A previous report showed that histamine in denuded mesenteric vascular beds produced a triphasic response; an initial small histamine H(2) receptor-mediated vasodilation, a transient histamine H(1) receptor-mediated vasoconstriction, and finally a long-lasting vasodilation. We further investigated the vascular effect of histamine in mesenteric preparations without an endothelium to clarify the possible involvement of perivascular nerves. Male Wistar rat mesenteric vascular beds without an endothelium were perfused with Krebs solution containing methoxamine to produce active tone and lafutidine to block histamine H(2) receptor-mediated vasodilation. Histamine (1-100μM) was perfused for 1min and perfusion pressure was measured with a pressure transducer. Histamine caused a biphasic vascular response; initial vasoconstriction followed vasodilation. Tetrodotoxin (a neurotoxin, 1μM) and procaine (a local anesthetic, 100μM) significantly inhibited the vasoconstriction and vasodilation. Ruthenium red (a transient receptor potential vanilloid 1 (TRPV1) antagonist, 1μM) also significantly inhibited both phases of the response. Pretreatment with capsaicin (a depletor of calcitonin gene-related peptide (CGRP)-containing nerves, 5μM) significantly inhibited the vasodilation without affecting the initial vasoconstriction. Both indomethacin (a cyclooxygenase inhibitor, 0.5μM) and seratrodast (a thromboxane A(2) receptor antagonist, 0.1μM) abolished the histamine-induced vasoconstriction and subsequent vasodilation. These results suggest that histamine-induced vasoconstriction and long-lasting vasodilation are mediated by activation of TRPV1 on capsaicin-sensitive and capsaicin-insensitive nerves. They also suggest that perivascular nerves and prostanoids, probably thromboxane A(2), are responsible for the vascular response to histamine.