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Vascular Smooth Muscle Actions of Carnosine as Its Zinc Complex Are Mediated by Histamine H1 and H2 Receptors

D. J. Miller* and A. O'Dowd

Clinical Research Initiative in “Heart Failure”, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow G12 8QQ, Scotland, UK; E-mail: D.J.Miller@bio.gla.ac.uk

* To whom correspondence should be addressed.

Received March 20, 2000
The endogenous dipeptide carnosine (beta-alanyl-L-histidine), at 0.1-10 mM, can provoke sustained contractures in rabbit saphenous vein rings with greater efficacy than noradrenaline. The effects are specific; anserine and homocarnosine are ineffective, as are carnosine's constituent amino acids histidine and beta-alanine. Zinc ions enhance the maximum carnosine-induced tension (to127 ± 13% of control at 10 µM Zntotal) and muscle sensitivity is potentiated (mean K0.5 reduced from 1.23 mM to 17 µM carnosine with 15 µM Zntotal). The dipeptide acts as a Zn-carnosine complex (Zn·Carn). The effects of carnosine at 1 µM-10 mM (total) in the presence of 1-100 µM Zn2+ (total) can be described as a unique function of [Zn·Carn] with an apparent K0.5 for the complex of 7.4·10-8 M. Contractures are reduced at low [Ca2+], unaffected by adrenoceptor antagonists, but can be blocked by antagonists to several receptor types. The most specific effect is by mepyramine, the H1 receptor antagonist. With Zn present, carnosine can inhibit the H1-specific binding of [3H]mepyramine to isolated Guinea pig cerebellar membranes. This effect of carnosine can be described as a function of the concentration of Zn·Carn with an apparent IC50 of 2.45 µM. Like histamine, carnosine evoked an H2-mediated (cimetidine-sensitive) relaxation in the presence of mepyramine, but was less potent (10.8 ± 3.1% of initial tension remaining at 10 mM carnosine compared with 13.4 ± 7.5% remaining at 0.1 mM histamine). Preliminary studies with a Zn-selective fluorescent probe indicate that functionally significant levels of Zn can be released from adventitial mast cells that could modulate actions of carnosine in the extravascular space as well as those of histamine itself. 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 the central nervous system. Carnosine's mode of action is virtually unique: a vascular muscle receptor apparently transduces the action of a dipeptide in the form of a metal chelate. The functional relationship of carnosine with histamine and the possible physiological relevance of Zn ions for the activity of both agents have not previously been reported.
KEY WORDS: carnosine, zinc, vascular smooth muscle, histamine receptors