Cardiovascular effects of YM-16151-4: a novel calcium entry blocking and selective beta 1-adrenoceptor blocking agent in rats and dogs.

The cardiovascular effects of YM-16151-4 were evaluated in rats and dogs. In conscious rats, YM-16151-4 (3-30 mg/kg p.o.) produced a dose-dependent hypotensive effect without increasing heart rate (HR) and plasma renin activity (PRA). Nifedipine (3-10 mg/kg p.o.) produced a dose-dependent hypotensive effect but significantly increased HR and PRA. Atenolol (30 mg/kg p.o.) decreased PRA but did not decrease blood pressure and HR. The cardiovascular effects of the combination of nifedipine and atenolol were similar to those of YM-16151-4. It is interesting that the time course of the hypotensive effect of YM-16151-4 was similar to that of its beta 1-adrenoceptor blocking effect, although the time courses of these effects of the combination of nifedipine and atenolol were different. In conscious dogs, YM-16151-4 (0.3-10 mg/kg p.o.) also produced a long-lasting hypotensive effect with almost no effect on HR and PQ-interval. The time course of the beta 1-adrenoceptor blocking effect was similar to that of its hypotensive effect. Furthermore, during 10-day repeated oral administration, neither tolerance nor augmentation was observed in the hypotensive and beta 1-adrenoceptor-blocking effects. In conclusion, the present results indicate that YM-16151-4 is an effective and long-lasting hypotensive agent that does not increase HR and PRA. These effects of YM-16151-4 may be attributable to its calcium-entry-blocking and beta 1-adrenoceptor-blocking activities, and the ratio of two activities was constant after single and repeated oral administrations.