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Vol. 291, Issue 2, 627-633, November 1999

Developmental Regulation of Endothelial Nitric Oxide Synthase in Cerebral Vessels of Newborn Pig by Prostaglandin E21

Isabelle Dumont , Xin Hou, Pierre Hardy, Krishna G. Peri, Martin Beauchamp, Taline Najarian , Stéphane Molotchnikoff, Daya R. Varma and Sylvain Chemtob

Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Sainte-Justine, Montreal, Quebec, Canada (I.D., X.H., P.H., K.G.P., M.B., T.N., S.C.); Faculty of Biological Sciences, University of Montreal, Montreal, Quebec, Canada (I.D., S.M.); and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (T.N., D.R.V., S.C.)

We investigated whether prostaglandins regulate endothelial nitric oxide synthase (eNOS) in the pig cerebral vasculature during the neonatal period. Prostaglandins, eNOS mRNA, eNOS protein, and NO production were higher in cerebral microvessels of newborn (1 day old) than in those of adult (6- to 8-month-old) pigs. The treatment of isolated cerebral microvessels of newborn animals with ibuprofen for 24 h reduced eNOS mRNA and nitrite production to levels in the adult; this effect of ibuprofen was prevented by concurrent treatment with prostaglandin (PG)E2 analog 16,16-dimethyl-PGE2, nonselective PGE2 receptor analog 11-deoxy PGE1, and prostaglandin EP3 receptor agonists sulprostone and M&B 28,767 but was not modified by PGI2 analog carbaprostacyclin, PGD2, and EP1 receptor agonist 17-phenyl trinor PGE2. Correspondingly, 16,16-dimethyl-PGE2 and M&B 28,767 increased eNOS mRNA expression of adult microvessels to values in the newborn. Data similar to those with isolated cerebral vessels were obtained through histochemical analysis (NADPH-diaphorase positivity) of brain from newborn animals treated in vivo with ibuprofen in combination or not with sulprostone. Furthermore, substance P-induced NO-mediated cerebral vasorelaxation was decreased to adult values through the treatment of newborn pigs with ibuprofen; this effect was prevented by concomitant treatment with sulprostone. It is concluded that PGE2 regulates eNOS in newborn pig cerebral microvessels via EP3 receptors; this may be physiologically required during normal neurovascular development.

0022-3565/99/2912-0627$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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