Shibasaki K, Uchida W, Takizawa K, Masuda N, Okazaki T, Inagaki O, Asano M, Takenaka T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Biol Pharm Bull. 1997 Mar;20(3):230-6. doi: 10.1248/bpb.20.230.
We evaluated the cardiovascular effects of YM430, a novel 1,4-dihydropyridine derivative with beta-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 micrograms/kg i.v.)-induced tachycardia. These two effects of YM430 may be attributable to its calcium entry blocking and beta(1)-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 (beta(1)-adrenoceptor blocking effect). These results indicate that the ratio of the two activities (calcium entry blocking and beta(1)-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.
我们评估了新型1,4 - 二氢吡啶衍生物YM430对犬和大鼠的心血管作用，该衍生物具有β - 肾上腺素受体阻断活性。在麻醉犬中，静脉注射YM430（0.01 - 0.3mg/kg）可剂量依赖性地降低平均血压、总外周阻力和双乘积，且不增加心率。静脉注射YM430（0.01 - 0.3mg/kg）可增加冠状动脉以及椎动脉血流量，而对颈动脉、肠系膜动脉、股动脉和肾动脉血流量的影响较小。在产生血管舒张作用的相同剂量范围内，YM430对最大dp/dt或PQ间期几乎没有影响。在清醒犬中，静脉注射YM430（0.1 - 1mg/kg）可产生剂量依赖性低血压并伴有心动过速。在清醒大鼠中，口服YM430（100mg/kg）可产生持久的降压作用并伴有轻微心动过速。YM430还可抑制异丙肾上腺素（0.1μg/kg静脉注射）诱导的心动过速。YM430的这两种作用可能分别归因于其钙通道阻滞和β(1) - 肾上腺素受体阻断活性。口服给药后YM430的降压（钙通道阻滞）作用的时间进程与其对异丙肾上腺素诱导的心动过速的抑制作用（β(1) - 肾上腺素受体阻断作用）非常相似。这些结果表明，口服给药后YM430的两种活性（钙通道阻滞和β(1) - 肾上腺素受体阻断）的比例是恒定的。总之，由于YM430具有双重活性，它可能既是一种抗心绞痛药物又是一种抗高血压药物。
