Endothelium-dependent blunted membrane potential responses to ATP-sensitive K+ channel modulators in aortae from rats with cirrhosis

Background/Aims: In vivo studies have shown that arterial vasodilation induced by synthetic openers of ATP-sensitive K+ (KATP) channels is decreased in rats with cirrhosis. Since vasodilation induced by these substances is mediated by membrane potential hyperpolarization in arterial smooth muscle cells, membrane potential hyperpolarization in response to KATP channel openers may be altered in cirrhotic smooth muscle cells. The aim of the present study was to investigate the effects of KATP channel modulators (i.e. openers and blockers of these channels) on the membrane potential in smooth muscle cells in isolated aortae from cirrhotic and normal rats. The influence of endothelin-1 production by endothelial cells on smooth muscle cells membrane potential responses to KATP channel modulators was also studied. Methods: Cells were impaled in situ (in intact and endothelium-denuded aortae) with a microelectrode that was used to measure membrane potentials. KATP channel openers were diazoxide or cromakalim; blockers were glibenclamide or tolbutamide. Bosentan (a mixed endothelin receptor antagonist) and exogenous endothelin-1 were also used. Preproendothelin-1 mRNA was assayed in aortae by RNase protection assay. Aortic wall endothelin-1 concentration was measured by double antibody radioimmunoassay technique. Results: As expected, in smooth muscle cells in intact normal aortae, KATP channel openers induced membrane potential hyperpolarization and KATP channel blockers membrane potential depolarization. In smooth muscle cells in intact cirrhotic aortae, KATP channel openers and blockers did not significantly change the membrane potential. Endothelium removal or exposure of intact aortae to bosentan restored normal membrane potential responses to KATP channel modulators in cirrhotic smooth muscle cells and did not alter the effects of these substances in normal smooth muscle cells. In endothelium-denuded aortae, exposure to exogenous endothelin-1 suppressed membrane potential responses to KATP channel modulators. In intact aortae, the abundance of preproendothelin-1 mRNA and endothelin-1 did not significantly differ between normal and cirrhotic rats. Conclusions: KATP channel opener-induced membrane hyperpolarization and KATP channel blocker-elicited membrane depolarization are blunted in smooth muscle cells in intact cirrhotic aortae. This blunting is due to the activation of the endothelin-1 pathway in the aortic wall, downstream to the endothelial production of endothelin-1.