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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Carbon Monoxide-Mediated Activation of Large-Conductance Calcium-Activated Potassium Channels Contributes to Mesenteric Vasodilatation in Cirrhotic Rats

Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy (M.B., D.S., A.P., M.D.P., F.Z., S.Q., P.A., C.M., A.G.); and Department of Surgical Research, Vascular Biology Unit, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom (R.M.)

Large-conductance calcium-activated potassium channels (BK_Cas) 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 µm) 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 -subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BK_Ca 1-subunit was lower. In conclusion, an overexpression of BK_Ca -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.

Address correspondence to: Dr. Massimo Bolognesi, Clinica Medica 5, Dipartimento di Medicina Clinica e Sperimentale, Policlinico Universitario, Via Giustiniani 2, 35128 Padova, Italy. E-mail: massimo.bolognesi{at}unipd.it

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