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.[1]References
- Analysis of an H1 receptor-mediated, zinc-potentiated vasoconstrictor action of the histidyl dipeptide carnosine in rabbit saphenous vein. O'Dowd, A., Miller, D.J. Br. J. Pharmacol. (1998) [Pubmed]
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