Comparison of the acute effects of a selective endothelin ETA and a mixed ETA/ETB receptor antagonist in heart failure.
OBJECTIVE
Both the selective endothelin (ET) ETA receptor and mixed ETA/ETB receptor antagonists improve haemodynamics in patients and experimental models with congestive heart failure (CHF) and reduce the mortality in CHF rats. However, it remains unclear which of these antagonists is superior in the treatment of CHF. In addition, there is little information as to whether these ET receptor antagonists contribute to the neuroendocrine regulation and body fluid balance. We therefore investigated the cardiorenal and neurohumoral benefits of selective ETA receptor and mixed ETA/ETB receptor antagonists in CHF.


METHODS
We administered acutely either the selective ETA receptor antagonist FR139317 (FR, n = 6, 1 and 10 mg/kg) or the mixed ETA/ETB receptor antagonist TAK-044 (TAK, n = 6, 1 and 3 mg/kg) to conscious dogs with CHF induced by rapid right ventricular pacing for ten days.


RESULTS
Both FR and TAK decreased the cardiac pressures and the plasma atrial natriuretic peptide level and increased the cardiac output and urinary sodium excretion. FR increased the urine flow rate in association with an increased glomerular filtration rate and renal plasma flow, while TAK reduced the plasma aldosterone level. Neither antagonist increased the plasma renin activity or norepinephrine levels.


CONCLUSIONS
These ETA/ETB antagonist. However, the long-term administration of a mixed ETA/ETB receptor antagonist would improve not only the haemodynamics but also prevent fluid retention by suppressing secretion of aldosterone during the treatment of chronic CHF.
Ohnishi
M
M
First Department of Internal Medicine, Shiga University of Medical Science, Japan.
Wada
A
A
Tsutamoto
T
T
Fukai
D
D
Kinoshita
M
M
D000450:Aldosterone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001381:Azepines / Q000627:therapeutic use*; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects*; D007211:Indoles / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D017595:Renal Plasma Flow / Q000187:drug effects; D012964:Sodium / Q000652:urine
D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; C079574:FR 139317; C088196:TAK 044; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D012964:Sodium