NITRIC-OXIDE INHIBITION ATTENUATES SYSTEMIC HYPOTENSION PRODUCED BY PROTAMINE

Background: Protamine reversal of heparin anticoagulation often causes systemic hypotension, and in vitro studies suggest that this may be m ediated by release of nitric oxide from the endothelium. The present i nvestigations were designed to evaluate the direct myocardial effects of protamine and to determine in vivo whether nitric oxide inhibition can prevent hypotension during protamine infusion. Methods/Results: Pr otamine sulfate (50 mu g/ml) was added to perfusate of eight isolated rabbit heart preparations; in six other preparations, a similar concen tration of protamine was added to heparinized (5 U/ml) Krebs perfusate . Left ventricular developed pressure, maximum rate of pressure rise, and heart rate declined significantly (p < 0.01) in hearts exposed to protamine only (65.0% +/- 6.6%, 55.5% +/- 6.0%, and 87.6% +/- 2.5% of baseline, respectively), whereas protamine added to heparinized perfus ate caused little change in developed pressure, maximum rate of pressu re rise, and heart rate (85.3% +/- 5.4%, 84.9% +/- 5.5%, and 98.8% +/- 1.6%). To study systemic effects of protamine, we measured hemodynami c parameters in 12 heparinized dogs (150 U/kg). During protamine infus ion (1.5 mg/kg intravenously over 30 seconds), mean blood pressure dec reased by 46% +/- 7% from baseline (p < 0.05), cardiac output decrease d by 38% +/- 4% (p < 0.05), and systemic vascular resistance decreased by 14% +/- 9%. After hemodynamic stabilization, N-g-monomethyl-L-argi nine (2 mg/kg), a competitive inhibitor of nitric oxide synthesis, was administered to six dogs, and methylene blue (2 mg/kg), an inhibitor of cyclic guanosine monophosphate synthesis, was administered to the r emaining six dogs. After treatment with N-g-monomethyl-L-arginine and methylene blue, the second infusion of protamine sulfate caused no sig nificant change in blood pressure or cardiac output. In an additional six dogs, N-g-monomethyl-L-arginine pretreatment (5 mg/kg) blocked the effects of the first dose of protamine. The effect of N-g-monomethyl- L-arginine could be reversed by the addition of (5 mg/kg) L-arginine h ut not D-arginine. Conclusions: Protamine-heparin complex does not cau se direct myocardial depression but does lead to severe hypotension in vivo. The finding that hypotension can be blocked by inhibitors of th e nitric oxide pathway confirms previous in vitro studies indicating t hat the effects of protamine are mediated, in part, by the vascular en dothelium. Further, these studies suggest a novel approach to preventi on of hemodynamic complications caused by heparin reversal after cardi opulmonary bypass.