Role of heparin and nitric oxide in the cardiac and regional hemodynamic properties of protamine in conscious chronically instrumented dogs

Background: Because protamine is administered to reverse heparin, a drug th at might itself affect the pharmacologic properties of protamine, this stud y was designed to assess the properties of protamine alone and in the prese nce of heparin in conscious dogs. Methods: Twelve dogs were instrumented to continuously record cardiac and r egional 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 protam ine (8 mg/kg) in the absence of heparin on a separate occasion. Results: Protamine alone produced limited cardiac and regional changes. In the presence of heparin, protamine produced hypotension at 3, 5, and 8 mg/k g, vasodilatation at 3 and 5 mg/kg, and a more pronounced dose-dependent in crease in pulmonary pressure at 3, 5, and 8 mg/kg. Simultaneously, transien t carotid vasodilatation at 3 and 5 mg/kg, coronary and hepatic vasodilatat ion at 3, 5, and 8 mg/kg, as well as a decrease in vertebral vascular resis tance were recorded at i, 3, and 8 mg/kg. Protamine produced an immediate i ncrease followed by a secondary decrease in renal vascular resistance. Prot amine-induced secondary pulmonary presser effects were attenuated. In the p resence of heparin, nitric oxide synthase blockade selectively attenuated p rotamine-induced immediate hypotension, systemic vasodilatation, and corona ry, mesenteric, and hepatic vasodilations as well as the decrease in portal blood now and accentuated the renal vasoconstriction. Conclusions: The presence of heparin accentuated the decrease in cardiac fu nction 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.