Uchida W, Shibasaki K, Matsuda Y, Asano M, Takenaka T
Cardiovascular Research Laboratory, Yamanouchi Institute for Drug Discovery Research, Ibaraki, Japan.
J Cardiovasc Pharmacol. 1993 Aug;22(2):247-52.
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.
在大鼠和犬中评估了YM-16151-4的心血管效应。在清醒大鼠中，YM-16151-4（口服3 - 30mg/kg）产生剂量依赖性降压作用，且不增加心率（HR）和血浆肾素活性（PRA）。硝苯地平（口服3 - 10mg/kg）产生剂量依赖性降压作用，但显著增加HR和PRA。阿替洛尔（口服30mg/kg）降低PRA，但不降低血压和HR。硝苯地平和阿替洛尔联合用药的心血管效应与YM-16151-4相似。有趣的是，YM-16151-4的降压作用时间进程与其β1 - 肾上腺素能受体阻断作用的时间进程相似，尽管硝苯地平和阿替洛尔联合用药的这些效应的时间进程不同。在清醒犬中，YM-16151-4（口服0.3 - 10mg/kg）也产生持久的降压作用，对HR和PQ间期几乎无影响。β1 - 肾上腺素能受体阻断作用的时间进程与其降压作用相似。此外，在10天重复口服给药期间，降压和β1 - 肾上腺素能受体阻断作用均未观察到耐受性或增强作用。总之，目前的结果表明YM-16151-4是一种有效且持久的降压药物，不增加HR和PRA。YM-16151-4的这些效应可能归因于其钙通道阻滞和β1 - 肾上腺素能受体阻断活性，且单次和重复口服给药后两种活性的比例恒定。
