the highest concentration of plasma aldosterone was three times control value. In contrast, in group S, plasma aldosterone was unchanged from the control value. Plasma cortisol concentration of group N was significantly increased than the control value. However, in group S, plasma cortisol concentration showed a slight but not significant increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptor binding properties of the new calcium antagonist benidipine hydrochloride.

The in vitro receptor binding affinity of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-diyhydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) to 3H-nitrendipine, alpha 1-adrenergic, alpha 2-adrenergic, beta-adrenergic, muscarinic cholinergic, H1-histaminergic, D2-dopaminergic, S2-serotonergic, A1 adenosine and A2 adenosine receptors was compared with that of nifedipine, nitrendipine and nicardipine. KW-3049 bound stereospecifically to 3H-nitrendipine binding sites of rat myocardium with high affinity (Ki = 0.13 nmol/l) and to the rat brain alpha 1-receptor (Ki = 1.2 mumol/l). KW-3049 exhibited no remarkable binding affinity to alpha 2, beta-, D2-, H1-, S2-, A1-, A2- and muscarinic cholinergic receptors at 100 mumol/l. KW-3049 showed competitive inhibition against 3H-nitrendipine binding when it was added simultaneously with the ligand and rat heart membranes. KW-3049 did not affect the dissociation of 3H-nitrendipine from the receptor sites. The inhibitory activity of various isomers of KW-3049 at the 3H-nitrendipine binding sites was shown in the order of S-S-(+) greater than KW-3049 (racemate, S-S-(+), R-R-(-] greater than R-R-(-) greater than S-R-(-) greater than racemate (R-S-(+), S-R-(-] greater than R-S-(+). S-S-(+)isomer was 12 times more potent than R-R-(-)isomer on Ki basis, whereas alpha 1-adrenoceptors followed the order of S-S-(+), R-S-(+), KW-3049, racemate (R-S-(+), S-R-(-], S-R-(-) and R-R-(-).

Synthesis of expected metabolites of benidipine hydrochloride.

(+/-)-(R*)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049, 1), a highly potent and long-acting calcium antagonistic 1,4-dihydropyridine derivative, is now under clinical study as an antihypertensive and as an antianginal agent. In order to confirm the structures of the metabolites of KW-3049, 19 compounds were prepared. Among them 11 compounds were found to be metabolites (the compounds 2, 3, 6, 8, 14, 15, 16, 28, 31, 32 and 34) of KW-3049 in rats and/or dogs.

Synthesis and pharmacological activity of stereoisomers of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester.

1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 1-(phenylmethyl)-3-piperidinyl ester 1, a highly potent calcium antagonist, was separated into stereo- and optical isomers to investigate the differences of antihypertensive activities between them. Fractional crystallization of the hydrochlorides of 1 gave alpha- and beta-diastereoisomers. The alpha-isomer (benidipine hydrochloride, KW-3049) showed very strong hypotensive effect, but little activity was observed in the beta-isomer. From optically resolved 1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-3- pyridinecarboxylic acids 2, and 1-benzyl-3-piperidinols 3, four optical isomers of 1 were synthesized, and their absolute configurations were deduced. The hypotensive activity of (+)-alpha, namely (S)-(S)-1, was 30 to 100 times stronger than that of (-)-alpha in intravenously administered spontaneously hypertensive rats.

Slow dissociation of the new slow-onset and long-acting calcium antagonist benidipine hydrochloride from 3H-nitrendipine binding sites.

The dissociation rates of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) and some calcium antagonists from 3H-nitrendipine binding sites were studied by a centrifugation technique and a filter-absorbed tissue method. KW-3049 dissociated from 3H-nitrendipine binding sites more slowly than other calcium antagonist, namely nifedipine, nitrendipine, nilvadipine, nicardipine and nisoldipine. The slow dissociation of KW-3049 from 3H-nitrendipine binding sites was supported by the equilibrium binding studies. When KW-3049 was preincubated with rat cardiac membrane, its inhibitory potency was enhanced 2.6-fold, whereas nifedipine did not alter its potency. In ex vivo binding, following administration of KW-3049 to rat, 3H-nitrendipine binding site was occupied in a dose-dependent manner and this occupation returned to a control level after 24 h. These results of receptor binding studies are in agreement with the pharmacological characteristics of KW-3049.

Physico-chemical properties and stabilities of the highly potent calcium antagonist benidipine hydrochloride.

