Myocardial Fibrosis in DOCA-Salt Hypertensive Rats

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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 ETA-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 (PA antagonist–treated DOCA-salt rats (PPA 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 ETA antagonist treatment. TGF-β1 mRNA and TGF-β1 protein increased at 1 week in DOCA-salt rats and were lowered in ETA antagonist–treated rats. Conclusions—ETA receptor–mediated collagen deposition in hearts of DOCA-salt rats results from increased procollagen synthesis associated with an initial increment in expression of TGF-β1. 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.