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Carbon monoxide-mediated activation of large-conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats.

Bolognesi M, Sacerdoti D, Piva A, Di Pascoli M, Zampieri F, Quarta S, Motterlini R, Angeli P, Merkel C, Gatta A

Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy. massimo.bolognesi@unipd.it

Large-conductance calcium-activated potassium channels (BK(Ca)s) are important regulators of arterial tone and represent a mediator of the endogenous vasodilator carbon monoxide (CO). Because an up-regulation of the heme oxygenase (HO)/CO system has been associated with mesenteric vasodilatation of cirrhosis, we analyzed the interactions of BK(Ca) and of HO/CO in the endothelium-dependent dilatation of mesenteric arteries in ascitic cirrhotic rats. In pressurized mesenteric arteries (diameter, 170-350 microm) of ascitic cirrhotic rats, we evaluated the effect of inhibition of BK(Ca), HO, and guanylyl-cyclase on dilatation induced by acetylcholine and by exogenous CO; and HO-1 and BK(Ca) subunit protein expression. Inhibition of HO and of BK(Ca) reduced acetylcholine-induced vasodilatation more in cirrhotic rats than in control rats, whereas inhibition of guanylyl-cyclase had a similar effect in the two groups. CO was more effective in cirrhotic rats than in control rats, and the effect was hindered by BK(Ca) inhibition. The expression of HO-1 and of BK(Ca) alpha-subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BK(Ca) beta1-subunit was lower. In conclusion, an overexpression of BK(Ca) alpha-subunits, possibly due to HO up-regulation with increased CO production, participates in the endothelium-dependent alterations and mesenteric arterial vasodilatation of ascitic cirrhotic rats.

Published 19 March 2007 in J Pharmacol Exp Ther, 321(1): 187-94.
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