Endothelium-dependent relaxation of rabbit middle cerebral artery to a histamine H3-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 H3-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 H3-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, NG-nitro-L-arginine methyl ester (L-NAME) and NG-monomethyl-L-arginine (L-NMMA), inhibited the relaxation induced by (R)-alpha-methylhistamine. The inhibitory effects of 10(-5) M NG-nitro-L-arginine methyl ester and 10(-5) M NG-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 H3-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.
Ea Kim
L
L
Laboratoire de Pharmacologie, UFR de Pharmacie, Limoges, France.
Javellaud
J
J
Oudart
N
N
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D002536:Cerebral Arteries / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects*; D011464:Epoprostenol / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008761:Methylhistamines / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000378:metabolism*; D011817:Rabbits; D011968:Receptors, Histamine / Q000187:drug effects*; D018100:Receptors, Histamine H3; D014191:Tranylcypromine / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*; D019323:omega-N-Methylarginine
D008761:Methylhistamines; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D014665:Vasodilator Agents; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D014191:Tranylcypromine; C069357:alpha-methylhistamine; D003907:Dexamethasone; D001120:Arginine; D011464:Epoprostenol; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin