Myocardial Fibrosis in DOCA-Salt Hypertensive Rats

  • Ammarguellat F
  • Larouche I
  • Schiffrin E
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Abstract

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. Methods and 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-β 1 mRNA and TGF-β 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-β 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.

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Ammarguellat, F., Larouche, I., & Schiffrin, E. L. (2001). Myocardial Fibrosis in DOCA-Salt Hypertensive Rats. Circulation, 103(2), 319–324. https://doi.org/10.1161/01.cir.103.2.319

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