Diuretic activity of N'-disubstituted morpholinoguanidine analogs of U-37883A in rats and dogs.
U-37883A is a K+ sparing diuretic which selectively blocks openers of vascular ATP-sensitive K channels. Many N'-disubstituted morpholinoguanidine (N'-DMG) analogs of U-37883A were synthesized and tested for diuretic activity. In conscious rats, 10-100 mg/kg orally of the most active N'-DMGs increased urine volume (V) and Na+ excretion by up to 4-fold with little kaliuresis. The N'-DMGs U-37997A and U-38658A were less potent than standard diuretics, but did not induce the K+ loss seen with hydrochlorothiazide and furosemide or the K+ retention of amiloride and triamterene. In conscious dogs, 10 mg/kg i.v. of the N'-DMGs U-40389A and U-52090 increased V and Na+ excretion by over 7-fold with little kaliuresis. Despite their attractive diuresis, all of the N'-DMGs had narrow margins of safety. Reflecting their direct myocardial depressant action, in isolated rat hearts, bolus intracoronary U-37883A, U-18177A, and U-38658A (0.25-10 mumol) severely reduced the rate (-10 to -100%) and force (-9 to -100%) of contraction. These studies characterize the eukalemic diuretic activity of N'-DMG analogs of U-37883A, and demonstrate the marked cardiac depression characteristic of the morpholinoguanidine diuretic series.
D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004232:Diuretics / Q000494:pharmacology*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009025:Morpholines / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D010477:Perfusion; D011188:Potassium / Q000652:urine; D051381:Rats; D012964:Sodium / Q000652:urine; D013045:Species Specificity
D004232:Diuretics; D009025:Morpholines; C082658:U 37883A; D012964:Sodium; D000218:Adamantane; D011188:Potassium