A common pathway for nitric oxide release from NO-aspirin and glyceryl trinitrate.
NO-Aspirin (NCX-4016) releases nitric oxide (NO) in biological systems through as yet unidentified mechanisms. In LLC-PK1 kidney epithelial cells, a 5-h pretreatment with glyceryl trinitrate (GTN, 0.1-1 microM) significantly attenuated the cyclic GMP response to a subsequent challenge with both NO-aspirin or GTN. Similarly, NO-aspirin (10-100 microM) was found to induce tolerance to its own cyclic GMP stimulatory action and to that of GTN. In contrast, cyclic GMP stimulation by the spontaneous NO donor SIN-1, which releases NO independently of enzymatic catalysis, remained unimpaired in cells pretreated with GTN or NO-aspirin. The observed cross-tolerance between NO-aspirin and GTN cells indicates that bioactivation pathways of organic nitrates, which have been shown to involve cytochrome P450, may also be responsible for NO release from NO-aspirin. Prolonged treatment with NO-aspirin causes down-regulation of the cellular cyclic GMP response, suggesting that tolerance may occur during therapy with NO-aspirin.
Grosser
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Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Str. 4, Halle (Saale), 06099, Germany.
Schröder
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H
D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives* / Q000378:metabolism; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D005996:Nitroglycerin / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D013552:Swine
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D020030:Nitric Oxide Donors; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; C002385:linsidomine; D003577:Cytochrome P-450 Enzyme System; D008981:Molsidomine; C102148:nitroaspirin; D005996:Nitroglycerin; D006152:Cyclic GMP; D001241:Aspirin