Thiopentone inhibits endothelium-dependent relaxations of rat aortas regulated by endothelial Ca2+-dependent K+...

The present study was designed to examine the mechanisms of inhibitory effect of barbiturates on endothelial function by determining whether thiopentone and phenobarbitone reduce relaxations to acetylcholine mediated by endothelial Ca2+-dependent K+ channels in rat aortas. Cumulative applications (10(-9) to 10(-5) M) of acetylcholine induced endothelium-dependent relaxations, which are abolished by inhibitors of nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 10(-4) M) and of soluble guanylate cyclase (1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one; ODQ, 5 x 10(-6) M). Selective inhibitors of large-conductance Ca2+-dependent K+ channels (iberiotoxin, 5 x 10(-8) M), but not of those with small-conductance (apamin, 5 x 10(-8) M), significantly reduced the acetylcholine-induced vasorelaxation. ODQ, but neither iberiotoxin nor apamin, blocked the relaxations of arteries without endothelium induced by nitric oxide donors, sodium nitroprusside (10(-9) to 10(-5) M) and 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10(-10) to 10(-5) M). Thiopentone (10(-4) and 3 x 10(-4) M) but not phenobarbitone (3 x 10(-4) M) significantly impaired relaxations to acetylcholine, whereas thiopentone did not alter relaxations to sodium nitroprusside. Thiopentone (3 x 10(-4) M) did not affect relaxations to acetylcholine in arteries treated with iberiotoxin (5 x 10(-8) M), whereas it reduced these relaxations in arteries treated with apamin (5 x 10(-8) M). These results suggest that in rat aortas, large-conductance, but not small-conductance, Ca2+-dependent K+ channels in endothelial cells, play a role in endothelium-dependent relaxations to acetylcholine, and that thiopentone, but not phenobarbitone, impairs relaxations to acetylcholine mediated by these channels.