Endothelin mediates the altered renal hemodynamics associated with experimental congestive heart failure.
Congestive heart failure (CHF) is commonly associated with renal dysfunction. The goal of the current study was to evaluate the role of endothelin in the renal dysfunction of experimental CHF by using tezosentan, a potent dual endothelin receptor antagonist. Rats were subjected to coronary artery ligation. Cardiac and renal hemodynamics were assessed after 3-5 weeks, when CHF had developed. Compared with control rats, CHF rats had significantly higher left ventricular end-diastolic pressure (LVEDP), lower mean arterial pressure, and reduced dP/dt(max). CHF rats had severe renal vasoconstriction, as assessed by increased renal vascular resistance (RVR, p < 0.001), decreased renal plasma flow (RPF, p < 0.001), and glomerular filtration rate (GFR, p < 0.001). Filtration fraction rose (p < 0.001). Urine flow rate and sodium excretion were markedly lower. Acute administration of tezosentan induced a marked decrease in LVEDP without change of dP/dt(max) and heart rate. Tezosentan decreased RVR (-43%, p < 0.001) and increased RPF and GFR. Filtration fraction decreased slightly. Tezosentan also increased urine flow rate and sodium excretion. These findings demonstrate that endothelin at least partly mediates the altered renal hemodynamics associated with experimental CHF. Dual endothelin receptor blockade could be useful for the improvement of both cardiac and renal function in CHF.
Qiu
C
C
Actelion Pharmaceuticals, Allschwil, Switzerland.
Ding
S S
SS
Hess
P
P
Clozel
J P
JP
Clozel
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D017466:Receptors, Endothelin; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan