Mechanistic Interactions Between Potassium Channel Openers, U-37883A and Glyburide in Vascular Smooth Muscle
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The vascular pharmacology of ATP-sensitive potassium channels ([K+] ATP) was studied in isolated rabbit mesenteric artery (RMA) using [K+] ATP channel blockers, U-37883A and glyburide against potassium channel openers (PCas) pinacidil (1µ M), minoxidil sulfate (5µ M), cromakalim (0.5µM) and RP-49356 (1µM). Time courses for each PCO induced relaxation in norepinephrine (NE) precontracted RMA were found to be very similar. Each PCO induced immediate relaxation. Within 15 minutes, the tissue reached approximately 80% relaxation. Pretreatment of RMA for 75 minutes with U-37883A (0.1µM to 10.µM) caused a dose-dependent inhibition of PCO relaxation time course. Using the data for PCO relaxation at t = 15 minutes, it was found that the, U-37883A IC 50 (concentration of U-37883A to produce 50% of maximum inhibition of PCO relaxation) for pinacidil was about 780nM; for minoxidil sulfate was about 840nM; for cromakalim was about 1400nM; and for RP-49356 was about 1000nM, with maximum inhibition occurring at 5µM to 7.5µM. This is the first report to establish the inhibition dose-response curves for U-37883A against four PCOs. Comparison with glyburide induced inhibition dose response curves against the same PCOs shows that U-37883A is ten times less potent than glyburide. Subsequent experiments investigated the effects of various pre- and post-treatments of U-37883A (5µM) on 1µM pinacidil-induced relaxation in NE precontracted RMA. The onset of U-37883A [K+] ATP channel inhibiting effects occurred approximately 3 minutes after U-37883A administration. Full reversal of relaxation occurred in 15 minutes. The rate of action of U-37883A was much faster than glyburide. When glyburide (0.05µM) was added to the U-37883A pretreatment, the potency of the K+ channel blockers was increased eight times. Glyburide potentiated the effect of U-37883A on minoxidil sulfate and cromakalim, also, but had no effect on Ca2+ antagonist, D600. The combined effect of U-37883A and glyburide was observed only when PCOs !were used as the vasodilators. These data were interpreted to suggest that PCO induced relaxation occurred via the converging pathways mechanism. [K+] ATP channel blockade by U-37883A and glyburide may occur at different sites on a [K+] ATP channel associated protein, essential to channel function. In summary, the result of this study should provide a basis for further experimental understanding of the characteristics of U-37883A, the mechanism of PCO-induced relaxation of smooth muscle via [K+] ATP channels and the mechanism of [K+] ATP channel blockade by [K+] ATP antagonists, U-37883A and glyburide.