Cardiovascular Effects of YM‐16151–4: A Novel Calcium Entry Blocking and Selective β1-Adrenoceptor Blocking Agent in Rats and Dogs

Summary: 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 β1-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 β1-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 β1-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 β1-adrenoceptor-blocking activities, and the ratio of two activities was constant after single and repeated oral administrations.