Cardiovascular and renal effects of cyclooxygenase inhibition in transgenic rats harboring mouse renin-2 gene (TGR[mREN2]27).
The present study examined the role of cyclooxygenase-synthetized prostanoids in the pathogenesis of angiotensin-II-induced inflammatory response and vascular injury in transgenic rats harboring mouse renin-2 gene (mREN2 rats). Five- to six-week-old, heterozygous mREN2 rats received the following drug regimens for 8 weeks: (1) controls; (2) cyclooxygenase-2 inhibitor (MF-tricyclic [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl) phenyl)-2(5H)-furanone], 14 mg kg(-1) p.o.); (3) cyclooxygenase-1/cyclooxygenase-2 inhibitor (sulindac, 14 mg kg(-1) p.o.); (4) angiotensin II receptor antagonist (losartan 40 mg kg(-1) p.o.); (5) MF-tricyclic + losartan; (6) sulindac + losartan. Normotensive Sprague-Dawley rats served as controls. mREN2 rats developed pronounced hypertension, cardiac hypertrophy, and albuminuria as compared to normotensive Sprague-Dawley controls. mREN2 rats showed pronounced perivascular inflammation and morphological damage in the kidneys and the heart. Both MF-tricyclic and sulindac further increased blood pressure and albuminuria in mREN2 rats. Neither MF-tricyclic nor sulindac were able to prevent angiotensin-II-induced perivascular inflammation and morphological changes in the heart or in the kidneys. Myocardial and renal cyclooxygenase-2 mRNA expressions were decreased in mREN2 rats, whereas no difference was found in cyclooxygenase-1 mRNA expressions. Sulindac increased both cyclooxygenase-1 and cyclooxygenase-2 gene expressions, whereas MF-tricyclic increased only cyclooxygenase-2 gene expressions. Losartan normalized blood pressure, cardiac hypertrophy, albuminuria, inflammatory response and morphological changes in mREN2 rats, both in the presence and absence of cyclooxygenase inhibitors. Our findings indicate that cyclooxygenase does not play a central role in the pathogenesis of angiotensin-II-induced inflammatory response and vascular injury in mREN2 rats.
Cheng
Zhong Jian
ZJ
Institute of Biomedicine, Pharmacology, Biomedicum Helsinki, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland.
Finckenberg
Piet
P
Louhelainen
Marjut
M
Merasto
Saara
S
Tikkanen
Ilkka
I
Vapaatalo
Heikki
H
Mervaala
Eero M A
EM
D000419:Albuminuria / Q000139:chemically induced / Q000517:prevention & control; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000139:chemically induced / Q000517:prevention & control; D002319:Cardiovascular System / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D005663:Furans / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007527:Isoenzymes / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics* / Q000502:physiology; D013467:Sulindac / Q000494:pharmacology; D014554:Urination / Q000187:drug effects
D000959:Antihypertensive Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D005663:Furans; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D000804:Angiotensin II; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D013467:Sulindac; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat; D012083:Renin; D019808:Losartan