Inhibition of cyclooxygenase-2: effects on renin secretion and expression in fetal lambs.
The importance of prostaglandins in the regulation of the renin-angiotensin system during development is not known. These experiments were conducted to examine the effects of prostaglandin synthesis inhibitors on basal and isoproterenol-induced plasma renin concentration and renin gene expression in the late-gestation fetal lamb. Eighteen lamb fetuses ranging in gestational age from 129 to 138 days underwent surgical insertion of femoral arterial and venous catheters under general endotracheal anesthesia. After a period of recovery, animals underwent an infusion of isoproterenol after administration of a saline bolus (control experiments); 24-48 h later a second study was performed after administration of NS-398, a cyclooxygenase (COX)-2 inhibitor, or saline for a second control study. Administration of COX-2 inhibitor significantly reduced baseline plasma renin levels and attenuated responses in fetal renin secretion to isoproterenol infusions. Renal cortical cells from animals receiving COX-2 inhibitor had significantly lower levels of renin mRNA compared with animals receiving only saline. Renal cortical cells in culture from animals receiving only saline exhibited increased levels of renin mRNA when treated with isoproterenol, forskolin, or IBMX. Only forskolin increased renin mRNA levels in renal cortical cells in culture from animals receiving COX-2 inhibitor. We conclude that prostaglandins play a stimulatory role in the regulation of the renin-angiotensin system and are necessary for beta-adrenergic stimulation of renin secretion and gene expression in the late-gestation fetal lamb.
Mertz
Heather L
HL
Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
Liu
Jingfang
J
Valego
Nancy K
NK
Stallings
Shawn P
SP
Figueroa
Jorge P
JP
Rose
James C
JC
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001784:Blood Gas Analysis; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000032:analysis; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D007672:Kidney Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009578:Nitrobenzenes / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011247:Pregnancy; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012083:Renin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D034561:Sheep, Domestic / Q000196:embryology* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology
D000318:Adrenergic beta-Agonists; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D009578:Nitrobenzenes; D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D005576:Colforsin; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D012083:Renin; D015232:Dinoprostone; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine