Acute pulmonary vasoconstriction and thromboxane release during protamine reversal of heparin anticoagulation in awake sheep. Evidence for the role of reactive oxygen metabolites following nonimmunological complement activation

Abstract

When protamine (2 mg/kg) was injected intravenously into awake sheep 5 minutes after infusing heparin (200 units/kg), there was transient diffuse pulmonary vasoconstriction with mean pulmonary arterial pressure increasing from 18.0 ± 0.7 to 43.8 ± 2.7 mm Hg at 1 minute (x ± SEM; n = 10). In addition, there was profound leukopenia (36.9 ± 7.7% of baseline values at 2 minutes) with transpulmonary leukocyte sequestration and transiently elevated plasma concentrations of C3a (from 420 ± 146 to 1,599 ± 249 ng/ml; n = 3, p < 0.01) and thromboxane B2 (from 0.30 ± 0.05 to 6.3 ± 2.8 ng/ml; n = 10, p < 0.0001), without significant increases of plasma 6-keto-prostaglandin F(1α), prostaglandin F(2α), leukotrienes, or histamine. Intravenous injection of protamine alone produced no hemodynamic effects and did not increase plasma levels of vasoconstrictor eicosanoids. Intravenous pretreatment with either a cyclooxygenase inhibitor or a hydrogen peroxide scavenger (dimethylthiourea) blocked both the increases of thromboxane levels and the pulmonary vasoconstriction.