Synergistic effects of glyburide and U-37883A, two structurally different vascular ATP-sensitive potassium channel antagonists.

Glyburide, a sulfonylurea, and U-37883A, a guanidine (4-Morpholinecarboximidine-N-1-Adamantyl-N' cyclohexylhydrochloride), have been previously characterized as antagonists of the vascular ATP-sensitive K+ channels (KATP). In this report, the in vitro interaction between these two chemically distinct KATP antagonists was investigated using isolated rabbit mesenteric artery. The KATP antagonism was functionally studied as the inhibition of vasodilation produced by various KATP openers as follows: pinacidil (1 microM), minoxidil sulfate (5 microM), cromakalim (0.5 microM) and RP-49356 (1 microM). Glyburide alone produced inhibition in the concentration range of 50 to 500 nM with the glyburide IC50 ranging from 72 to 148 nM. U-37883A alone produced inhibition in the concentration range of 0.5 to 5 microM, with the U-37883A IC50 ranging from 0.78 to 1.4 microM. In the presence of a threshold U-37883A concentration of 0.5 microM, the glyburide inhibition dose-response curve against pinacidil was significantly shifted to the left and the glyburide IC50 was lowered from 72 to 3.9 nM, representing an 18-fold decrease. Similarly, in the presence of a threshold glyburide concentration of 50 nM, the U-37883A inhibition dose-response curve against pinacidil was significantly shifted to the left and the U-37883A IC50 was lowered from 780 to 96 nM, representing an eightfold decrease. Thus, glyburide and U-37883A potentiated each other's effects as KATP blockers. This synergistic interaction between glyburide and U-37883A was observed independently of the pinacidil, cromakalim or minoxidil sulfate used to produce vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)