Gβγ subunit activation of KV7 and BKCa channels underlies calcitonin gene-related peptide vasorelaxation in myogenic rat coronary resistance arteries.

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 KV7 and BKCa channel expression in VSMC and endothelial cells. A combination of the KV7 channel inhibitor, linopirdine and the BKCa 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 KV7 and BKCa 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 KV7 and BKCa channels. These data enhance understanding of coronary microvascular physiology and inform the design of future therapeutic strategies targeting coronary vascular dysfunction.