Reversal of cardiac dysfunction by selective ET-A receptor antagonism.
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.
Allan
Anthony
A
Department of Physiology and Pharmacology, School of Biomedical Sciences, The University of Queensland, Brisbane 4072, Australia.
Fenning
Andrew
A
Levick
Scott
S
Hoey
Andrew
A
Brown
Lindsay
L
D000109:Acetylcholine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000077868:Atrasentan; D001835:Body Weight / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D003900:Desoxycorticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects; D065130:Endothelin A Receptor Antagonists; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009392:Nephrectomy / Q000379:methods; D009638:Norepinephrine / Q000494:pharmacology; D010210:Papillary Muscles / Q000187:drug effects / Q000503:physiopathology; D011189:Potassium Chloride / Q000494:pharmacology; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D020257:Ventricular Remodeling / Q000187:drug effects / Q000502:physiology
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D003900:Desoxycorticosterone; D011189:Potassium Chloride; D003094:Collagen; D000109:Acetylcholine; D000077868:Atrasentan; D009638:Norepinephrine