Cyclooxygenase‐1 and ‐2 inhibition alter hypothalamic‐pituitary‐adrenal axis (HPA) activity and COX expression in fetal brain.

Abstract

In fetal sheep, reflex responses to hypotension are in part mediated by generation of prostaglandins (PG) in the CNS. We have previously demonstratd that inhibition of COX1 reduces the responsiveness of the fetal HPA to hypotension and increases expression of COX2 in specific regions of the fetal CNS. We hypothesized that generation of PG alters the transcription of COX2. The present study was designed to test this hypothesis. Chronically catheterized twin fetal sheep received cerebral ventricular infusions of inhibitor or vehicle. We used either the COX2 inhibitor nimesulide (NIM) at 1mg (HD) or 10 ug/day (LD), or the COX1 inhibitor resveratrol (RES) at 1 mg/day. Blood samples were collected to measure fetal blood gases, proopiomelanocortin (POMC), ACTH, and cortisol. After 5 days, fetal hypothalami and pituitaries were harvested, and COX1 and 2 mRNA were analyzed by real-time PCR. Arterial blood gases were unchanged by HD nimesulide or resveratrol. LD nimesulide significantly decreased pO2 of vehicle treated fetuses. HD NIM significantly reduced hypothalamic COX1 and 2 mRNA, but did not alter pituitary levels. COX1 and 2 were unchanged in the RES and LD NIM groups. Hypothalamic AVP, CRH, and POMC mRNA levels were unchanged in all groups. Plasma ACTH, POMC, and cortisol concentrations were unchanged in the HD NIM group, yet RES and LD NIM treatment significantly reduced plasma cortisol without changing POMC or ACTH. We conclude that blockade of COX2 with HD NIM alters the expression of COX1 and 2 mRNA; and 2) unstimulated fetal ACTH secretion is not altered by blockade of CNS COX isoforms, although adrenal sensitivity to ACTH appears to be influenced by both COX1 and 2 activity in the CNS. Supported by HD42135 and a Predoctoral Fellowship from the American Heart Association.