Studies on the Interactions Between Pinacidil (K + Agonist) and U-37,883A (K+ Antagonist) in Vascular Smooth Muscle
Swirtz, Michael A.
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The mechanism of pinacidil, a new potent vasodilator, and putative K+ channel agonist, was studied in rabbit mesenteric artery. Its relaxant ability was examined on NE and high K+-induced contractions. Pretreatments with TEA, BaCl2, and KCl were used to help classify the mechanism of action. The effects of the guanidine diuretic, U-37,883A, which has been found to be a K+ channel antagonist, were also studied on pinacidil. Additionally the specificity of U-37,883A was examined by comparing its effect on pinacidil with its effect on other vasodilators, forskolin, nitroglycerine, and D600, which all involve different mechanisms. It was found that pinacidil was effective at relaxing NE-induced contractions, and also 80 mM K+induced contractions at higher concentrations. The relaxation of NE contractions could be blocked by TEA, BaCl2, Kel, and U-37,883A. It was also found that U-37,883A was a specific blocker. It had little or no effect on forskolin, nitroglycerine, or D600-induced relaxation of NE or 80 mM K+ contractions, nor pinacidil-induced relaxation of 80 mM K+ contractions. Thus, it appears that pinacidil functions by two separate mechanisms, one which is dependent on K+ channel activation, which can be blocked by U-37,883A, and one that is independent of K+ channel activation.