Inhibition of vascular KATP channels by U-37883A:: a comparison with cardiac and skeletal muscle

1 The aim of this study was to investigate the selectivity of the ATP-sensitive potassium (K-ATP) channel inhibitor U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-1-cyclohexyl). Membrane currents through K-ATP channels were recorded in single muscle cells enzymatically isolated from rat mesenteric artery, cardiac ventricle and skeletal muscle (flexor digitorum brevis). K-ATP currents were induced either by cell dialysis with 0.1 mM ATP and 0.1 mM ADP, or by application of synthetic potassium channel openers (levcromakalim or pinacidil). 2 U-37883A inhibited K-ATP currents in smooth muscle cells from rat mesenteric artery. Half inhibition of 10 mu M levcromakalim-induced currents occurred at a concentration of 3.5 mu M. 3 Relaxations of rat mesenteric vessels caused by levcromakalim were reversed by U-37883A. 1 mu M levcromakalim-induced relaxations were inhibited at a similar concentration of U-37883A (half inhibition, 1.1 mu M) to levcromakalim-induced K-ATP currents. 4 K-ATP currents activated by 100 mu M pinacidil were also studied in single myocytes from rat mesenteric artery, skeletal muscle and cardiac ventricle. 10 mu M U-37883A substantially inhibited K-ATP currents in vascular cells, but had little effect in skeletal or cardiac myocytes. Higher concentrations of U-37883A (100 mu M) caused a modest decrease in K-ATP currents in skeletal and cardiac muscle. The sulphonylurea K-ATP channel antagonist glibenclamide (10 mu M) abolished currents in all muscle types. 5 The effect of U-37883A on vascular inward rectifier (K-IR) and voltage-dependent potassium (K-v) currents was also examined. While 10 mu M U-37883A had little effect on these currents, some inhibition was apparent at higher concentrations (100 mu M) of the compound. 6 We conclude that U-37883A inhibits K-ATP channels in arterial smooth muscle more effectively than in cardiac and skeletal muscle. Furthermore, this compound is selective for KATP channels over K-v and K-IR channels in smooth muscle cells.