Akihiro Haruno

Antihypertensive effects of MPC-1304, a novel calcium antagonist, in experimental hypertensive rats and dogs

Summary: Antihypertensive effects of a novel calcium antagonist, MPC-1304, (±)-methyl 2-oxopropyl 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylate and its active metabolites were investigated in experimental hypertensive rats and dogs and compared with those of other dihydropyridine derivatives (nifedipine, nisoldipine, nicardipine, and nitrendipine). MPC-1304 had a dose-related antihypertensive effect with a slight increase in heart rate (HR) in rats. The antihypertensive effects of MPC-1304 were more potent than those of other dihydropyridines, and its active metabolites had antihypertensive effects comparable to those of other dihydropyridines. The hypotensive effects of MPC-1304 were stronger in hypertensive rats than in normotensive rats. During repeated oral administration of MPC-1304 to spontaneously hypertensive rats (SHR, once daily for 4 weeks, 0.3-3 mg/kg), dose-response curves of the antihypertensive effect did not change and body weight gain was equal to that of the vehicle-treated group. When given orally to conscious renal hypertensive dogs, MPC-1304 0.1-0.3 mg/kg had a potency and duration of antihypertensive action comparable to that of nitrendipine (1-3 mg/kg). MPC-1304 increased coronary blood flow (CBF) and aortic blood flow (ABF) in conscious normotensive dogs. In conclusion, MPC-1304 and its active metabolites have potent antihypertensive effects and cause slight tachycardia, and they may be useful in treating hypertension

Cardiovascular profile of MPC-1304, a novel dihydropyridine calcium antagonist : comparison with other calcium antagonists

The cardiovascular profile of a novel calcium antagonist, MPC-1304 and its active metabolites were investigated in experimental animals in vitro and in vivo, and were compared with those of other calcium antagonists or nitroglycerin (NTG). The ratio of negative chronotropic/negative inotropic effect of MPC-1304 was 23 times higher than that of nifedipine in paced left and spontaneously beating right atria of guinea pigs. MPC-1304 and nifedipine did not change atrial-His (AH) conduction time or His-ventricular (HV) conduction time at hypotensive doses in open-chest dogs, whereas diltiazem prolonged AH time. MPC-1304 increased coronary blood flow, and strongly decreased myocardial oxygen consumption (MVO2) by decreasing blood pressure (BP) and heart rate (HR) in open-chest dogs. Left ventricular pressure (LVP) was not changed. Contractile force (dp/dt) was slightly increased by its action on afterload. MPC-1304 and nifedipine did not dilate the large coronary artery, but NTG did. MPC-1304 increased blood flow of the peripheral arteries, especially vertebral and CBF in anesthetized dogs. Cerebral blood flow (CBF) also increased. MPC-1304 decreased serum cholesterol levels and the plaque area of the aorta in cholesterol-fed rabbits. Because of this cardiovascular profile, MPC-1304 should be useful in treatment of hypertension as well as angina pectoris.

Effects of gallopamil, a Ca2+ channel blocker in models of ventricular arrhythmia in dogs

The antiarrhythmic effects of gallopamil on adrenaline-, digitalis- and two-stage coronary ligation-induced arrhythmias and on adrenaline-induced triggered arrhythmia were investigated. Gallopamil suppressed adrenaline-induced and adrenaline-induced triggered arrhythmias, and these antiarrhythmic effects of gallopamil were similar to those of verapamil. Gallopamil also showed some antiarrhythmic effect on the 48-h coronary ligation-induced arrhythmia. The plasma concentration of gallopamil which decreased the arrhythmic ratio for adrenaline-induced arrhythmia by 50% (IC50) was 32 ng/ml. These results indicate that gallopamil may be a clinically useful antiarrhythmic drug.

Antiarrhythmic effects of bisaramil in canine models of ventricular arrhythmia

The antiarrhythmic effects of bisaramil were examined in canine models of digitalis-, adrenaline- and two-stage coronary ligation- induced arrhythmia. Bisaramil (0.3-1.5 mg/kg i.v.) suppressed all the arrhythmias. The antiarrhythmic plasma concentration (IC50) for arrhythmias induced by digitalis, adrenaline, and 24 h two-stage coronary ligation were 0.11, 0.81, and 0.75 micrograms/ml, respectively. Bisaramil is a potent class I agent, judging from its low antiarrhythmic plasma concentrations. Oral bisaramil (10 mg/kg) also suppressed 24-h coronary ligation-induced arrhythmia. These results indicate that bisaramil may be a useful drug for the treatment of various clinical ventricular arrhythmias.

Effects of a new antiarrhythmic drug TYB-3823 on canine ventricular arrhythmia models

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, TYB-3823 [1− (2,6-dimethylphenyl)-4,4-dimethyl-aminoguanidine hydrochloride], were investigated. To determine the antiarrhythmic effects, spontaneously occurring adrenaline-, digitalis-, and two-stage coronary ligation-induced arrhythmias were used. TYB-3823 suppressed these three arrhythmia models. The antiarrhythmic plasma concentrations, IC50, of TYB-3823 for digitalis-, coronary ligation-, and adrenaline-induced arrhythmias were 7.8, 16.8, and 5.0 μg/ml, respectively. In the blood perfused sinoatrial (SA) node and papillary muscle (PM) preparations, TYB-3823 decreased the sinoatrial rate (SAR) and contractile force following an initial small positive inotropic effect and increased the intraventricular conduction time and coronary blood flow. These results indicate that TYB-3823 is similar to other class 1 antiarrhythmic agents, such as aprindine and nicainoprol, in the antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

Antiarrhythmic plasma concentrations of NIK-244 on canine ventricular arrhythmias

Summary: Using two-stage coronary ligation-, digitalis-, and epinephrine (EPI)-induced canine ventricular arrhythmias, we examined antiarrhythmic effects of NIK-244 and determined the minimum effective plasma concentration for each arrhythmia model. NIK-244 suppressed coronary ligation- and digitalis-induced arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24-h and 48-h coronary ligation and digitalis were 0.41 ± 0.10 (by 1 mg/kg i.v.), 0.70 ± 0.13 (by 1 mg/kg i.v.), and 0.21 ± 0.08 (by 0.5 mg/kg i.v.) μg/ml, respectively (mean ± SD of the mean, n = 6). The concentration for digitalis-induced arrhythmia was significantly lower than those for coronary ligation arrhythmias. NIK-244 was not effective on EPI arrhythmia, and 1 mg/kg worsened the arrhythmia to ventricular fibrillation in three of six dogs. This pharmacologic profile is similar to those of disopyramide, procainamide, and SUN 1165. Since NIK-244 had no deleterious effects on blood pressure and sinus node activity, its clinical usefulness is expected.