Effect of cromakalim and glibenclamide on spontaneous and evoked motility of the guinea-pig isolated renal pelvis and ureter.
1. We have investigated the effect of the potassium (K) channel opener, cromakalim, on the spontaneous myogenic activity of the guinea-pig isolated renal pelvis and on myogenic contractions evoked by direct electrical stimulation of the guinea-pig isolated ureter. 2. In the presence of Bay K 8644 (1 microM), electrical stimulation of the guinea-pig ureter (10 Hz for 1 s, pulse width 5 ms, 60 V) produced regular tetrodotoxin-(1 microM) resistant phasic contractions which were suppressed by 3 microM cromakalim. Glibenclamide (0.1-3 microM), 4-aminopyridine (4-AP, 0.1-2 mM) and tetraethylammonium (TEA, 1-10 mM) produced a concentration-dependent inhibition of the effect of cromakalim with the rank order of potency (EC50 in parentheses): glibenclamide (0.64 microM) >> 4-AP (1.11 mM) > TEA (6.6 mM). Apamin (0.1-0.3 microM) was without effect. 3. Cromakalim (0.1-10 microM) produced concentration-dependent inhibition and suppression of spontaneous contractions of the guinea-pig isolated renal pelvis and of evoked contractions of the ureter with EC50 values of 0.71 and 0.47 microM, respectively. 4. Glibenclamide (1 microM) produced a rightward shift of the concentration-response curve to cromakalim in both the renal pelvis and ureter, without producing depression of the maximal inhibitory effect. Glibenclamide did not affect the spontaneous activity of the renal pelvis while it produced a slight enhancement (10-15% increase) of evoked contractions of the ureter. Glibenclamide did not affect the inhibitory action of the adenylate cyclase activator, forskolin, in the renal pelvis or ureter. 5. In electrophysiological experiments (sucrose gap), cromakalim (0.3 and 1 microM) produced hyperpolarization of ureter smooth muscle. Cromakalim also produced a transient suppression of action potentials and accompanying phasic contractions evoked by electrical stimulation. Before suppression of evoked contractions, a shortening of action potential duration was observed concomitant with the developing hyperpolarization produced by cromakalim. A lower concentration (0.1 MicroM) of cromakalim did not affect membrane potential but shortened action potential duration and reduced the evoked contraction.6. Glibenclamide (1 MicroM) inhibited the hyperpolarizing action of cromakalim and prevented its inhibitory action on evoked action potentials and contractions of the ureter. Glibenclamide also produced a slight prolongation of action potential duration and increased the amplitude and duration of the accompanying mechanical response.7. These findings demonstrate that activation of cromakalim- and glibenclamide-sensitive K channels produces a powerful mechanism for regulation of pyeloureteral motility and suppression of latent pacemakers of the ureter in guinea-pig. Glibenclamide-sensitive K channels take part in determining action potential shape and duration in the guinea-pig ureter.
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
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Santicioli
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D019806:Cromakalim; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007682:Kidney Pelvis / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology*; D014513:Ureter / Q000187:drug effects* / Q000502:physiology*
D001578:Benzopyrans; D015221:Potassium Channels; D011758:Pyrroles; D019806:Cromakalim; D005905:Glyburide