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 indu ced by synthetic openers of ATP-sensitive K+ (K-ATP) channels is decreased in rats with cirrhosis, Since vasodilation induced by these substances is m ediated by membrane potential hyperpolarization in arterial smooth muscle c ells, membrane potential hyperpolarization in response to K-ATP channel ope ners may be altered in cirrhotic smooth muscle cells. The aim of the presen t study was to investigate the effects of K-ATP channel modulators (i.e. op eners and blockers of these channels) on the membrane potential in smooth m uscle cells in isolated aortae from cirrhotic and normal rats. The influenc e of endothelin-1 production by endothelial cells on smooth muscle cells me mbrane potential responses to K-ATP channel modulators was also studied. Methods: Cells were impaled in situ (in intact and endothelium-denuded aort ae) with a microelectrode that was used to measure membrane potentials. K-A TP channel openers were diazoxide or cromakalim; blockers were glibenclamid e or tolbutamide. Bosentan (a mixed endothelin receptor antagonist) and exo genous endothelin-1 were also used. Preproendothelin-1 mRNA was assayed in aortae by RNase protection assay. Aortic wall endothelin-1 concentration wa s measured by double antibody radioimmunoassay technique. Results: As expected, in smooth muscle cells in intact normal aortae, K-ATP channel openers induced membrane potential hyperpolarization and K-ATP cha nnel blockers membrane potential depolarization. In smooth muscle cells in intact cirrhotic aortae, K-ATP channel openers and blockers did not signifi cantly change the membrane potential. Endothelium removal or exposure of in tact aortae to bosentan restored normal membrane potential responses to K-A TP channel modulators in cirrhotic smooth muscle cells and did not alter th e effects of these substances in normal smooth muscle cells. In endothelium -denuded aortae, exposure to exogenous endothelin-1 suppressed membrane pot ential responses to K-ATP channel modulators. In intact aortae, the abundan ce of preproendothelin-1 mRNA and endothelin-1 did not significantly differ between normal and cirrhotic rats. Conclusions: K-ATP channel opener-induced membrane hyperpolarization and K- ATP channel blocker-elicited membrane depolarization are blunted in smooth muscle cells in intact cirrhotic aortae. This blunting is due to the activa tion of the endothelin-1 pathway in the aortic wall, downstream to the endo thelial production of endothelin-1.