NO release and the opening of K-ATP(+) channels mediate vasodilator responses to histamine in the cat

Responses to histamine were investigated in the hindlimb vascular bed of the cat under constant-flow conditions. Injections of histamine, the H-1 agonist HTMT, the H-2 agonist dimaprit, and the H-3 agonist R(-)-alpha-methylhistamine caused dose-related decreases in hindlimb perfusion pressure. Pyrilamine reduced the responses to histamine and HTMT by similar to 80%, whereas cimetidine reduced the responses to histamine by 20% and to dimaprit by similar to 50%. The H-3-receptor antagonist thioperamide reduced the responses to R(-)-alpha-methylhistamine by similar to 60% but was without effect on the other histamine agonists. These data suggest the presence of H-1, H-2, and H-3 receptors in the kindlimb vascular bed of the cat, that histamine acts, for the most part, by stimulating H-1 receptors, and that H-3-receptor activation is not involved in mediating the responses to histamine. The responses to histamine and the H-1-, H-2-, and H-3-receptor agonists were significantly reduced by a nitric oxide synthase inhibitor and enhanced in duration by the guanosine 3',5'-cyclic monophosphate (cGMP)-selective phosphodiesterase inhibitor zaprinast, suggesting that the responses are mediated, in part, by the release of nitric oxide and an increase in cGMP levels. The responses to histamine agonists but not to nitric oxide donors were significantly reduced by the nonselective K+-channel antagonist tetraethylammonium. The responses to histamine and the H-1,, H-2, and H-3 agonists were not affected by the cyclooxygenase inhibitor meclofenamate. The responses to histamine and HTMT are also reduced 30-50% by U-37883A, an ATP-sensitive K+ (K-ATP(+))-channel antagonist, at a time when the responses to the H-2 and H-3 agonists were unaltered. The present data suggest that vasodilation of the hindlimb vascular bed in response to H-1-, H-2-, and H-3-receptor activation is mediated by a tetraethylammonium-sensitive mechanism that is associated with the release of nitric oxide and an increase in cGMP levels. These data further suggest that the response to H-1-receptor activation is mediated by the complementary, yet independent, release of nitric oxide and the opening of a K-ATP(+) channel.