title: Acute hemodynamic effects of ciprokiren, a novel renin inhibitor, in sodium-depleted dogs.
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.
authors.affiliation: Pharma Division, F. Hoffmann-La Roche, Basel, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
authors.forename: M
authors.initials: M
authors.lastname: Véniant
authors.forename: U
authors.initials: U
authors.lastname: Sprecher
authors.forename: W
authors.initials: W
authors.lastname: Fischli
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D007275:Injections, Intravenous; D012083:Renin / Q000097:blood; D012964:Sodium / Q000172:deficiency; D000092502:Renin Inhibitors
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D012083:Renin; D012964:Sodium; D000092502:Renin Inhibitors; C085570:ciprokiren