Gβγ subunit activation of K _V 7 and BK _Ca channels underlies calcitonin gene‐related peptide vasorelaxation in myogenic rat coronary resistance arteries

Abstract Background and Purpose CGRP is a potent, clinically relevant coronary vasodilator known to play a role in cardioprotection. Here, we investigated the precise intracellular signalling pathways leading to vasodilation in small coronary arteries. Experimental Approach This study used ex vivo myography and intracellular recording techniques to investigate α‐CGRP‐induced vasorelaxation and vascular smooth muscle cell (VSMC) hyperpolarization in myogenically active rat isolated coronary arteries. Key Results CGRP‐induced vasorelaxation was not dependent on the endothelium, but relied heavily on K + channel activation. Immunohistochemistry indicated K V 7 and BK Ca channel expression in VSMC and endothelial cells. A combination of the K V 7 channel inhibitor, linopirdine and the BK Ca channel inhibitor, paxilline, significantly attenuated CGRP‐induced vasorelaxation in endothelium‐intact or denuded arteries. Electrophysiology confirmed that CGRP caused hyperpolarization and showed this was prevented by linopirdine and paxilline, also demonstrating a role for K V 7 and BK Ca channels in suppressing depolarizing smooth muscle spikes. These spikes were also suppressed by NO• and HNO donors, resulting in hyperpolarization. Gβγ subunit inhibition with gallein markedly right‐shifted CGRP‐induced vasorelaxation in both endothelium‐intact and denuded coronary arteries. Conclusion and Implications α‐CGRP stimulates robust vasorelaxation in the coronary microvasculature that relies on Gβγ subunit‐activated VSMC hyperpolarization involving K V 7 and BK Ca channels. These data enhance understanding of coronary microvascular physiology and inform the design of future therapeutic strategies targeting coronary vascular dysfunction.