Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production

Abstract

Increased production of nitric oxide (NO) and prostaglandins contribute to development of hypotension during endotoxemia. We have previously demonstrated that endotoxemia-induced increase in NO production suppresses renal cytochrome P450 (CYP) 4A expression and activity, and that selective inhibition of inducible NO synthase (iNOS) with 1,3-PBIT restores renal CYP 4A protein and activity and mean arterial pressure (MAP). By using cyclooxygenase (COX) inhibitor indomethacin, we investigated herein whether prostaglandins, via NO production, inhibit renal CYP 4A1 protein expression and CYP 4A activity and contribute to the endotoxin-induced hypotension. In conscious male Sprague-Dawley rats, endotoxin (10 mg/kg, intraperitoneal (i.p.)) reduced MAP, increased serum nitrite and bicyclo PGE2 levels, renal nitrite production and iNOS protein expression, and decreased renal CYP 4A1 protein expression and CYP 4A activity after 4 h injection. All of the endotoxin-induced changes, except for increase in renal nitrite production, were prevented by indomethacin (5 mg/kg, i.p. 1 h after endotoxin). The effects of indomethacin on the endotoxin-induced decrease in MAP, CYP 4A1 protein expression and CYP 4A activity were minimized by the CYP 4A inhibitor, aminobenzotriazole (50 mg/kg, i.p. 1 h after endotoxin). These data suggest that prostaglandins produced during endotoxemia increase iNOS protein expression and NO synthesis, and decrease CYP 4A protein expression and CYP 4A activity and that inhibition of iNOS or COX restores renal CYP 4A protein level and CYP 4A activity and MAP presumably due to increased production of arachidonic acid metabolites derived from CYP 4A.