Contribution of Vasoactive Eicosanoids and Nitric Oxide Production to the Effect of Selective Cyclooxygenase-2 Inhibitor, NS-398, on Endotoxin-Induced Hypotension in Rats

Our previous studies with the use of non-selective cyclooxygenase (COX) inhibitor, indomethacin, demonstrated that prostanoids produced during endotoxaemia increase inducible nitric oxide synthase (iNOS) protein expression and nitric oxide synthesis, and decrease cyctochrome P450 (CYP) 4A1 protein expression and CYP 4A activity. The results suggest that dual inhibition of iNOS and COX by indomethacin restores blood pressure presumably due to increased production of 20-hydroxyeicosatetraenoic acid (20-HETE) derived from CYP 4A in endotoxaemic rats. The present study examined whether increased levels of vasoconstrictor eicosanoids, 20-HETE, prostaglandin F-2 alpha (PGF(2 alpha))and thromboxane A(2) (TxA(2)), would contribute to the effect of selective COX-2 inhibition to prevent endotoxin (ET)-induced fall in blood pressure associated with an increase in the production of vasodilator prostanoids, prostaglandin I-2 (PGI(2)) and prostaglandin E-2 (PGE(2)) and nitric oxide synthesis. Mean arterial blood pressure fell by 31 mmHg and heart rate (HR) rose by 90 beats/min. in male Wistar rats treated with ET (10 mg/kg, i.p.). The fall in mean arterial pressure and increase in HR were associated with increased levels of 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)), PGE(2), TxB(2), and nitrite in the serum, kidney, heart, thoracic aorta and/or superior mesenteric artery. Systemic and renal 20-HETE and PGF(2 alpha) levels were also decreased in endotoxaemic rats. These effects of ET were prevented by a selective COX-2 inhibitor, N-(2-cyclohexyloxy-4-nitrophenyl)methansulphonamide (10 mg/kg, i.p.), given 1 hr after injection of ET. These data suggest that an increase in 20-HETE and PGF(2 alpha) levels associated with decreased production of PGI(2), PGE(2), and TxA(2), and nitric oxide synthesis contributes to the effect of selective COX-2 inhibitor to prevent the hypotension during rat endotoxaemia.