Effect of pinacidil on the membrane electrical activity of guinea pig detrusor muscle.
The effects of pinacidil on the guinea pig detrusor smooth muscle membrane were studied to investigate the electrophysiological mechanisms by which this drug relaxes smooth muscle tissue and, thus, might be of value in the treatment of detrusor instability. Pinacidil (> or = 3 x 10(-7) M) hyperpolarized the membrane in a concentration-dependent manner, with a reduction in spontaneous spike discharges. The membrane hyperpolarization induced by pinacidil was consistently associated with an increase in membrane ionic conductance. Glybenclamide (10(-6) M) completely inhibited the membrane hyperpolarization induced by pinacidil (up to 10(-5) M). Membrane hyperpolarization with pinacidil was consistently greater in a low-K+ solution, and it decreased in the presence of a high-K+ solution, compared with that measured in normal Krebs solution. Pinacidil consistently suppressed carbachol-induced depolarization of the membrane, with a reduction in the frequency of spontaneous action potentials. Glybenclamide (10(-6) M) did not inhibit the effect of pinacidil on increased action potential frequency induced by carbachol but blocked the membrane hyperpolarization induced by pinacidil (10(-5) M). In addition, the amplitude and maximum velocity of depolarization of carbachol- and current-induced action potentials were significantly decreased by pinacidil in the presence of glybenclamide. These results suggest that pinacidil blocks action potential generation in detrusor smooth muscle by inducing membrane hyperpolarization secondary to an increase in K+ permeability. Pinacidil, at high concentrations (> or = 10(-5) M), might block action potentials by inhibiting the voltage-sensitive Ca++ influx independently of hyperpolarization of the membrane. These mechanisms might be of benefit therapeutically in relaxation of unstable detrusor contractions.
Seki
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James Buchanan Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Karim
O M
OM
Mostwin
J L
JL
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006146:Guanidines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D008564:Membrane Potentials / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009543:Nifedipine / Q000494:pharmacology; D020110:Pinacidil; D001743:Urinary Bladder / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D006146:Guanidines; D014665:Vasodilator Agents; D020110:Pinacidil; D002217:Carbachol; D009543:Nifedipine; D005905:Glyburide