Potassium channels activated in the endothelium‐dependent hyperpolarization in guinea‐pig coronary artery

1. Properties of endothelium-dependent hyperpolarization evoked by acetylcholine (ACh) in smooth muscle of the guinea-pig coronary artery were investigated using conventional microelectrode techniques. 2. ACh hyperpolarized the membrane in an endothelium-dependent manner. The hyperpolarization comprised two components: an initial and a slow hyperpolarization. The former appeared during application of ACh, while the latter occurred after withdrawal of ACh. 3. Indomethacin and f1p4ofenac, inhibitors of the enzyme cyclo-oxygenase, blocked only the slow hyperpolarization, indicating that this potential was produced by endothelial prostanoids. 4. Clotrimazole and SKF 525a, known inhibitors of the enzyme cytochrome P450, inhibited both the initial and the slow hyperpolarizations, suggesting that these chemicals acted as non-selective inhibitors of arachidonic acid metabolism. Inhibition of the lipoxygenase pathway of arachidonic acid metabolism by nordihydroguaiaretic acid had no effect on either component of the hyperpolarization. 5. The slow hyperpolarization was inhibited by 4-aminopyridine (4-AP; 10(4) 10(-3) M) and glibenclamide (10(-6) M). The initial hyperpolarization was greatly inhibited by charybdotoxin (CTX; 5 x 10(-8) M) and partially inhibited by apamin (10(-7) M), but was not inhibited by glibenclamide (10(-5) M). Ba2+ (10(-4) M) depolarized the membrane and increased the amplitude of both components of the ACh-induced hyperpolarization. 6. Hyperpolarizations produced by Y-26763, a K+ channel opener, were inhibited by glibenclamide, but not by 4-AP. 7. The results indicate that the slow hyperpolarization is produced by endothelial prostanoids through activation of 4-AP-sensitive K+ channels (possibly delayed rectifier type). The initial hyperpolarization is produced mainly through activation of CTX-sensitive K+ channels (possibly Ca(2+)-sensitive type).