Clozel J P, Véniant M, Sprecher U, Fischli W
Pharma Division, F. Hoffmann-La Roche, Basel, Switzerland.
J Cardiovasc Pharmacol. 1995 Oct;26(4):674-7. doi: 10.1097/00005344-199510000-00025.
We evaluated the acute hemodynamic effects of ciprokiren (Ro 44-9375), a new potent renin inhibitor, in sodium-depleted dogs. After dogs were sodium depleted by administration of furosemide, they were anesthetized, and effects of increasing doses of ciprokiren (0.1-3 mg/kg) or placebo on arterial blood pressure (BP), cardiac output (CO), coronary blood flow (CBF), left ventricular (LV) + dP/dtmax, and plasma renin activity (PRA) were evaluated. Ciprokiren dose-dependently decreased arterial BP and peripheral vascular resistance (PVR), beginning at the 0.1-mg/kg dose and having maximal effect at 1 mg/kg. Ciprokiren did not change heart rate (HR), LV + dP/dtmax or coronary vascular resistance. Finally, a maximal effective dose of an angiotensin-converting enzyme (ACE) inhibitor (cilazapril 1.0 mg/kg intravenously, i.v.) had no additional hemodynamic effect. At 0.1 mg/kg ciprokiren, arterial BP was reduced, with no change in PRA, showing the dissociation between hemodynamic effects and inhibition of renin in plasma. Acutely, renin inhibition with ciprokiren produces a marked peripheral vasodilation which appears to be dissociated from the renin inhibition in plasma and which is not increased by additional ACE inhibition.
我们评估了新型强效肾素抑制剂西普罗瑞林（Ro 44 - 9375）对钠缺乏犬的急性血流动力学影响。通过给予呋塞米使犬钠缺乏后，将其麻醉，然后评估递增剂量的西普罗瑞林（0.1 - 3毫克/千克）或安慰剂对动脉血压（BP）、心输出量（CO）、冠状动脉血流量（CBF）、左心室（LV）+ dP/dtmax以及血浆肾素活性（PRA）的影响。西普罗瑞林剂量依赖性地降低动脉血压和外周血管阻力（PVR），从0.1毫克/千克剂量开始起效，在1毫克/千克时达到最大效应。西普罗瑞林未改变心率（HR）、LV + dP/dtmax或冠状动脉血管阻力。最后，血管紧张素转换酶（ACE）抑制剂（静脉注射西拉普利1.0毫克/千克）的最大有效剂量未产生额外的血流动力学效应。在0.1毫克/千克西普罗瑞林时，动脉血压降低，而PRA无变化，表明血流动力学效应与血浆中肾素抑制之间存在解离。急性情况下，西普罗瑞林抑制肾素会产生明显的外周血管舒张，这似乎与血浆中的肾素抑制无关，且不会因额外的ACE抑制而增强。
