title: AT1 receptor blockade increases cardiac bradykinin via neutral endopeptidase after induction of myocardial infarction in rats.
abstract: ACE inhibition protects the heart against ischemic injury by reducing angiotensin II and promoting bradykinin (BK) accumulation. Since neutral endopeptidase (NEP) metabolizes BK, we determined its activity after induction of myocardial infarction (MI) and examined whether it is influenced by treatment with an ACE inhibitor or AT1 receptor blocker. Rats were studied 6 days and 3 wk after coronary occlusion. Starting 48 h after MI induction, additional animals were treated with the ACE inhibitor quinapril (2 mg x kg(-1) x day-1) or the AT1 blocker irbesartan (50 mg x kg(-1) x day-1). Animals were hemodynamically characterized. Finally, NEP-specific activity and BK concentrations were detected in homogenates of heart compartments. Quinapril and irbesartan treatment improved left ventricular function 6 days and 3 wk after MI induction, and NEP activity was elevated only in the infarcted area of untreated compared with sham-operated rats. After 6 days, irbesartan reversed this increase by 80% and quinapril by 35%. Quinapril had no effect after 3 wk, whereas irbesartan almost completely blocked the increased NEP activity in the infarcted area and concomitantly induced a further rise in the BK concentrations. These results indicate mechanisms of NEP regulation influenced by the AT1 receptor. Our data suggest that NEP is more decisive than ACE in mediating BK degradation and may indicate BK involvement in the cardioprotective effects of AT1 antagonists.
authors.affiliation: Department of Cardiology and Pneumology, Free University of Berlin, Berlin, Germany. thomas.walther@ukbf.fu-berlin.de
authors.forename: Thomas
authors.initials: T
authors.lastname: Walther
authors.forename: Wolf-E
authors.initials: WE
authors.lastname: Siems
authors.forename: Dorian
authors.initials: D
authors.lastname: Hauke
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
authors.forename: Winfried
authors.initials: W
authors.lastname: Krause
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001920:Bradykinin / Q000096:biosynthesis*; D006439:Hemodynamics; D000077405:Irbesartan; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D015260:Neprilysin / Q000378:metabolism*; D000077583:Quinapril; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D007546:Isoquinolines; D044140:Receptor, Angiotensin, Type 1; D044005:Tetrahydroisoquinolines; D013777:Tetrazoles; D015260:Neprilysin; D000077405:Irbesartan; D000077583:Quinapril; D001920:Bradykinin