Significant roles of endothelin-A- and -B-receptors in renal function in congestive heart failure.
Endothelin-1 (ET-1) not only causes potent vasoconstriction but also leads to fluid retention, both actions mediated by ET(A)- and/or ET(B)-receptors. Selective ET(A)- and combined ET(A)/ET(B)-receptor antagonists improve hemodynamics in heart failure; however, it is also important to evaluate the effects of these antagonists on urine output in heart failure. We administered an acute dose of either the selective ET(A)-receptor antagonist FR139317 (FR, n=5, 1 and 3 mg/kg) or the mixed ET(A)/ET(B)-receptor antagonist TAK-044 (TAK, n = 5, 1 and 3 mg/kg) to dogs with heart failure induced by rapid ventricular pacing. Renal hemodynamic and tubular functions were subsequently investigated. FR increased urinary excretion in association with increased renal plasma flow (RPF) and glomerular filtration rate (GFR) with no significant changes in the fractional reabsorption of water distally (FRWD). In contrast, despite increased GFR, TAK did not alter urine volume or RPF with significantly increased FRWD. The increase of GFR and RPF induced by FR was significantly larger than that of TAK. These findings indicate that ET(B)-receptor activation may result in diuresis by renal vasodilatation and reduction of water reabsorption in the distal tubules and collecting ducts. Acute ET(A)-receptor antagonism may therefore be more beneficial to diuresis than dual ET(A)/ET(B)-receptor inhibition in heart failure.
Ohnishi
M
M
The First Department of Internal Medicine, Shiga University of Medical Science, Otsu, Japan. ohnishi@suncuore.med1.shiga-med.ac.jp
Wada
A
A
Tsutamoto
T
T
Sawaki
M
M
Fujii
M
M
Matsumoto
T
T
Kinoshita
M
M
D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004285:Dogs; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*
D001381:Azepines; D007211:Indoles; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C079574:FR 139317; C088196:TAK 044