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

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 BKCa and of HO/CO in the endothelium-dependent dilatation of mesenteric arteries in ascitic cirrhotic rats. In pressurized mesenteric arteries (diameter, 170-350 mu m) of ascitic cirrhotic rats, we evaluated the effect of inhibition of BKCa, HO, and guanylylcyclase on dilatation induced by acetylcholine and by exogenous CO; and HO-1 and BKCa subunit protein expression. Inhibition of HO and of BKCa 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 BKCa inhibition. The expression of HO-1 and of BKCa alpha-subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BKCa alpha 1-subunit was lower. In conclusion, an overexpression of BKCa 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.