Sustained improvement of cardiac function and prevention of cardiac remodeling after long-term dual ECE-NEP inhibition in rats with congestive heart failure.
Acute inhibition of endothelin converting enzyme (ECE) and neutral endopeptidase (NEP) exerts beneficial hemodynamic effects in chronic heart failure (CHF). However, the long-term effects of dual ECE-NEP inhibition are unknown. We evaluated, in rats with CHF, the long-term effects of the dual ECE-NEP inhibitor CGS 26303 (10 mg.kg(-1).day(-1)) on systemic and left ventricular (LV) hemodynamics and LV remodeling, and compared them to those induced by the selective NEP inhibitor CGS 24592 (10 mg.kg(-1).day(-1)), both administered subcutaneously by mini-pump for 30 days starting 7 days after left coronary artery ligation. After 30 days, CGS 26303, but not CGS 24592, reduced systolic blood pressure, while both drugs never affected heart rate. Echocardiographic studies showed that only CGS 26303 diminished LV end-diastolic and systolic diameters and increased LV fractional shortening and cardiac output. Moreover, CGS 26303, but not CGS 24592, reduced LV end-diastolic pressure, while LV dP/dtmax/min was not affected. Both drugs reduced collagen accumulation in the 'viable' part of the LV, but only CGS 26303 reduced LV weight. Thus, long-term treatment with CGS 26303 decreases both preload and afterload, increases cardiac output, and diminishes LV hypertrophy, dilatation, and cardiac fibrosis, suggesting that dual ECE-NEP inhibition might be beneficial in human CHF.
Mulder
Paul
P
Rouen University Medical School, France. paul.mulder@univ-rouen.fr
Barbier
Stephane
S
Monteil
Christelle
C
Jeng
Arco Y
AY
Henry
Jean Paul
JP
Renet
Sylvanie
S
Thuillez
Christian
C
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002302:Cardiac Output / Q000187:drug effects / Q000502:physiology; D000072396:Endothelin-Converting Enzymes; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology / Q000627:therapeutic use; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
C086164:CGS 24592; D063065:Organophosphonates; D013777:Tetrazoles; C089987:CGS 26303; D010649:Phenylalanine; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes