title: Effects of K+ channel blockers and cromakalim (BRL 34915) on the mechanical activity of guinea pig detrusor smooth muscle.
abstract: There is strong evidence that cromakalim (BRL 34915) relaxes smooth muscle by opening cell membrane K+ channels. The aim of this study was to use relatively selective K+ channel blockers to investigate 1) the K+ channel type(s) opened by cromakalim in guinea pig detrusor and 2) the role of different K+ channel types in the control of basal tension. Cromakalim produced a concentration-related relaxation (IC50 = 0.50 +/- 0.03 microM, n = 42) of 15 mM K(+)-evoked mechanical activity. The ATP-sensitive K+ channel blocker glyburide (0.3-3 microM) antagonized the effects of cromakalim in an apparently competitive manner (pA2 = 6.76). Charybdotoxin and iberiatoxin (3-30 nM), blockers of the large conductance, Ca(++)-activated K+ channel, appeared to functionally antagonize cromakalim. Apamin (1 microM) and leiurotoxin I (0.3 microM), blockers of the small conductance, Ca(++)-activated K+ channel, and noxiustoxin (0.3 microM), a blocker of squid axon delayed rectifer K+ channels, all failed to antagonize cromakalim. Cumulative administration of charybdotoxin and iberiatoxin produced marked, concentration-related stimulation of mechanical activity per se whereas glyburide, noxiustoxin, apamin and leiurotoxin I had no effect. Apamin and leiurotoxin I did stimulate mechanical activity to a small extent when administered noncumulatively, however. The results suggest that cromakalim opens ATP-sensitive K+ channels in detrusor and suggest that cromakalim does not open CA(++)-activated K+ channels and noxiustoxin-sensitive, delayed rectifier K+ channels. The marked stimulatory effects of charybdotoxin and iberiatoxin per se suggest an important role for large conductance, Ca(++)-activated K+ channels in the control of basal tension and, presumably, membrane potential in detrusor smooth muscle cells.
authors.affiliation: Department of Pharmacology, ICI Americas Inc., Wilmington, Delaware.
authors.forename: T L
authors.initials: TL
authors.lastname: Grant
authors.forename: J S
authors.initials: JS
authors.lastname: Zuzack
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018999:Charybdotoxin; D019806:Cromakalim; D004347:Drug Interactions; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000494:pharmacology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*
chemical_list: D001578:Benzopyrans; D018377:Neurotransmitter Agents; D010455:Peptides; D015221:Potassium Channels; D011758:Pyrroles; D012604:Scorpion Venoms; D014665:Vasodilator Agents; D019806:Cromakalim; D018999:Charybdotoxin; C064719:iberiotoxin