Chronic effects of an endothelin-converting enzyme inhibitor on cardiorenal and hormonal function in heart failure.
Endothelin (ET)-converting enzyme (ECE) is a rate-limiting step in ET-1 generation, and its expression and activity are increased significantly with the development of congestive heart failure (CHF). The selective enzymic inhibition of ET-1 formation thus seems to be a very important target in the prevention of CHF. We evaluated the chronic effects of a specific ECE inhibitor, FR901533 (0.3 mg x kg(-1) x h(-1), n=5) on cardiac, hormonal, and body fluid balance in dogs with CHF induced by rapid right ventricular pacing (270 beats/min, 22 days). Vehicle dogs were given placebo (n=5). Despite no significant difference in blood pressure, FR901533 decreased pulmonary capillary wedge pressure and increased cardiac output compared with the vehicle. FR901533 prevented the reduction of urine flow rate and urinary sodium excretion in association with an increase in the glomerular filtration rate and renal plasma flow compared with the vehicle. FR901533 also suppressed significantly the elevation of plasma atrial natriuretic peptide and aldosterone levels which is an established prognostic factor in CHF. These results indicate that the role of ECE in CHF is important and that chronic ECE inhibition could possess therapeutic potential in the treatment of CHF not only on haemodynamics but also in the prevention of fluid retention.
First Department of Internal Medicine, Shiga University of Medical Science, Tsukinowa, Seta, Otsu 520-2192, Japan. wada@belle.shiga-med.ac.jp
Atsuyuki
A
Wada
Masato
M
Ohnishi
Takayoshi
T
Tsutamoto
Masanori
M
Fujii
Takehiro
T
Matsumoto
Takashi
T
Yamamoto
Xinwen
X
Wang
Masahiko
M
Kinoshita
D000450:Aldosterone / Q000097:blood; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D009320:Atrial Natriuretic Factor / Q000097:blood; D002302:Cardiac Output / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D004285:Dogs; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D008666:Metalloendopeptidases; D023421:Models, Animal; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D012079:Renal Circulation / Q000187:drug effects; D013754:Tetracyclines / Q000627:therapeutic use*
D004791:Enzyme Inhibitors; D013754:Tetracyclines; C088494:WS 79089B; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes