4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydrochloride (U- 37883A): pharmacological characterization of a novel antagonist of vascular ATP-sensitive K+ channel openers

KD Meisheri, SJ Humphrey, SA Khan, LA Cipkus-Dubray, MP Smith and AW Jones

Cardiovascular Diseases Research, Upjohn Laboratories, Kalamazoo, Michigan.

This study describes the in vitro and in vivo characteristics of a guanidine 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl-hydroc hloride (U-37883A), as an antagonist of vascular ATP-sensitive K+ channels (KATP). In isolated rabbit mesenteric artery, the antagonistic effects of U-37883A (0.5-5 microM) were studied against vasorelaxation produced by cromakalim (0.5 microM), minoxidil sulfate (5 microM), pinacidil (1 microM) and RP-49356 (1 microM). The dose-response curves for U-37883A against all four potassium channel openers were similar with U-37883A, IC50S ranging from 0.78 to 1.4 microM, suggesting that U- 37883A is producing inhibition by acting at a step that is common to all four potassium channel openers during their activation of the vascular KATP. In contrast, U-37883A at 10 microM did not inhibit relaxation dose-response curves by nitroglycerine, forskolin or D600. U- 37883A (1 or 10 microM) effectively inhibited as well as reversed 42K efflux-stimulated by cromakalim (1 microM) or minoxidil sulfate (5 microM). Finally, U-37883A (3 mg/kg i.v.) was found to inhibit significantly as well as reverse hypotension produced by minoxidil (1 mg/kg i.v. or 3 mg/kg p.o.), cromakalim (0.5 mg/kg p.o.) and pinacidil (0.3 mg/kg i.v.) in rats, cats and dogs. In contrast, the in vivo responses to phenylephrine, nitroglycerine, sodium nitroprusside or isoproterenol were not altered. U-37883A thus appears to be the first nonsulfonylurea shown to block consistently and selectively the in vitro as well as the in vivo pharmacological responses to various potassium channel openers. This structurally novel KATP antagonist therefore would be useful for further characterizing the mechanisms of pharmacological modulation of the KATP in a variety of cell systems.

Volume 266, Issue 2, pp. 655-665, 08/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

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