Reversal of cardiac dysfunction by selective ET-A receptor antagonism

Abstract

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. 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 (APD20-UNX 6.8+/-1.1, DOCA-salt 10.1+/-1.5* ms; APD90-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). 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 (APD20 - 7.6+/-1.4**, APD90 - 41.5+/-6.9** ms) and normalised changes in vascular function. ET-A receptor antagonism both reverses and prevents the cardiac and vascular remodelling in DOCA-salt hypertension and improves cardiovascular function.

Figure 1

Daily water intake measurements for UNX (n=21), UNX+A-127722 (n=16), DOCA-salt (n=36) and DOCA-salt+A-127722 (n=20) treated rats; ^*P<0.05 vs UNX rats.

Figure 2

Daily body weight measurements for UNX (n=21), UNX+A-127722 (n=16), DOCA-salt (n=36) and DOCA-salt+A-127722 (n=20) treated rats; ^*P<0.05 vs UNX rats.

Figure 3

Daily A-127722 dose for UNX+A-127722 (n=16) and DOCA-salt+A-127722 (n=20).

Figure 4

Immunohistochemical analysis of ED1 cells in left ventricular interstitium; ^*P<0.05 vs UNX rats; ^**P<0.05 vs DOCA-salt rats.

Figure 5

Representative action potentials (a) and action potential durations (b) at 20, 50 and 90% repolarisation in isolated papillary muscles from UNX (n=8), UNX+A-127722 (n=6), DOCA-salt (n=6 at 2 weeks, n=8 at 4 weeks) and DOCA-salt+A-127722 (n=8) treated rats; ^*P<0.05 vs UNX rats, ^**P<0.05 vs DOCA-salt rats (4 weeks), ^#P<0.05 vs DOCA-salt rats (2 weeks).

Figure 6

Cumulative concentration–response curves for (a) noradrenaline, (b) acetylcholine and (c) sodium nitroprusside in thoracic aortic rings from UNX (n=12), UNX+A-127722 (n=7), DOCA-salt (n=7 at 2 weeks, n=12 at 4 weeks) and DOCA-salt+A-127722 (n=8) treated rats; maximal contractile response to noradrenaline from UNX (9.9±1.9 mN), UNX+A-127722 (9.4±1.3 mN), DOCA-salt 2 weeks (8.9±1.3 mN), DOCA-salt 4 weeks (4.7±0.5^*# mN) and DOCA-salt+A-127722 (8.8±1.6^** mN); maximal contractile response to potassium chloride (100 mM) from UNX (13.9±4.2 mN), UNX+A-127722 (15.5±1.6 mN), DOCA-salt 2 weeks (10.5±3.8 mN), DOCA-salt 4 weeks (5.4±0.6^* mN) and DOCA-salt+A-127722 (10.1±1.8^** mN); maximal relaxant response to acetylcholine from UNX (5.2±1.9 mN), UNX+A-127722 (5.4±0.2 mN), DOCA-salt 2 weeks (2.9±0.8^* mN), DOCA-salt 4 weeks (1.8±0.4^* mN) and DOCA-salt+A-127722 (3.9±0.9^** mN); maximal relaxant response to sodium nitroprusside from UNX (8.3±1.9 mN), UNX+A-127722 (9.1±1.5 mN), DOCA-salt 2 weeks (9.2±2.7 mN), DOCA-salt 4 weeks (6.1±1.8 mN) and DOCA-salt+A-127722 (9.9±2.3 mN); ^*P<0.05 vs UNX rats; ^**P<0.05 vs DOCA-salt rats, ^#P<0.05 vs DOCA-salt rats (2 weeks).