Receptor Binding Characterization in Dog Renal Cortex Membranes of (3H) U-37883, a Novel ATP-Sensitive K+ Channel Blocker and In Vivo Diuretic/Natriuretic
Rop, Eric C.
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U-37883A, a novel blocker of ATP-sensitive K+ channels, produces a unique, nonkaliuretic, natriuretic diuresis in vivo by directly affecting the kidney. Specific binding of the renal U-37883A receptor was characterized by testing the abilities of several classes of chemically diverse compounds to compete for 3H-U-37883 binding in dog renal cortex membranes. Classes of K ATP modulators tested for their ability to competitively bind at the renal U-37883A receptor included U-37883A guanidine analogs, the sulfonylurea and K ATP' blocker glyburide, cyanoguanidine K ATP blockers and openers, other structurally diverse K ATP openers, and several imidazoline compounds. Several U-37883A guanidine analogs competitively displaced 3H-U37883 binding at 10 µM. Of all other structurally diverse classes of K ATP modulators tested, only the imidazoline compounds phentolamine and antazoline showed significant (95 .2 and 73 .0% respectively) displacement of 3H-U37883 at 10 µM . The general correlation of a compound's activity in the renal 3H-U37883 binding assay and in the in vitro K ATP channel blockade assay, demonstrated the similarity of the U-37883A receptors in these two tissues. However, some compounds were found to be either kidney selective (U56521E) or vascular selective (U-38313E). Thus, this study shows that the U-37883A receptor specifically mediates the K ATP channel blocking activity of several U-37883A guanidine analogs and imidazolines, and that the U-37883A receptors in the kidney and the vasculature are very similar, but can be differentiated.