Comparative studies on the relaxing action of several adenosine 5'-triphosphate-sensitive K+ channel openers in pig...

The relaxing effects of the adenosine 5'-triphosphate (ATP)-sensitive K+ channel openers (K(ATP) openers; diazoxide, minoxidil, pinacidil, (+/-)-cromakalim, (+)-cromakalim and (-)-cromakalim) were investigated on the resting tone of pig proximal urethra. In addition, patch clamp techniques were utilized for recording cromakalim-induced ionic currents in cells dispersed from the same urethral region. The (-)-cromakalim-induced relaxation of urethral muscle strips was stable, reversible and reproducible. The rank order of potency regarding of K(ATP) openers in lowering the resting urethral tone was (-)-cromakalim>pinacidil>diazoxide>minoxidil. K(ATP) opener-induced urethral relaxation was suppressed by subsequent application of glibenclamide (1 microM). (+)-Cromakalim (< or =10 microM) did not relax the urethra nor antagonize the (-)-cromakalim-induced urethral relaxation. However, at higher concentrations, (+)-cromakalim (> or =30 microM) caused a small but significant urethral relaxation. In accordance with these observations, the relaxation induced by 5 microM (-)-cromakalim was identical to that induced by 10 microM (+/-)-cromakalim, as expected from a theoretical half potency for (+/-)-cromakalim. In whole-cell recording, (-)-cromakalim and (+) cromakalim (100 microM) activated a glibenclamide-sensitive outward current which was due to the activation of the glibenclamide-sensitive 43 pS K+ channel (K(GS)-43 pS). The potency of (+)-cromakalim to activate K(GS)-43 pS was much weaker than that of (-)-cromakalim. These results indicate that the ability of K(ATP) openers to relax pig urethral smooth muscle can be accounted for by activation of glibenclamide-sensitive K+ channels.