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Systemic hypotension is commonly observed in association with protamine administration after cardiopulmonary bypass. However, little information is available concerning the action of protamine on vascular smooth muscle. Thus, we investigated the action of protamine on vascular tissues using tension recording and microelectrode methods. Protamine (5–500 μg/ml) inhibited contractions induced by norepinephrine (NE)- or elevated K+ in a concentration-dependent manner in both endothelium-intact and -denuded strips. Protamine inhibition of NE contractions was less profound after endothelial denudation, whereas protamine inhibition of K+-induced contractions was less affected by prior denudation. In endothelium-intact strips, the protamine-induced inhibition was significantly reduced by inhibitors of the endothelium-derived relaxing factor pathway, including oxyhemoglobin, methylene blue, or NG-nitro-L-arginine, whereas the contractile inhibition was enhanced by superoxide dismutase. In endothelium-denuded strips, protamine inhibited Ca2+-induced contraction evoked in Ca2+-free solution containing 100 mM K+ and inhibited the NE-induced contraction under the following conditions: 1) in Ca2+-free solution; 2) after nifedipine treatment; and 3) after depletion of stored Ca2+ by A23187 or ryanodine. In membrane-permeabilized strips, protamine did not modify Ca2+-induced contraction. Protamine (50–500 μg/ml) did not modify the membrane potential of either endothelium-intact or -denuded strips. Furthermore, protamine irreversibly impaired acetylcholine-induced endothelium-dependent relaxant response, implying a toxic effect of protamine on the endothelium. We conclude that protamine exerts its inhibition on vascular smooth muscles in both an endothelium-dependent and -independent manner; i.e., the endothelium-dependent component is mediated probably by endothelium-derived relaxing factor, and direct smooth muscle effects are due to the inhibition of both Ca2+-influx and the NE-induced Ca2+ release from intracellular stores.