ABSTRACT
Title
Nitric oxide compensates for the COX-dependent vascular effects of cyclooxygenase inhibitors.
Authors
C. Storini, C. De Nardi, M. Bolla, J. Padron, D. Miglietta
NicOx Research Institute, Bresso, Milan, Italy
NicOx Research Institute, Bresso, Milan, Italy
Abstract
Non steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase (COX)-2 inhibitors, may predispose to hypertension and blood pressure destabilization, likely by inhibiting formation of COX-derived prostanoids in the vascular bed. Nitric oxide (NO), a key modulator for vascular homeostasis and relaxation, could mitigate NSAID-dependent blood pressure alterations. In this study we assessed the effects of COX inhibition and NO donation on systolic blood pressure (SBP) in rats made hypertensive by NO deprivation. SBP was measured in L-NAME-induced hypertensive rats, following intravenous administration of different doses of naproxen. Then, NCX 429, a compound showing a dual action due to naproxen and NO donation was used to evaluate the functional interaction between COX-inhibiton and NO.
Single administration of L-NAME (50mg/kg i.p.), inhibitor of NO endogenous synthesis, markedly increased SBP compared to basal values (182±2 vs 129±2.3 mmHg). Naproxen(1, 3 and 10 mg/kg i.v.) caused an additional significant increase of about 15 mmHg in SBP for all doses tested (p<0.001 vs. L-NAME-treated group). All doses effectively inhibited COX, as measured by serum thromboxane synthesis. The R-enantiomer of naproxen, which is a weak COX inhibitor, did not significantly raise SBP. Conversely, NCX 429 at 16 mg/kg i.v. (equimolar to naproxen 10 mg/kg) did not change SBP, even in presence of complete thromboxane inhibition. Interestingly, its R-enantiomer, which shows NO activity without COX inhibition, reduced SBP by about 20 mmHg.
Our study demonstrates that in conditions of endogenous NO deprivation, COX inhibition induces blood pressure increases, whereas NO donation seems to counteract this effect. Thus, these findings suggest that NO could mitigate vascular side effects of NSAIDs in patients with reduced NO function.
Single administration of L-NAME (50mg/kg i.p.), inhibitor of NO endogenous synthesis, markedly increased SBP compared to basal values (182±2 vs 129±2.3 mmHg). Naproxen(1, 3 and 10 mg/kg i.v.) caused an additional significant increase of about 15 mmHg in SBP for all doses tested (p<0.001 vs. L-NAME-treated group). All doses effectively inhibited COX, as measured by serum thromboxane synthesis. The R-enantiomer of naproxen, which is a weak COX inhibitor, did not significantly raise SBP. Conversely, NCX 429 at 16 mg/kg i.v. (equimolar to naproxen 10 mg/kg) did not change SBP, even in presence of complete thromboxane inhibition. Interestingly, its R-enantiomer, which shows NO activity without COX inhibition, reduced SBP by about 20 mmHg.
Our study demonstrates that in conditions of endogenous NO deprivation, COX inhibition induces blood pressure increases, whereas NO donation seems to counteract this effect. Thus, these findings suggest that NO could mitigate vascular side effects of NSAIDs in patients with reduced NO function.