Large‐conductance calcium‐activated potassium channels modulate vascular tone in experimental cirrhosis

Background: Large‐conductance calcium‐activated potassium (BK_Ca) channels regulate vascular tone in different vascular systems. Moreover, activated hepatic stellate cells (HSC) contain BK_Ca channels. The aim of this study was to evaluate the role of BK_Ca channels in the regulation of vascular tone in control (CT) and carbon tetrachloride‐cirrhotic (CH) rat livers. Methods: Changes in intrahepatic vascular resistance were assessed by evaluating the portal perfusion pressure (PP) response to methoxamine (Mtx) in the presence of Iberiotoxin (Ibtx; a BK_Ca channel blocker), NS1619 (a BK_Ca channel opener), Ibtx plus the nitric oxide (NO) synthase inhibitor, N^G‐nitro‐l ‐arginine (l ‐NNA) or l ‐NNA alone. In addition, in CH livers, PP dose–response curves to the NO donor, S‐nitroso‐N‐acetyl‐d,l ‐penicillamine (SNAP), were performed after pre‐incubation with Ibtx or its vehicle. BK_Ca mRNA expression was assessed in liver homogenates, and BK_Ca protein expression in HSC isolated from CT and CH livers. Results: In CH livers, Ibtx significantly increased baseline PP and exacerbated the PP response to Mtx. Conversely, NS1619 induced a mild nonsignificant decrease of baseline PP and attenuated the hyperresponse to Mtx. CH livers exhibited an upregulation of both mRNA and protein of the α‐subunit of BK_Ca. Conclusion: Large‐conductance calcium‐activated potassium channels are overexpressed in CH livers and might represent a compensatory mechanism modulating the increased hepatic vascular tone of cirrhosis.