Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin antagonist on survival, hemodynamics, and cardiac remodeling.
BACKGROUND
Plasma levels of the vasoconstrictor peptide endothelin (ET) are increased in chronic heart failure (CHF), and ET levels are a major predictor of mortality in this disease. Thus, ET may play a deleterious role in CHF. The purpose of this study was to assess the effects of chronic treatment with the ET receptor antagonist bosentan in a rat model of CHF.


RESULTS
Rats were subjected to coronary artery ligation and were treated for 2 or 9 months with placebo or bosentan (30 or 100 mg x kg(-1) x d(-1)). Bosentan 100 mg x kg(-1) markedly increased survival (after 9 months: untreated, 47%; bosentan, 65%; P<.01). Throughout the 9-month treatment period, bosentan significantly reduced arterial pressure and heart rate. After 2 or 9 months of treatment, the ET antagonist reduced central venous pressure and left ventricular (LV) end-diastolic pressure as well as plasma catecholamines, urinary cGMP, and LV ventricular collagen density. Bosentan also reduced LV dilatation (evidenced at 2 months by a shift in the pressure/volume relationship ex vivo). Echocardiographic studies performed after 2 months showed that the ET antagonist reduced hypertrophy and increased contractility of the noninfarcted LV wall. The lower dose of bosentan (30 mg x kg(-1)), which had no major hemodynamic or structural effects, also had no effect on survival.


CONCLUSIONS
Long-term treatment with an ET antagonist markedly increases survival in this rat model of CHF. This increase in survival is associated with decreases in both preload and afterload and an increase in cardiac output as well as decreased LV hypertrophy, LV dilatation, and cardiac fibrosis. Thus, chronic treatment with ET antagonists such as bosentan might be beneficial in human CHF and might increase long-term survival in this disease.
Mulder
P
P
VACOMED, Department of Pharmacology, Rouen University Medical School and Rouen University Hospital, France.
Richard
V
V
Derumeaux
G
G
Hogie
M
M
Henry
J P
JP
Lallemand
F
F
Compagnon
P
P
Macé
B
B
Comoy
E
E
Letac
B
B
Thuillez
C
C
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D002306:Cardiac Volume / Q000187:drug effects; D002908:Chronic Disease; D003094:Collagen / Q000032:analysis; D003243:Consciousness; D003331:Coronary Vessels / Q000187:drug effects / Q000473:pathology*; D006152:Cyclic GMP / Q000652:urine; D004452:Echocardiography; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000097:blood*; D016232:Endothelins / Q000494:pharmacology; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality; D006352:Heart Ventricles / Q000737:chemistry / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood; D011312:Pressure; D011498:Protein Precursors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides / Q000494:pharmacology; D016019:Survival Analysis; D016277:Ventricular Function, Left
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D003094:Collagen; D006152:Cyclic GMP; D000077300:Bosentan; D009638:Norepinephrine