Analysis of an H1 receptor-mediated, zinc-potentiated vasoconstrictor action of the histidyl dipeptide carnosine in rabbit saphenous vein.
The contractile action of the dipeptide carnosine (beta-alanyl-L-histidine), active as a Zn.carnosine complex (Zn. Carn), was investigated in isolated rings of rabbit saphenous vein (RSV) and was found to be antagonized by the H1 antagonist mepyramine. Mepyramine-sensitive, histamine-induced contractures in RSV, were smaller (73+/-0.1%) and less well sustained than carnosine-induced contractures. Schild plot values for mepyramine antagonism were, for carnosine-induced contractures; pA2 = 7.97+/-0.12, slope= 1.33+/-0.06 (r = 0.793) and for histamine-induced contractures; pA2 = 8.48+/-0.07, slope = 0.63+/-0.05, r = 0.957). Serotonergic antagonists methiothepin and ketanserin, antagonize both carnosine- and histamine-induced contractures in RSV, probably reflecting coincidental inhibition at the H1-receptor. Carnosine, with Zn present, can inhibit the H1-specific binding of [3H]-mepyramine to isolated guinea-pig cerebellar membranes (log IC50s - 2.78+/-0.02, -3.93+/-0.03 and -4.64+/-0.03 at 10, 30 and 80 microM Zn respectively; values corrected for the Zn-specific inhibition which has a logIC50 of -4.20). In the radioligand binding assay, the effect of carnosine can be described as a function of Zn. Carn concentration with an apparent logIC50 of -5.61. This value is consistent with that obtained from the functional studies on RSV. Histamine-induced contractures have an indomethacine-sensitive component (27.2+/-8.3% of control response), not apparent with carnosine-induced contractures. Like histamine, carnosine evoked an H2-mediated (cimetidine-sensitive) relaxation in the presence of mepyramine, but was less potent (10.8+/-3.1% residual tension at 10 mM carnosine compared with 13.4+7.5% at 0.1 mM histamine). Carnosine, like mepyramine, can 'reveal' the H2-mediated relaxation of histamine providing further evidence that carnosine binds at the H1 receptor. We conclude that carnosine can act at the smooth muscle H1-receptor to provoke vasoconstriction and that it also has the potential to act at H1-receptors in CNS.
O'Dowd
A
A
MRC Clinical Research Initiative in Heart Failure and Institute of Biomedical & Life Sciences, University of Glasgow.
Miller
D J
DJ
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002336:Carnosine / Q000378:metabolism / Q000494:pharmacology*; D002927:Cimetidine / Q000494:pharmacology; D004347:Drug Interactions; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008719:Methiothepin / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D011738:Pyrilamine / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000502:physiology*; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology; D012501:Saphenous Vein / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure*; D012702:Serotonin Antagonists / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D015032:Zinc / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D012702:Serotonin Antagonists; D014662:Vasoconstrictor Agents; D008719:Methiothepin; D002927:Cimetidine; D006632:Histamine; D002336:Carnosine; D007650:Ketanserin; D011738:Pyrilamine; D015032:Zinc; D007213:Indomethacin