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 alpha-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.