Chronic endothelin receptor blockade prevents renal vasoconstriction and sodium retention in rats with chronic heart failure.
OBJECTIVE
Importance of endothelin in mediating the chronic renal alterations of chronic heart failure was studied in rats chronically treated with bosentan after myocardial infarction.


METHODS
Rats were subjected to coronary artery ligation and were treated for 8 weeks with placebo or bosentan, a dual ET(A) and ET(B) receptor antagonist, (approximately 100 mg/kg/day) as food admix. Sham-operated rats served as normal controls. Cardiac and renal functions were measured at the end of 8-week treatment.


RESULTS
Bosentan significantly reduced the elevated left ventricular end-diastolic pressure (from 26.6+/-3.3 to 11.4+/-2.2 mmHg, P<0.001) and the increased heart-to-body-weight ratio seen in untreated rats with myocardial infarction. Bosentan prevented the marked increase in renal vascular resistance (bosentan, 7.7+/-0.6; untreated, 15.6+/-2.5 mmHg/ml/min; P<0.001). This led to a significant increase in renal plasma flow resulting in a decrease in filtration fraction. Bosentan furthermore increased urinary sodium excretion.


CONCLUSIONS
Prolonged ET receptor blockade in rats with myocardial infarction has chronic renal vasodilatory effect and improves renal sodium excretory function. Thus, dual ET antagonists such as bosentan might be useful in the treatment of the progressive renal failure associated with human chronic heart failure.
Ding
Shuang-Shuang
SS
Actelion Pharmaceuticals Ltd., CH-4123 Allschwil, Switzerland.
Qiu
Changbin
C
Hess
Patrick
P
Xi
Jian-Fei
JF
Clozel
Jean-Paul
JP
Clozel
Martine
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077300:Bosentan; D004334:Drug Administration Schedule; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000150:complications; D009318:Natriuresis / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D000959:Antihypertensive Agents; D065128:Endothelin Receptor Antagonists; D013449:Sulfonamides; D000077300:Bosentan