Interaction of the diuretics torasemide and U-37883A with the K(ATP) channel in rat isolated aorta.
In this study we have investigated the interaction of the loop diuretics torasemide and furosemide and of the eukalemic diuretic U-37883A (4-morpholinocarboximidine-N-1-adamantyl-N'-cyclohexylhyd rochloride) with the ATP-sensitive K+ channel (K(ATP) channel) in rat aortic rings. Torasemide contains a sulphonylurea group which might enable the compound to interfere with K(ATP) channels; this group is lacking in furosemide. U-37883A blocks several types of K(ATP) channels. The interaction with the vascular K(ATP) channel was probed in binding studies, 86Rb+ efflux experiments and vasorelaxation assays. Torasemide inhibited the binding of the K(ATP) channel inhibitor [3H]glibenclamide and of the opener [3H]P1075 with IC50 values of 19 and 45 microM, respectively; furosemide and U-37883A were inactive or interfered with binding in a nonspecific way. In 86Rb+ efflux experiments, the loop diuretics, at microM concentrations, inhibited basal tracer efflux to 50% whereas U-37883A had no effect. P1075-stimulated 86Rb+ efflux, a qualitative measure of K(ATP) channel opening, was inhibited by U-37883A and torasemide with IC50 values of 0.06 and 130 microM, respectively; furosemide induced only a small (23%) inhibition. In experiments measuring isometric force, torasemide and furosemide partially relaxed endothelium-denuded aortic rings precontracted with noradrenaline or KCl with EC50 values between 6 and 10 microM. The vasorelaxant effect of P1075 was inhibited in a noncompetitive manner by torasemide (300 microM) but unaffected by furosemide. U-37883A increased noradrenaline-induced force and inhibited the vasorelaxant effect of P1075 in an apparently competitive manner with an inhibition constant of 0.4 microM. The data show that torasemide interferes specifically with the binding of the K(ATP) channel modulators [3H]glibenclamide and [3H]P1075 and with the K(ATP) channel opening and vasorelaxant effects of P1075 whereas furosemide is inactive. This suggests that the interaction of torasemide with the vascular K(ATP) channel is due to the sulphonylurea group present in torasemide. U-37883A, which does not inhibit P1075 binding, is one of the most potent blockers of P1075-induced 86Rb+ efflux yet described but is relatively weak as an inhibitor of P1075-mediated vasorelaxation. The opposite vascular actions of torasemide and U-37883A are expected to contribute to the renal effects of these drugs.
Löffler-Walz
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Department of Pharmacology, Faculty of Medicine, University of Tübingen, Germany.
Quast
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D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D001667:Binding, Competitive; D004232:Diuretics / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005665:Furosemide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015221:Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012413:Rubidium / Q000378:metabolism; D012414:Rubidium Radioisotopes; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077786:Torsemide
D004232:Diuretics; D009025:Morpholines; D015221:Potassium Channels; D012414:Rubidium Radioisotopes; D013449:Sulfonamides; C082658:U 37883A; D005665:Furosemide; D000255:Adenosine Triphosphate; D012413:Rubidium; D000218:Adamantane; D000077786:Torsemide