Effect of cromakalim and pinacidil on 86Rb efflux from guinea pig urinary bladder smooth muscle.
86Rb efflux assay was used to investigate the effect of cromakalim, pinacidil and P1075 in guinea pig urinary bladder strips. The type of K channel opened by cromakalim and pinacidil was determined using specific K channel blockers through 86Rb efflux assay in detrusor strips. Cromakalim, pinacidil and P1075 all three potassium channel openers (PCOs) evoked a concentration-dependent increase in 86Rb efflux in bladder strips. This increase in isotope release was inhibited by pretreatment of bladder with 10 and 30 microM glibenclamide suggesting that both cromakalim and pinacidil interact with ATP-sensitive K channels (KATP). Further, an increase in basal 86Rb efflux was observed when 2-deoxy-D-glucose was substituted for glucose together with 0.24 micrograms/ml of oligomycin (known to lower intracellular ATP) indicating the presence of KATP channels in bladder smooth muscle. Charybdotoxin and apamin, blockers of large and small conductance Ca(2+)-dependent K channels, were found not to be involved in the action of these PCOs in bladder strips. alpha-Dendrotoxin, known to block voltage-dependent K channels, slightly reduced pinacidil-induced 86Rb release without affecting cromakalim-induced 86Rb efflux. The present studies show that ATP-sensitive K channels are present in guinea pig urinary bladder and that cromakalim and pinacidil act by opening these ATP-sensitive K channels in detrusor strips.
Trivedi
S
S
Department of Pharmacology, Zeneca Pharmaceuticals Group, Zeneca Inc., Wilmington, Del 19897.
Stetz
S
S
Levin
R
R
Li
J
J
Kau
S
S
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D012414:Rubidium Radioisotopes / Q000378:metabolism*; D013237:Stereoisomerism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D001578:Benzopyrans; D006146:Guanidines; D015221:Potassium Channels; D011725:Pyridines; D011758:Pyrroles; D012414:Rubidium Radioisotopes; D014665:Vasodilator Agents; D019806:Cromakalim; C073896:N-cyano-N'-(1,1-dimethylpropyl)-N''-(3-pyridinyl)guanidine; D020110:Pinacidil; D000255:Adenosine Triphosphate