TY - JOUR T1 - Activation of Large Conductance, Calcium-Activated K Channels by Nitric Oxide Mediates Apelin-Induced Relaxation of Coronary Arteries JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.248682 SP - jpet.118.248682 AU - Amreen Mughal AU - Chengwen Sun AU - Stephen T O'Rourke Y1 - 2018/01/01 UR - http://jpet.aspetjournals.org/content/early/2018/05/17/jpet.118.248682.abstract N2 - Apelin increases coronary blood flow, cardiac contractility and cardiac output. Based on these favorable hemodynamic effects, apelin and apelin-like analogs are being developed for treating heart failure and related disorders; however, the molecular mechanisms underlying apelin-induced coronary vasodilation are unknown. This study aimed to elucidate the signaling pathways by which apelin causes smooth muscle relaxation in coronary arteries. Receptors for apelin (APJ receptors) were expressed in coronary arteries, as determined by Western blot and PCR analyses. Immunofluorescence imaging studies identified APJ receptors on endothelial and smooth muscle cells. In isolated endothelial cells, apelin caused an increase in DAF-2 fluorescence that was abolished by nitro-l-arginine (NLA) and F13A, an APJ receptor antagonist, consistent with increased NO production. In arterial rings, apelin caused endothelium-dependent relaxations that were abolished by NLA, F13A, and iberiotoxin. Neither ODQ nor DT-2, a protein kinase G inhibitor, had any effect on apelin-induced relaxations, and apelin itself had no effect on intracellular cGMP accumulation in coronary arteries. Patch clamp studies in isolated smooth muscle cells demonstrated that the NO donors, DEA NONOate and sodium nitroprusside, caused increases in large conductance, calcium-activated K (BKCa) currents, which were inhibited by iberiotoxin but not ODQ. Thus, apelin causes endothelium-dependent relaxation of coronary arteries by stimulating endothelial APJ receptors and releasing NO, which acts in a cGMP-independent manner and increases BKCa activity in the underlying smooth muscle cells. The results provide a mechanistic basis for apelin-induced coronary vasodilation and may provide guidance for the future development of novel apelin-like therapeutic agents. ER -