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

Background and aims: The 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. Methods: The 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. Results: The 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 beta 1 subunit expression were increased in arteries from OZR. Conclusions: The present study suggests that an enhanced activity of VSM BKCa channels, associated with up-regulation of channel b1 subunit and with a higher intracellular Ca2+ mobilization, contributes to the preserved NO-mediated vasodilatation and basal tone of coronary arteries in obesity. (C) 2017 Elsevier B.V. All rights reserved.