Nitric oxide deficiency promotes vascular side effects of cyclooxygenase inhibitors.

The cardiovascular safety of COX-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has recently been called into question. The factors that predispose to adverse events by NSAIDs are unknown. Because patients with arthritis have decreased nitric oxide (NO) bioavailability, the in vivo effects of NSAIDs on murine vascular tone and platelet activity in the presence or absence of NO were examined. Here, we show that acute hypertensive and prothrombotic activities of the COX-2-selective inhibitor celecoxib are revealed only after in vivo inhibition of NO generation. The nonselective NSAID indomethacin was hypertensive but antithrombotic when NO was absent. In vitro myography of aortic rings confirmed that vasoconstriction required inhibition of both NOS and COX-2 and was abolished by supplementation with exogenous NO. These data indicate that NO suppresses vascular side effects of NSAIDs, suggesting that risk will be greatest in patients with impaired vascular function associated with decreased NO bioavailability.

Type II nitric oxide synthase activity is cardio-protective in experimental sepsis.

Overproduction of nitric oxide (NO) via the induction of NO synthase (NOS) II is implicated in the pathogenesis of the refractory hypotension that characterizes septic shock. However, clinical trials of nonselective NOS inhibitors have failed to afford a mortality benefit in patients with sepsis, and in those with depressed left ventricular function, death rates were increased. Such observations have led to the suggestion that a selective inhibitor of NOSII would be more effective in treating septic shock, although precisely how NO modulates cardiac function in these circumstances remains unclear. We therefore used an isolated ejecting rodent heart model to study the effects of NO and experimental sepsis (endotoxin 20 mg kg i.p.) on cardiac functions. Coronary flow and cardiac output and ventricular functions were reduced by LPS, effects that were partially obviated by supplementation of perfusate with the NO substrate, L-arginine. These improvements were partially blocked by the selective NOSII inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400W) and further reduced by the combined NOSI, II and III inhibitor L-nitro L-arginine methyl ester (L-NAME). These findings suggest that NOSII is cardio-protective in the heart in sepsis and explain why its inhibition in man led to increased mortality in a subpopulation of patients.