Comparison of the effects of selective endothelin ETA and ETB receptor antagonists in congestive heart failure.
OBJECTIVE
This study was designed 1) to determine the extent to which endogenous endothelin (ET) affects hemodynamic, hormonal and body fluid balance through ETA and ETB receptors in congestive heart failure (CHF); and 2) to assess the therapeutic benefits and adverse effects of ET receptor antagonists for ETA and ETB on cardiorenal and neurohormonal variables.


BACKGROUND
ET has two receptors, ETA and ETB, both of which are distributed in various tissues and cells. In vascular beds, ETA receptors mediate vasoconstriction, whereas ETB receptors mediate vasorelaxation. However, ETB receptors also exist in smooth muscle and mediate vasoconstriction.


METHODS
We administered either the ETA receptor antagonist FR139317 (FR [n = 8], 1 and 10 mg/kg body weight) or the ETB receptor antagonist RES-701-1 (RES [n = 8], 0.2 and 1.5 mg/kg) to dogs with CHF induced by rapid ventricular pacing. The effects of both antagonists on cardiorenal and hormonal functions were studied.


RESULTS
FR decreased cardiac pressures and the plasma atrial natriuretic peptide (ANP) level and increased cardiac output (CO). Urinary flow rate and urinary sodium excretion increased in association with an increase in the glomerular filtration rate and renal plasma flow (RPF). In contrast, RES increased cardiac pressures and decreased CO. It also decreased the plasma aldosterone level and RPF. Neither antagonist affected plasma norepinephrine levels.


CONCLUSIONS
Endogenous ETs increase cardiac pressures and the retention of body fluid through ETA receptors in CHF. The vasodilative action through ETB receptors is overall functionally more important than the constrictive action through ETB receptors. ETs may regulate the secretion of ANP and aldosterone. Our findings suggest that selective ETA receptor antagonists have potential therapeutic benefits affecting both hemodynamic variables and diuresis, whereas ETB receptor antagonists have adverse hemodynamic effects, with the possibility of preventing fluid retention through suppression of aldosterone secretion in dogs with CHF.
Wada
A
A
First Department of Internal Medicine, Shiga University of Medical Science, Seta, Otsu, Japan. wada@belle.shiga-med.ac.jp
Tsutamoto
T
T
Fukai
D
D
Ohnishi
M
M
Maeda
K
K
Hisanaga
T
T
Maeda
Y
Y
Matsuda
Y
Y
Kinoshita
M
M
D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001381:Azepines / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D005260:Female; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014563:Urodynamics / Q000187:drug effects
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D007211:Indoles; D010456:Peptides, Cyclic; C079574:FR 139317; C087120:RES 701-1; D009320:Atrial Natriuretic Factor