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(Circulation Research. 2000;87:1149.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Prolonged Hypercapnia-Evoked Cerebral Hyperemia via K⁺ Channel– and Prostaglandin E₂–Dependent Endothelial Nitric Oxide Synthase Induction

Taline Najarian¹, Anne Marilise Marrache¹, Isabelle Dumont, Pierre Hardy, Martin H. Beauchamp, Xin Hou, Krishna Peri, Fernand Gobeil, Jr, Daya R. Varma, Sylvain Chemtob

From the Department of Pharmacology and Therapeutics (T.N., A.M.M., D.R.V., S.C.), McGill University, Montreal; Departments of Pediatrics, Ophthalmology, and Pharmacology (T.N., A.M.M., I.D., P.H., X.H., F.G., S.C.), Research Center, Hôpital Ste-Justine, Montreal; and Theratechnologies (K.P.), St Laurent, Quebec, Canada.

Correspondence to Sylvain Chemtob, MD, PhD, FRCPC, Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Center of Hôpital Ste-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, Canada, H3T 1C5. E-mail chemtobs{at}ere.umontreal.ca

Abstract—Mechanisms for secondary sustained increase in cerebral blood flow (CBF) during prolonged hypercapnia are unknown. We show that induction of endothelial NO synthase (eNOS) by an increase in prostaglandins (PGs) contributes to the secondary CBF increase during hypercapnic acidosis. Ventilation of pigs with 6% CO₂ (PaCO₂65 mm Hg; pH 7.2) caused a 2.5-fold increase in CBF at 30 minutes, which declined to basal values at 3 hours and gradually rose again at 6 and 8 hours; the latter increase was associated with PG elevation, nitrite formation, eNOS mRNA expression, and in situ NO synthase (NOS) reactivity (NADPH-diaphorase staining). Subjecting free-floating brain sections to acidotic conditions increased eNOS expression, the time course of which was similar to that of CBF increase. Treatment of pigs with the cyclooxygenase inhibitor diclofenac or the NOS inhibitor N-nitro-L-arginine blunted the initial rise and prevented the secondary CBF increase during hypercapnic acidosis; neuronal NOS blockers 1-(2-trifluoromethylphenyl) imidazole and 3-bromo-7-nitroindazole were ineffective. Diclofenac abolished the hypercapnia-induced rise in cerebrovascular nitrite production, eNOS mRNA expression, and NADPH-diaphorase reactivity. Acidosis (pH 7.15, PCO₂40 mm Hg; 6 hours) produced similar increases in prostaglandin E₂ (PGE₂) and eNOS mRNA levels in isolated brain microvessels and in NADPH-diaphorase reactivity of brain microvasculature; these changes were prevented by diclofenac, by the receptor-operated Ca²⁺ channel blocker SK&F96365, and by the K_ATP channel blocker glybenclamide. Acidosis increased Ca²⁺ transients in brain endothelial cells, which were blocked by glybenclamide and SK&F96365 but not by diclofenac. Increased PG-related eNOS mRNA and NO-dependent vasorelaxation to substance P was detected as well in rat brain exposed to 6 hours of hypercapnia. PGE₂ was the only major prostanoid that modulated brain eNOS expression during acidosis. Thus, in prolonged hypercapnic acidosis, the secondary CBF rise is closely associated with induction of eNOS expression; this seems to be mediated by PGE₂ generated by a K_ATP and Ca²⁺ channel–dependent process.

Key Words: hypercapnia • acidosis • endothelial nitric oxide synthase • prostaglandin E₂ • potassium channels

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