Acute Hemodynamic Effects of Ciprokiren, a Novel Renin Inhibitor, in Sodium-Depleted Dogs

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Abstract
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.

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