Cardiovascular effects of YM430, a 1,4-dihydropyridine derivative with β-adrenoceptor blocking activity, in dogs and rats

We evaluated the cardiovascular effects of YM430, a novel 1,4- dihydropyridine derivative with β-adrenoceptor blocking activity, in dogs and rats. In anesthetized dogs, YM430 (0.01-0.3 mg/kg, i.v.) dose-dependently decreased mean blood pressure, total peripheral resistance and double product without increasing the heart rate. YM430 (0.01-0.3 mg/kg, i.v.) increased coronary artery as well as vertebral artery blood flow, whereas its effects on carotid, mesenteric, femoral and renal blood flow were small. At the same dose range as that which induced vasodilation effects, YM430 had little effect on the max. dp/dt or PQ-interval. In conscious dogs, YM430 (0.1-1 mg/kg, i.v.) produced dose-dependent hypotension with tachycardia. In conscious rats, oral dosing of YM430 (100 mg/kg p.o.) produced a long- lasting hypotensive effect with slight tachycardia. YM430 also inhibited isoproterenol (0.1 μg/kg i.v.)-induced tachycardia. These two effects of YM430 may be attributable to its calcium entry blocking and β₁-adrenoceptor blocking activity, respectively. The time course of the hypotensive (calcium entry blocking) effect of YM430 after oral dosing was very similar to that of its inhibition of isoproterenol-induced tachycardia (β₁-adrenoceptor blocking effect). These results indicate that the ratio of the two activities (calcium entry blocking and β₁-adrenoceptor blocking) of YM430 is constant after oral administration. In conclusion, YM430 could be both an antianginal and antihypertensive agent, because of its dual activities.