ENDOTHELIUM-DEPENDENT RELAXATION OF RABBIT MIDDLE CEREBRAL-ARTERY TO A HISTAMINE H-3 AGONIST IS REDUCED BY INHIBITORS OF NITRIC-OXIDE AND PROSTACYCLIN SYNTHESIS

1 The possible involvement of prostanoids and endothelium-derived relaxing factor (EDRF) in the vasodilatation induced by a histamine H-3-agonist was examined in the rabbit perfused middle cerebral artery preconstricted with K+ (50 mM). 2 The endothelium-dependent relaxation to (R)-alpha-methylhistamine [(R)-alpha-MeHA] was competitively antagonized by thioperamide (an H-3-antagonist) with a pA2 of 9.05, but unaffected by propranolol, atropine, L- and D-sulpiride. This effect was stereoselective since the (S)-isomer was 100 times less potent than the (R)-isomer. 3 Two inhibitors of nitric oxide synthesis, N(G)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-L-arginine (L-NMMA), inhibited the relaxation induced by (R)-alpha-methylhistamine. The inhibitory effects of 10(-5) M N(G)-nitro-L-arginine methyl ester and 10(-5) M N(G)-monomethyl-L-arginine were reversed by equimolar concentrations of L-arginine, but strongly enhanced by 10(-4) M tranylcypromine. Tranylcypromine alone (10(-5) M-10(-4) M) partially reduced the (R)-alpha-methylhistamine-induced relaxation. Both dexamethasone and indomethacin also inhibited this relaxation. 4 The results suggest that the H-3-mediated relaxation of the rabbit middle cerebral artery may involve release of both a prostanoid, probably prostacyclin, and endothelium-derived relaxing factor. The relaxant effects of these two endogenous compounds appear to be synergistic.