DIFFERENTIAL INHIBITION BY TEDISAMIL (KC-8857) AND GLIBENCLAMIDE OF THE RESPONSES TO CROMAKALIM AND MINOXIDIL SULFATE IN RAT ISOLATED AORTA

The effects of the K+ channel blockers tedisamil and glibenclamide on cromakalim- and minoxidil sulphate-induced K-42+ and Rb-86+ efflux and vasorelaxation in rat aorta, were investigated. In aortic strips preloaded with K-42+ or Rb-86+, cromakalim (1-mu-mol/l) induced increases in tracer efflux, which were concentration-dependently inhibited by tedisamil with similar potencies (pD2 almost-equal-to 7.3) but different amplitudes (maximum inhibition of Rb-86+ efflux to 0% of control, K-42+ efflux to 10 +/- 1%). The K-42+ efflux elicited by a low concentration of cromakalim (100 nmol/l) was, however, fully inhibited by tedisamil. The tracer effluxes induced by minoxidil sulphate were fully inhibited by tedisamil and glibenclamide (300 nM). Cromakalim and minoxidil sulphate, produced a concentration-dependent inhibition of noradrenaline (100 nmol/l)-induced tone, with pD2 values of almost-equal-to 7.3. Tedisamil (300 nmol/l) and glibenclamide (300 nmol/l), which inhibited cromakalim- and minoxidil sulphate-induced K-42+ and Rb-86+ efflux by greater-than-or-equal-to 80%, produced 2-fold and 40-fold shifts in the concentration-relaxation curve for cromakalim, and 3.5-fold and 2200-fold shifts in the concentration-relaxation curve for minoxidil sulphate, respectively. Similar shifts of the cromakalim concentration-relaxation curve in the presence of tedisamil and glibenclamide were also observed when the tissues were precontracted with potassium chloride (25 mmol/l). The results show that tedisamil and glibenclamide inhibit the cromakalim- and minoxidil sulphate-induced tracer effluxes with similar potencies whereas they differ greatly in their ability to inhibit the vasorelaxant effects of the two K+ channel openers. This suggests that the opening of K-42+/Rb-86+ permeable K+ channels in the plasma membrane cannot fully explain the vasorelaxant effects of the two drugs. The mechanism(s) of vasorelaxation of cromakalim and minoxidil sulphate, which is not due to the opening of plasmalemmal K+ channels, is sensitive to inhibition by glibenclamide but comparatively insensitive to inhibition by tedisamil.