Reversal of cardiac dysfunction by selective ET-A receptor antagonism

1 The effectiveness of a selective endothelin receptor- A ( ET- A) antagonist, A- 127722 ( approximately 10 mg kg(-1) day(-1) as 200 mg kg(-1) 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% NaCl in drinking water for 28 days developed hypertension ( systolic blood pressure ( BP): UNX 128 +/- 6 mmHg, DOCA- salt 182 +/- 5* mmHg; *P<0.05 vs UNX), left ventricular hypertrophy (UNX 1.99 +/- 0.06 mg kg(-1) body wt, DOCA- salt 3.30 +/- 0.08* mg kg(-1) body wt), decreased left ventricular internal diameter (UNX 6.69 +/- 0.18 mm, DOCA- salt 5.51 +/- 0.37* mm), an increased left ventricular monocyte/macrophage infiltration together with an increased interstitial collagen from 2.7 +/- 0.3 to 11.7 +/- 1.3%, increased passive diastolic stiffness (UNX 21.1 +/- 0.5, DOCA- salt 30.1 +/- 1.3*), prolongation of the action potential duration at 20 and 90% of repolarisation (APD(20) - UNX 6.8 +/- 1.1, DOCA-salt 10.1 +/- 1.5* ms; APD(90) - UNX 34.4 +/- 3.5 ms, DOCA- salt 64.3 +/- 10.4* ms) and vascular dysfunctions ( 2.6- fold decrease in maximal contractile response to noradrenaline, 3.5- fold decrease in maximal relaxation response to acetylcholine). 3 Administration of A- 127722 for 14 days starting 14 days after surgery attenuated the increases in systolic BP ( 150 +/- 6** mmHg, ** P<0.05 vs DOCA- salt), left ventricular wet weight ( 2.65 +/- 0.06** mg kg(-1) body wt) and internal diameter (6.39 +/- 0.31** mm), prevented left ventricular monocyte/macrophage accumulation, attenuated the increased left ventricular interstitial collagen ( 7.6 +/- 1.3%**), reversed the increased passive diastolic stiffness ( 22.1 +/- 1.2**), attenuated the action potential duration prolongation (APD(20) - 7.6 +/- 1.4**, APD(90) - 41.5 +/- 6.9** 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.