Role of small-conductance Ca2+-dependent K+ channels in in vitro nitric oxide-mediated aortic hyporeactivity to α-adrenergic vasoconstriction in rats with cirrhosis

Background/Aims: In vitro studies have shown, that cirrhotic aortas are hyporeactive to the contractile effect of vasoconstrictors because upregulated endothelial nitric oxide-synthase (NOS) overproduces nitric oxide (NO). Although stimulation of endothelial small-conductance Ca2+-dependent K+ (SKCa) channels may elicit vasorelaxation in normal arteries, the role of these channels in cirrhosis-induced hyporeactivity is unknown. Thus, the aim of the present study was to investigate the role of endothelial SKCa channels in cirrhosis-induced, NO-mediated, in vitro aortic hyporeactivity to alpha (1)-adrenergic vasoconstrictors. Methods: Isolated thoracic aortas from cirrhotic and normal rats were used. The effects of apamin, a selective SKCa channel blocker, were measured on the vascular reactivity to phenylephrine. In addition, SKCa channel protein expression was studied. The effects of iberiotoxin and charybdotoxin, blockers of other K-Ca channels, were also studied in cirrhotic aortas. Results: Apamin suppressed cirrhosis-induced aortic hyporeactivity to phenylephrine in an endothelium-dependent, NOS-inhibitor-sensitive manner. SKCa channel protein was overexpressed in cirrhotic aortic walls. Iberiotoxin abolished cirrhosis-induced aortic hyporeactivity to phenylephrine in an endothelium-dependent but NOS-inhibitor-resistant manner. Charybdotoxin did not induce any significant increase in phenylephrine-elicited contraction. Conclusions: In cirrhotic aortas, the overexpression and overactivity of endothelial SKCa channels contributes to in vitro NO-mediated hyporeactivity to the contractile action of alpha (1)-adrenergic agonists. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved.