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 tinitrate (GTN, 0.1-1 μM) significantly attenuated the cyclic GMP response to a subsequent challenge with both NO-aspirin or GTN. Similarly, NO-aspirin (10-100 μM) 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. (C) 2000 Academic Press.
|Original language||English (US)|
|Number of pages||4|
|Journal||Biochemical and Biophysical Research Communications|
|State||Published - Jul 21 2000|
Bibliographical noteFunding Information:
This work was supported by the Deutsche Forschungsgemein-schaft (Schr 298/8-2).
- Cultured cells
- Glyceryl trinitrate
- Nitrate tolerance
- Nitric oxide
- Nitric oxide donor
- Nonsteroidal anti-inflammatory drugs