Vascular smooth muscle actions of carnosine as its zinc complex are mediated by histamine H_1 and H_2 receptors

摘要

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 maximum carnosine-induced tension (to 127 +- 13% of control at 10 #mu#M Zn_(total)) and musele sensitivity is potentiated (mean K_0.5 reduced from 1.23 mM to 17 #mu#M carnosine with 15 #mu#M Zn_(total)). The dipeptide acts as a Zinc-carnosine complex (Zn centre dot Carn). The effects of carnosine 1 #mu#M -10 mM (total) in the presence of 1-100 #mu#M Zn~(2+) (total) can be described as a unique function of [Zn centre dot Carn] with an apparent K_0.5 for the complex of 7.4 centre dot 10~_8 M. Contractures are reduced at low [Ca~2+], unaffected by adrenoceptor antagonists, but can be blocked by antagonists to several receptor types. The most specific effect is by mepyramine, the H_1 receptor antagonist. With Zn present, carnosine can inhibit the H_1-specific binding of [~3H]-mepyramine to isolated Guinea pig cerebellar membranes. This effect of carnosine can be descrbed as a function of the concentration of Zn centre dot Carn with an apparent IC_50 of 2.45 #mu#M. Like histamine, carnosine evoked an H_2-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 release from adventitial mast cells which 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 H_1-receptor to provoke vasoconstricition and that it also has the potential to act at H_1-receptors in CNS. 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.