Beneficial renal and cardiac effects of vasopeptidase inhibition with S21402 in heart failure.
S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction-induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg. kg(-1). d(-1)), an ACE inhibitor (captopril, 50 mg. kg(-1). d(-1)), a NEP inhibitor (SCH42495, 60 mg. kg(-1). d(-1)), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (P<0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (P<0.01). Both S21402 and captopril increased plasma renin activity (P<0.01), all treatment lowered plasma aldosterone (P<0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (P<0.01), SCH42495 inhibited NEP (P<0.01), and captopril inhibited ACE (P<0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (P<0.01), SCH42495 reduced right ventricular mass (P<0.01), and S21402 decreased left (P<0.05) and right ventricular mass (P<0.01), atrial mass (P<0.05), and lung mass (P<0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure.
Burrell
L M
LM
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Victoria, Australia. burrell@austin.unimelb.edu.au
Farina
N K
NK
Balding
L C
LC
Johnston
C I
CI
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002216:Captopril / Q000627:therapeutic use; D002319:Cardiovascular System / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006728:Hormones / Q000378:metabolism; D007668:Kidney / Q000187:drug effects; D008715:Methionine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000209:etiology; D015260:Neprilysin / Q000037:antagonists & inhibitors; D011422:Propionates / Q000627:therapeutic use*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000627:therapeutic use*; D014867:Water / Q000378:metabolism
D000806:Angiotensin-Converting Enzyme Inhibitors; D006728:Hormones; D011422:Propionates; D011480:Protease Inhibitors; C111219:S 21402-1; D013438:Sulfhydryl Compounds; D014867:Water; C069018:SCH 42495; D002216:Captopril; D008715:Methionine; D015260:Neprilysin