Reversal of cardiac dysfunction by selective ET-A receptor antagonism

Allan, Anthony and Fenning, Andrew and Levick, Scott and Hoey, Andrew and Brown, Lindsay (2005) Reversal of cardiac dysfunction by selective ET-A receptor antagonism. British Journal of Pharmacology, 146 (6). pp. 846-853. ISSN 0007-1188

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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 (25mg every 4th day sc) and 1% NaCl in drinking water for 28 days developed hypertension (systolic BP: UNX 128 6, DOCA-salt 182 5* mmHg; *P<0.05 vs UNX), left ventricular hypertrophy (UNX 1.99 0.06, DOCA-salt 3.30 0.08* mg/kg body wt), decreased left ventricular internal diameter (UNX 6.69 0.18, 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 repolarization (APD20 - UNX 6.8 1.1, DOCA-salt 10.1 1.5* msec; APD90 - UNX 34.4 3.5, DOCA-salt 64.3 10.4* msec) and vascular dysfunction (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 blood pressure (150 6** mmHg, **P<0.05 vs DOCA-salt), left ventricular wet weight (2.65 0.06** mg/kg 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** msec) and normalized 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.

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Item Type: Article (Commonwealth Reporting Category C)
Refereed: Yes
Item Status: Live Archive
Additional Information: Reproduced in accordance with the copyright policy of the publisher.
Faculty/School / Institute/Centre: Historic - Faculty of Sciences - Department of Biological and Physical Sciences (Up to 30 Jun 2013)
Faculty/School / Institute/Centre: Historic - Faculty of Sciences - Department of Biological and Physical Sciences (Up to 30 Jun 2013)
Date Deposited: 11 Oct 2007 00:21
Last Modified: 02 Jul 2013 22:32
Uncontrolled Keywords: endothelin, remodelling, hypertension, hypertrophy, collagen, rats
Fields of Research (2008): 11 Medical and Health Sciences > 1115 Pharmacology and Pharmaceutical Sciences > 111504 Pharmaceutical Sciences
11 Medical and Health Sciences > 1116 Medical Physiology > 111603 Systems Physiology
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