Myocardial fibrosis in DOCA-salt hypertensive rats: effect of endothelin ET(A) receptor antagonism.
BACKGROUND
To test the hypothesis that endothelin-1 contributes to cardiac fibrosis, cardiac collagen deposition was studied in deoxycorticosterone acetate-salt (DOCA-salt) hypertensive rats, in which the endothelin system is activated. The effects of the ET(A)-selective endothelin receptor antagonist A-127722 were evaluated.


RESULTS
A-127722 (30 mg/kg per day) was administered for 4 weeks. Myocardial fibrosis was evaluated after Sirius red F3BA staining. Systolic blood pressure was 103+/-1.6 mm Hg in unilaterally nephrectomized rats (Uni-Nx), 202+/-3.2 mm Hg in DOCA-salt rats (P:<0.01 versus Uni-Nx), and 182+/-3.1 mm Hg in ET(A) antagonist-treated DOCA-salt rats (P:<0.01 versus DOCA-salt or Uni-Nx). In DOCA-salt rats, interstitial and perivascular collagen density was increased in the subendocardial and midmyocardial regions of the left ventricle (3- to 4-fold, P:<0.05), whereas in subepicardial myocardium, the increase was predominantly perivascular. The ET(A) antagonist prevented cardiac fibrosis in DOCA-salt rats. Procollagen I and III mRNA, which were increased in hearts of DOCA-salt rats, were normalized by ET(A) antagonist treatment. TGF-beta(1) mRNA and TGF-beta(1) protein increased at 1 week in DOCA-salt rats and were lowered in ET(A) antagonist-treated rats.


CONCLUSIONS
ET(A) receptor-mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-beta(1). These results support the hypothesis of a role for endothelin-1 in cardiac collagen deposition in mineralocorticoid hypertension, which may have pathophysiological and pharmacological implications in hypertensive heart disease.
Ammarguellat
F
F
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, Montréal, Québec, Canada.
Larouche
I
I
Schiffrin
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EL
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003900:Desoxycorticosterone; D065130:Endothelin A Receptor Antagonists; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D009929:Organ Size / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1
D024042:Collagen Type I; D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D003094:Collagen; D000077868:Atrasentan