PROTAMINE INDUCES ENDOTHELIUM-DEPENDENT VASODILATATION OF THE PULMONARY-ARTERY

Background. Protamine sulfate, which is used for heparin neutralizatio n, has been reported to induce catastrophic pulmonary vasoconstriction after infusion. However, in the systemic circulation, protamine infus ion induces hypotension due to peripheral vasodilatation. Methods. To determine whether protamine also could induce vasodilatation in the pu lmonary circulation, third-order canine pulmonary artery segments were studied in vitro in organ chambers. Results. In pulmonary artery segm ents that were caused to contract with phenylephrine (10(-5) mol/L), p rotamine sulfate (40 to 400 mu g/mL, final organ bath concentration) p roduced concentration-dependent relaxation in canine pulmonary artery segments with endothelium (to 74% +/- 7% of the initial contraction to phenylephrine) that was significantly greater (p < 0.05) than in segm ents without endothelium (30% +/- 6% of the initial phenylephrine cont raction). Pretreatment of arterial segments with N-G-monomethyl-L-argi nine (10(-5) mol/L), the competitive inhibitor of nitric oxide synthes is from L-arginine, did not change tension of arterial segments, but N -G-monomethyl-L-arginine attenuated the relaxation to protamine. The i nhibitory effect of N-G-monomethyl-L-arginine could be reversed by the addition of L-arginine (10(-4) mol/L) but not D-arginine (10(-4) mol/ L). Endothelium-dependent vasodilation to protamine (40 to 400 mu g/mL ) also could be inhibited by heparin (8 U/mL, final organ bath concent ration). However, the inhibitory effect of heparin could be overcome b y adding higher concentrations of protamine. Conclusions. Protamine-me diated pulmonary vasodilatation could be an important mechanism to pro tect against the constrictive effects of autocoids generated during he parin neutralization. Such a mechanism might be dysfunctional in certa in persons and put them at risk for pulmonary vasoconstriction after p rotamine infusion.