Underlying mechanisms preserving coronary basal tone and NO-mediated relaxation in obesity: Involvement of β1 subunit-mediated upregulation of BK 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 BK channels in the NO-mediated coronary vasodilation in obesity remains to be elucidated.

METHODS

The effects of selective blockade of BK 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 Ca concentration ([Ca]) by Fura-2 fluorescence and tension in endothelium-denuded coronary arteries mounted in microvascular myographs. BK channel subunits expression was measured by Western blot.

RESULTS

The selective BK channel blocker iberitoxin largely reduced the relaxations and decreases in [Ca] induced by a NO donor in coronary arteries from OZR. Iberitoxin increased to a great extent both basal [Ca] and tone in OZR. The agonist of the voltage-gated L-type calcium channels Bay K8644 induced an increase in [Ca] and tone that was significantly smaller in arteries from OZR, which was restored to control levels in LZR after BK channel inhibition. Caffeine- and ryanodine-induced intracellular Ca mobilization and BK channel β1 subunit expression were increased in arteries from OZR.

CONCLUSIONS

The present study suggests that an enhanced activity of VSM BK channels, associated with up-regulation of channel β1 subunit and with a higher intracellular Ca mobilization, contributes to the preserved NO-mediated vasodilatation and basal tone of coronary arteries in obesity.