Large-conductance K+ channel opener CGS7184 as a regulator of endothelial cell function.

摘要

Large-conductance Ca(2+)-activated potassium (BK(Ca)) channels are present in endothelium, but their regulatory role remains uncharacterized. The aim of the present study was to investigate the pharmacological effects of the BK(Ca) channel opener ethyl-1-[[(4-chlorophenyl)amino]oxo]-2-hydroxy-6-trifluoromethyl-1H-indole-3-carb oxylate (CGS7184) on endothelium in the aorta and coronary circulation, particularly with regard to nitric oxide (NO)-dependent regulation of vascular tone, as well as effects of CGS7184 on NO production, calcium homeostasis, and mitochondrial function in cultured endothelial cells. The vasorelaxant action of CGS7184 was studied in coronary circulation and in the aorta using isolated perfused guinea pig heart and rat aortic rings, respectively. The effects of CGS7184 on calcium homeostasis, mitochondrial membrane potential, NO production, and mitochondrial respiration were tested in cultures of EA.hy 926 endothelial cells. The BK(Ca) channel opener CGS7184 caused a concentration-dependent (0.03-3 microM) relaxation of the rat aorta and coronary vasodilatation in the isolated guinea pig heart. Both responses were profoundly inhibited by the nitric oxide (NO) synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) (100 microM). CGS7184 (5 microM) also increased basal NO production in EA.hy 926 cells by approximately two-fold. Moreover, CGS7184 induced a concentration-dependent (0.1-10 microM) elevation in intracellular calcium concentration. Interestingly, CGS7184 affected mitochondrial function by causing mitochondrial potential depolarization and an increase in oxygen consumption in EA.hy 926 endothelial cells. The BK(Ca) channel opener CGS7184 activates NOS pathways and modulates mitochondrial function in the endothelium. Both effects may be triggered by the CGS7184-induced modulation of intracellular Ca(2+) homeostasis in EA.hy 926 endothelial cells.