Repression of angiotensin II and potentiation of bradykinin contribute to the synergistic effects of dual metalloprotease inhibition in heart failure.
Neutral endopeptidase inhibition (NEP-I) and angiotensin converting enzyme inhibition (ACE-I) act synergistically to produce acute beneficial hemodynamic effects in models of heart failure. Blockade of the formation of angiotensin II (Ang II) acting together with potentiation of the natriuretic peptides, bradykinin and other vasoactive peptides may mediate the interaction of dual enzyme inhibition. In this study, the potential roles of Ang II repression and bradykinin potentiation were evaluated in conscious cardiomyopathic hamsters with compensated heart failure. The Ang II AT1 receptor antagonist, SR 47436 (BMS-186295), was administered at 30 mumol/kg, i.v. followed by i.v. infusion at 1 mumol/kg/min in combination with NEP-I (SQ-28603 at 30 mumol/kg i.v.). Cardiac preload (left ventricular end diastolic pressure) and afterload (left ventricular systolic pressure) decreased significantly more after the combination of Ang II blockade and NEP-I than after either treatment alone. This indicated that repression of Ang II contributes importantly to the NEP-I/ACE-I interaction. Bradykinin B2 receptor antagonism by Hoe 140 at 100 micrograms/kg, i.v. significantly blunted the decrease in left ventricular end diastolic pressure but not the decrease in left ventricular systolic pressure after dual NEP-I/ACE-I (SQ-28603 and enalaprilat each at 30 mumol/kg, i.v.). This suggests that bradykinin potentiation contributes to the preload-reducing, but not the afterload-reducing, acute effects of NEP-I/ACE-I. Hence, both Ang II repression and bradykinin potentiation are factors contributing to the synergistic hemodynamic effects of combined NEP-I and ACE-I in hamsters with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Pharmacology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
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Panchal
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Fox
D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001810:Blood Volume / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D006224:Cricetinae; D004357:Drug Synergism; D015773:Enalaprilat / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D000077405:Irbesartan; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
D001713:Biphenyl Compounds; D013777:Tetrazoles; C065359:SQ 28603; D000804:Angiotensin II; C065679:icatibant; D015260:Neprilysin; D015773:Enalaprilat; D000077405:Irbesartan; D000409:Alanine; D001920:Bradykinin