R-(-)-ALPHA-METHYL-HISTAMINE HAS NITRIC OXIDE-MEDIATED VASODILATOR ACTIVITY IN THE MESENTERIC VASCULAR BED OF THE CAT

Responses to the histamine H-3 receptor agonist R-(-)-alpha-methyl-his tamine were investigated in the mesenteric vascular bed of the cat und er constant-flow conditions. Injections of R-(-)-alpha-methyl-histamin e and histamine caused dose-related decreases in mesenteric perfusion pressure with R-(-)-alpha-methyl-histamine being 1000-fold less potent than histamine when doses were compared on a nmol basis to take molec ular weight into account. Responses to R-(-)-alpha-methyl-histamine we re not altered by histamine H-1 or H-2 receptor antagonists at a time when responses to histamine were significantly reduced. The histamine H-3 receptor antagonist thioperamide reduced responses to R-(-)-alpha- methyl-histamine but was without effect on responses to histamine ino] -N-(4-trifluoromethylphenyl)heptanecardoxamide dimaleate] (HTMT), or d imaprit. These data suggest the presence of histamine H-1, H-2 and H-3 receptors mediating vasodilation in the mesenteric vascular bed. Resp onses to R-(-)-alpha-methyl-histamine and histamine were reduced by th e nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl este r (L-NAME) but were not altered by the cyclooxygenase inhibitor meclof enamate, the alpha-adrenoceptor blocker phentolamine, or adrenergic ne rve terminal depleting agent reserpine. The present data suggest that histamine H-3 receptors mediating vasodilation are present in the mese nteric vascular bed and that responses are mediated by the release of nitric oxide but not vasodilator prostaglandins or an effect on the ad renergic nervous system. These results indicate that vasodilator respo nses to histamine involve the activation of histamine H-1 and H-2 rece ptors and the release of nitric oxide in the mesenteric vascular bed o f the cat. (C) 1998 Elsevier Science B.V.