Reversal of cardiac dysfunction by selective ET-A receptor antagonism

1. The effectiveness of a selective endothelin receptor-A (ET-A) antagonist, A-127722 (approximately10 mgkg day as 200 mgkg powdered food), to reverse existing cardiac remodelling and prevent further remodelling was tested in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 2. Uninephrectomised rats (UNX) administered DOCA (25 mg every fourth day s.c.) and 1% NaClin drinking water for 28 days developed hypertension (systolic blood pressure (BP): UNX12876 mmHg, DOCA-salt 18275* mmHg; *P0.05 vs UNX), left ventricular hypertrophy (UNX1.9970.06 mgkg1 body wt, DOCA-salt 3.3070.08* mgkg body wt), decreased left ventricularinternal diameter (UNX 6.6970.18 mm, DOCA-salt 5.5170.37* mm), an increased left ventricularmonocyte/macrophage infiltration together with an increased interstitial collagen from 2.770.3 to11.771.3%, increased passive diastolic stiffness (UNX 21.170.5, DOCA-salt 30.171.3*), prolongation of the action potential duration at 20 and 90% of repolarisation (APD20–UNX 6.871.1, DOCAsalt10.171.5* ms; APD90–UNX 34.473.5 ms, DOCA-salt 64.3710.4* ms) and vascular dysfunctions (2.6-fold decrease in maximal contractile response to noradrenaline, 3.5-fold decrease in maximalrelaxation response to acetylcholine). 3. Administration of A-127722 for 14 days starting 14 days after surgery attenuated the increases in systolic BP (15076** mmHg, **Po0.05 vs DOCA-salt), left ventricular wet weight (2.6570.06**mg kg body wt) and internal diameter (6.3970.31** mm), prevented left ventricular monocyte/macrophage accumulation, attenuated the increased left ventricular interstitial collagen (7.671.3%**), reversed the increased passive diastolic stiffness (22.171.2**), attenuated the action potential duration prolongation (APD20 – 7 . 671.4**, APD90 – 41.576.9** ms) and normalised changes in vascular function. 4. ET-A receptor antagonism both reverses and prevents the cardiac and vascular remodelling in DOCA-salt hypertension and improves cardiovascular function.