(+/-)-(R*)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049), a highly potent calcium antagonist, was examined to clarify its physico-chemical properties, i.e. melting point, spectra (UV, IR, NMR, MS), X-ray diffraction pattern, thermal analysis, solubilities, pKá, partition coefficient and chromatography (TLC, HPLC). The stabilities of KW-3049 were studied under various conditions by HPLC. KW-3049 in solid state was very stable to heat and moisture, and fairly stable to light.

Antihypertensive effects of intravenous administration of benidipine hydrochloride and some other calcium antagonists in conscious, spontaneously hypertensive rats.

The antihypertensive effect of intravenously administered (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was examined in conscious, spontaneously hypertensive rats (SHR) and comparatively evaluated with those of nifedipine, nicardipine, nitrendipine, nisoldipine, verapamil and diltiazem. When nifedipine (10 and 100 micrograms/kg), nicardipine (10 and 100 micrograms/kg), nitrendipine (10 and 100 micrograms/kg), verapamil (100 and 1000 micrograms/kg) and diltiazem (100 and 1000 micrograms/kg) were intravenously administered to SHR, at their lower doses, only transient decreases of blood pressure were observed and, even at their higher doses, decreased blood pressures returned to the initial levels after 80 to 120 min. Nisoldipine at 10 micrograms/kg (i.v.) decreased the blood pressure (by 23 mmHg), lasting for 100 to 120 min, and the antihypertensive effect of 100 micrograms/kg (i.v.) of it (by 63 mmHg) lasted for longer than 240 min though a tendency of blood pressure to recover was observed. The peak effects of these 6 calcium antagonists were observed 1 min after the drug injection. When KW-3049 (1, 3, 10 and 30 micrograms/kg i.v.) was administered, a dose-dependent decrease of blood pressure (by 23 to 67 mmHg) was observed. The effect of KW-3049 was longer than those of the above 6 calcium antagonists, including nisoldipine. The maximal effects were attained 10 to 30 min after the drug injection and the decreased blood pressure did not return to an initial level even 180 min (at 1 and 3 micrograms/kg) and 240 min (at 10 and 30 micrograms/kg) after administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive effects of the new calcium antagonist benidipine hydrochloride in conscious, renal-hypertensive dogs.

The antihypertensive action of (+/-)-(R*)-2,6-dimethyl-4- (m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was evaluated in conscious, renal-hypertensive dogs. When KW-3049 (0.1, 0.3 and 1 mg/kg) was orally administered, antihypertensive action and increased heart rate with peak time after 60 to 120 min of administration were observed, and the duration of actions at the dose of 0.3 mg/kg (p.o.) or more lasted for more than 7 h. When nifedipine (0.3 and 1 mg/kg) and nicardipine (1 and 3 mg/kg) were orally given, the duration of antihypertensive action was shorter. Nitrendipine (1 and 3 mg/kg p.o.) showed antihypertensive action and increased heart rate with peak time after 45 to 60 min of administration, and the duration of action at 3 mg/kg (p.o.) lasted for 7 h or longer. The antihypertensive activity of KW-3049 at the action peak was 6.1, 12.1 and 8.9 fold as compared with those of nifedipine, nicardipine and nitrendipine, respectively. Also, when KW-3049 at 0.3 mg/kg (p.o.) was administered after 1 h of propranolol (20 mg/kg p.o.) administration, the increase of the heart rate was markedly inhibited while its antihypertensive action remained unchanged. From these results, it was demonstrated that KW-3049 shows potent and long-lasting antihypertensive action with gradual appearance of action, and was suggested that it may be an useful antihypertensive agent.

Antianginal effects of the new calcium antagonist benidipine hydrochloride in anesthetized rats and spontaneously hypertensive rats. Electrocardiographic study.

Antianginal effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in various experimental angina-pectoris models (anesthetized rats, spontaneously hypertensive rats (SHR] were compared with those of nifedipine, propranolol and hydralazine. Furthermore, the effects of these drugs on the pressure-rate product were evaluated. 1. Vasopressin test (SHR): The administration of KW-3049 at 10 micrograms/kg (i.v.) developed an inhibitory effect comparable to that of nifedipine at 200 micrograms/kg (i.v.) against the ischemic ECG changes caused by the intravenous administration of vasopressin at 1 U/kg. The effects of KW-3049 at 3 and 10 mg/kg (p.o.) lasted for 8 h or more. 2. Coronary occlusion test (rat): The rise of T-wave of epicardial ECG following ligation of coronary artery was inhibited by the administration of KW-3049 at doses of 30 and 100 micrograms/kg i.v. Nifedipine at dose of 200 micrograms/kg i.v. was slightly effective. 3. Isoproterenol (isoprenaline) test (rat): The fall of ST in ECG by the continuous infusion of isoprenaline (10 micrograms/kg/min) was almost completely prevented by propranolol (500 micrograms/kg i.v.). Also, KW-3049 (200 micrograms/kg i.v.) and nifedipine (200 micrograms/kg i.v.) significantly inhibited the decline of ST, in which the former was more effective than the latter. 4. Anoxia test (SHR): The fall of ST and rise of T-wave of ECG, induced by stopping artificial respiration of gallamine-immobilized SHR, were suppressed by the administration of KW-3049 at doses of 10 and 30 micrograms/kg i.v.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of benidipine hydrochloride on atrioventricular conduction time and postural reflex in gallamine-immobilized cats.

