Role of Heparin and Nitric Oxide in the Cardiac and Regional Hemodynamic Properties of Protamine in Conscious Chronically Instrumented Dogs

Abstract

Because protamine is administered to reverse heparin, a drug that might itself affect the pharmacologic properties of protamine, this study was designed to assess the properties of protamine alone and in the presence of heparin in conscious dogs. Twelve dogs were instrumented to continuously record cardiac and regional hemodynamics. On separate occasions, a dose of protamine (0.5, 1, 3, 5, and 8 mg/kg) was randomly administered either alone or in the presence of heparin (ratio 100 IU/mg). Heparin (300 IU/kg) and protamine (3 mg/kg) were administered in the presence of N-methyl-L-arginine, a specific nitric oxide synthase inhibitor. Identical experiments were performed with protamine (8 mg/kg) in the absence of heparin on a separate occasion. Protamine alone produced limited cardiac and regional changes. In the presence of heparin, protamine produced hypotension at 3, 5, and 8 mg/kg, vasodilatation at 3 and 5 mg/kg, and a more pronounced dose-dependent increase in pulmonary pressure at 3, 5, and 8 mg/kg. Simultaneously, transient carotid vasodilatation at 3 and 5 mg/kg, coronary and hepatic vasodilatation at 3, 5, and 8 mg/kg, as well as a decrease in vertebral vascular resistance were recorded at 1, 3, and 8 mg/kg. Protamine produced an immediate increase followed by a secondary decrease in renal vascular resistance. Protamine-induced secondary pulmonary pressor effects were attenuated. In the presence of heparin, nitric oxide synthase blockade selectively attenuated protamine-induced immediate hypotension, systemic vasodilatation, and coronary, mesenteric, and hepatic vasodilations as well as the decrease in portal blood flow and accentuated the renal vasoconstriction. The presence of heparin accentuated the decrease in cardiac function induced by protamine as well as its effects on regional circulation. The data provide evidence that the nitric oxide pathway is involved in the systemic and selective regional heparin-protamine-mediated vasodilatation in conscious dogs.