Underlying mechanisms preserving coronary basal tone and NO-mediated relaxation in obesity: Involvement of β1 subunit-mediated upregulation of BKCa channels

Abstract

Background and aimsThe impact of obesity on vasomotor regulation of coronary arteries and its underlying mechanisms are not completely understood and, in particular, the role of BKCa channels in the NO-mediated coronary vasodilation in obesity remains to be elucidated. MethodsThe effects of selective blockade of BKCa channel was tested on nitric oxide (NO)-mediated vasodilator responses of coronary arteries from lean and obese Zucker rats (LZR and OZR, respectively) by means of simultaneous measurements of intracellular Ca2+ concentration ([Ca2+]i) by Fura-2 fluorescence and tension in endothelium-denuded coronary arteries mounted in microvascular myographs. BKCa channel subunits expression was measured by Western blot. ResultsThe selective BKCa channel blocker iberitoxin largely reduced the relaxations and decreases in [Ca2+]i induced by a NO donor in coronary arteries from OZR. Iberitoxin increased to a great extent both basal [Ca2+]i and tone in OZR. The agonist of the voltage-gated L-type calcium channels Bay K8644 induced an increase in [Ca2+]i and tone that was significantly smaller in arteries from OZR, which was restored to control levels in LZR after BKCa channel inhibition. Caffeine- and ryanodine-induced intracellular Ca2+ mobilization and BKCa channel β1 subunit expression were increased in arteries from OZR. ConclusionsThe present study suggests that an enhanced activity of VSM BKCa channels, associated with up-regulation of channel β1 subunit and with a higher intracellular Ca2+ mobilization, contributes to the preserved NO-mediated vasodilatation and basal tone of coronary arteries in obesity.