Using gallamine-immobilized cats, the effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dic arb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was compared with those of other drugs in terms of the propensity for atrioventricular conduction disturbances and orthostatic hypotension. The administration of KW-3049 at doses of 1 to 300 micrograms/kg i.v. dose-dependently lowered the blood pressure and also reduced the heart rate. In terms of the maximum blood pressure lowering activity, KW-3049 was similar in degree to nifedipine and approximately 30 times as potent as diltiazem, verapamil and phenoxybenzamine. KW-3049 as well as nifedipine, at doses with which the mean blood pressure can be reduced by 50 mmHg, hardly affected the PR-interval of ECG, whereas diltiazem and verapamil at their hypotensive doses markedly prolonged the PR interval. These four calcium antagonists at their high doses elicited 2nd or 3rd degree atrioventricular blocks in some cases. On the other hand, phenoxybenzamine did not affect the atrioventricular conduction at its hypotensive doses. Inhibitory action on the pressor responses to head-up tilting in cats was observed neither in KW-3049, nifedipine, verapamil nor diltiazem. On the contrary, phenoxybenzamine strongly inhibited the orthostatic pressor reflexes. From these results, it was suggested that in terms of the prolongation action of atrioventricular conduction KW-3049 is less potent than diltiazem and verapamil but similar in degree to nifedipine, and that KW-3049 is not likely to cause orthostatic hypotension.

Vasodilating effects of the new calcium antagonist benidipine hydrochloride in anesthetized dogs and cats.

Vasodilating effects of a new 1,4-dihydropyridine derivative, (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) were investigated in anesthetized dogs and cats. Intravenous administrations of KW-3049 at doses of 0.3 to 10 micrograms/kg exhibited a greater vasodilation in vertebral and coronary arteries than in common carotid and femoral arteries. The maximal effects of KW-3049 were equal to or more potent than those of nifedipine and nicardipine. Vertebral and coronary vasodilation following intravenous administration of 10 micrograms/kg of KW-3049 continued for 240 min or more, whereas those following nifedipine or nicardipine (10 micrograms/kg i.v.) disappeared within 30 min. A gradual and long-lasting increase of the vertebral and coronary blood flows following the intraduodenal administration of KW-3049 (0.1 mg/kg) was observed as compared with those of nifedipine (0.3 mg/kg i.d.) and nicardipine (0.3 mg/kg i.d.). When KW-3049 at a dose of 0.1 micrograms/kg was intraarterially administered to vertebral or coronary arteries, the blood flow increased without affecting systemic blood pressure and its effects lasted longer than those of nifedipine and nicardipine (0.1 micrograms/kg i.a.). In particular, the duration time in increase of coronary blood flow by KW-3049 was extremely longer, i.e. 11-fold and 6-fold those by nifedipine and nicardipine, respectively. Coronary vasodilating effect of KW-3049 was influenced neither by propranolol, atropine, diphenhydramine nor by aminophylline. Moreover, KW-3049 did not affect the vasodilator effect of adenosine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the new calcium antagonist benidipine hydrochloride on cardiohemodynamics in anesthetized dogs.

The effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine -3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinylester, methylester hydrochloride (benidipine hydrochloride, KW-3049) on the cardiohemodynamics were investigated in open-chest, anesthetized dogs, in comparison with those of nifedipine. When KW-3049 at a dose of 3 micrograms/kg was intravenously administered, hypotensive action (delta dBP = -20 mmHg) with a peak attained 3 to 5 min after the administration was observed and its action lasted for 2 h or more. Simultaneously, a slight decrease of heart rate and continuous increases of LV max dp/dt and cardiac output were recognized. At the administration with 10 micrograms/kg i.v., hypotensive action (delta dBP = -35 mmHg) with a peak 3 min after the administration appeared and continued for 3 h or more. At this time, continuous decrease of heart rate by about 18% and continuous increase of cardiac output were observed. The LV max dp/dt transiently decreased and then turned to increase, and the cardiac work was continuously decreased. When nifedipine at doses of 10 or 50 micrograms/kg was intravenously administered, hypotensive action (delta dBP = -31 and -52 mmHg) with a peak attained 1 min after the administration was observed and its action rapidly began to recover. At the administration with 50 micrograms/kg i.v., the heart rate was slightly decreased (10%). The LV max dp/dt was transiently reduced by 18% at 10 micrograms/kg i.v. and by 45% at 50 micrograms/kg i.v., respectively, and the augmented cardiac output lasted for 30 to 60 min. At the administration of 50 micrograms/kg i.v., cardiac work was continuously decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Gas chromatographic method for the quantification of the new calcium antagonist benidipine hydrochloride in plasma using electron capture detection.

A gas chromatographic assay procedure was developed for measuring subnanogram order concentrations of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in plasma. KW-3049 yielded the oxidation product partially during gas chromatography. To avoid decomposition, KW-3049 was oxidized in advance by nitrogen dioxide, extracted by diethylether under alkaline condition, chromatographed on the OV-1 column and measured using electron capture detector.

Sensitive radioreceptor assay of the calcium antagonist benidipine hydrochloride in plasma and urine.

Plasma and urinary concentrations of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) were measured by the radioreceptor assay using 3H-nitrendipine and rat cardiac membrane receptor. After methanol deproteinization and ethyl ether extraction under alkaline conditions as pretreatment, the detection limit for KW-3049 in plasma was 0.2 ng/ml using 0.5 ml of sample. For the urine, 0.05 ml of urine sample was directly added to the assay system, and detection limit of drug was 1 ng/ml. The cross-reactivity of the presumable metabolites was 1% or less of the unchanged drug. This radioreceptor technique was applied to pharmacokinetic studies and useful for monitoring the drug after therapeutic dosing.

Beneficial effects of the new calcium antagonist benidipine hydrochloride on myocardial dysfunction following coronary occlusion and reperfusion in anesthetized dogs.

The protective effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) on ischemic myocardium was examined comparing with that of nifedipine in anesthetized dogs subjected to a brief (10 min) coronary artery occlusion and reperfusion (2h). Occlusion of left anterior descending coronary artery elicited elevation of ST-segment and T-wave of epicardial ECG in the ischemic area. Regional myocardial contractile force in this area was depressed throughout the reperfusion period as well as during coronary occlusion period. LV max dp/dt, stroke volume and cardiac output tended to be reduced. In the dogs pretreated with 10 micrograms/kg of KW-3049 (i.v.) and 50 micrograms/kg of nifedipine (i.v.), both of which lowered the blood pressure to the same extent, elevation of ST-segment and T-wave was inhibited, and the prevention of irreversible depression of regional myocardial contraction observed at reperfusion periods was slightly more prominent in KW-3049 administration group. Stroke volume and cardiac output in both KW-3049 and nifedipine administration groups were maintained at higher levels than those in control group throughout coronary occlusion and the following reperfusion periods. LV max dp/dt of KW-3049 administration group was kept higher than that of the control group, while the value of the nifedipine administration group changed as that of the control group. These results demonstrate that KW-3049 as well as nifedipine exert protective effects on ischemic myocardium induced by coronary occlusion and reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological actions of benidipine hydrochloride in several isolated smooth muscles and myocardium.

Using various isolated smooth muscles and myocardium, the calcium antagonistic effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049), and its specificity were examined. Furthermore, the in vitro duration of action and the antispasmodic actions in coronary arteries were investigated in comparison with those of nifedipine, verapamil and diltiazem. 1. Ca antagonisms of KW-3049 When the Ca antagonistic effect of KW-3049 was investigated, for which the contractile responses to KCl in isolated mesenteric arteries in rabbits were taken as an indicator, the activity of KW-3049 was of about the same degree as nifedipine and approx. 30 times greater than those of verapamil and diltiazem. On the other hand, the negative inotropic action in isolated atria in rabbits was weaker than that of nifedipine. 2. Influences on responses to various agonists From the investigations using various isolated organs, it was evident that KW-3049 had neither agonistic nor antagonistic actions or very weak actions on the following receptors: alpha 1, alpha 2, beta 1, beta 2, H1, H2, muscarinic acetylcholine, 5HT2, angiotensin II, and prostaglandin F2 alpha. 3. Duration of in vitro actions Inhibitory actions of KW-3049 on 55 mmol/l-induced contractions in isolated mesenteric arteries in rabbits persisted even 180 min after the removal of drug solution and the repeated wash-out of tissues. On the other hand, those of nifedipine, verapamil and diltiazem disappeared within 60 to 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)