Effect of angiotensin II blockade on the fibroproliferative response to phenylephrine in the rat heart.
In this study we infused phenylephrine into adult Wistar rats and used losartan to test for a possible role of angiotensin II in the phenylephrine-induced fibrosis. Phenylephrine, given by Alzet minipumps at a rate of 25 mg.kg-1.d-1, produced a rapid and striking fibrotic response that was obvious after 1 day and progressed throughout a 3-day infusion period. Northern and Western blot analyses showed large increases in cardiac fibronectin expression and atrial natriuretic peptide mRNA, corresponding to fibroblast proliferation and myocyte hypertrophy, respectively. Cardiac fibrosis, fibronectin mRNA, and atrial natriuretic peptide mRNA were blocked by prazosin (7 mg.kg-1.d-1). Administration of losartan (10 mg.kg-1.d-1) resulted in a threefold decrease in interstitial and perivascular fibroblast proliferation, as measured by proliferating cell nuclear antigen immunoreactivity (p < .05), a marked reduction of fibronectin mRNA in the heart, and a moderate reduction of cardiac atrial natriuretic peptide mRNA. The data suggest that effects mediated by a1-adrenergic and angiotensin type 1 receptors may promote cardiac fibrosis.
Farivar
R S
RS
Boston University School of Medicine, MA 02118, USA.
Crawford
D C
DC
Chobanian
A V
AV
Brecher
P
P
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015152:Blotting, Northern; D005355:Fibrosis; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D010656:Phenylephrine / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012084:Renin-Angiotensin System / Q000502:physiology; D013777:Tetrazoles / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D007093:Imidazoles; D007211:Indoles; D018809:Proliferating Cell Nuclear Antigen; D013777:Tetrazoles; D000804:Angiotensin II; C052035:trandolapril; D010656:Phenylephrine; D012313:RNA; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D019808:Losartan