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 vasodilator effect of acetylcholine (Ach) was examined to address the hypothesis 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 was constricted with phenylephrine and treated with nitroarginine and indomethacin to inhibit nitric oxide synthase and cyclooxygenase, respectively. The nonspecific K+ channel inhibitors, procaine and tetraethylammonium (TEA), reduced vasodilator responses to Ach and cromakalim, but not those to nitroprusside. Glibenclamide, an inhibitor of ATP-sensitive 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 without affecting those to cromakalim or nitroprusside. Iberiotoxin and apamin, inhibitors of large- and small-conductance Ca(++)-activated K+ channels, respectively, did not reduce vasodilation induced by Ach, cromakalim or nitroprusside. The inhibitor of cytochrome P450, clotrimazole, reduced the renal vasodilator effects of Ach and bradykinin but not those of nitroprusside or SCA 40, an agonist for Ca(++)-activated K+ channels. These results suggest that in the rat kidney, Ach, like bradykinin, 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.
Mieyal
P
P
Department of Pharmacology, New York Medical College, Valhalla, USA.
Fulton
D
D
McGiff
J C
JC
Quilley
J
J
D000109:Acetylcholine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D018999:Charybdotoxin / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology*; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects*
D065607:Cytochrome P-450 Enzyme Inhibitors; D015221:Potassium Channels; D018999:Charybdotoxin; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D003577:Cytochrome P-450 Enzyme System; D000109:Acetylcholine; D002118:Calcium