NO-INDEPENDENT VASODILATION TO ACETYLCHOLINE IN THE RAT ISOLATED KIDNEY UTILIZES A CHARYBDOTOXIN-SENSITIVE, INTERMEDIATE-CONDUCTANCE CA-ACTIVATED K+ CHANNEL(+)

The role of K+ channels in the nitric oxide-independent renal vasodila tor effect of acetylcholine (Ach) was examined to address the hypothes is that the mechanism underlying this response was different from that of bradykinin, because an earlier study indicated the possibility of different mediators. We used the rat isolated, perfused kidney that wa s constricted with phenylephrine and treated with nitroarginine and in domethacin to inhibit nitric oxide synthase and cyclooxygenase, respec tively. The nonspecific K+ channel inhibitors, procaine and tetraethyl ammonium (TEA), reduced vasodilator responses to Ach and cromakalim, b ut not those to nitroprusside. Glibenclamide, an inhibitor of ATP-sens itive K+ channels, reduced vasodilator responses to cromakalim but did not affect those to Ach or nitroprusside. Charybdotoxin, an inhibitor of Ca++-activated K+ channels, reduced vasodilator responses to Ach w ithout affecting those to cromakalim or nitroprusside. Iberiotoxin and apamin, inhibitors of large-and small-conductance Ca++-activated K+ c hannels, respectively, did not reduce vasodilation induced by Ach, cro makalim or nitroprusside. The inhibitor of cytochrome P450, clotrimazo le, reduced the renal vasodilator effects of Ach and bradykinin but no t those of nitroprusside or SCA 40, an agonist for Ca++-activated K+ c hannels. These results suggest that in the rat kidney, Ach, like brady kinin, utilizes a charybdotoxin-sensitive Ca++-activated K+ channel of intermediate conductance to elicit vasodilation and that this effect may be dependent on cytochrome P450 activity.