Effects of angiotensin II generated by an angiotensin converting enzyme-independent pathway on left ventricular performance in the conscious baboon.
Human chymase is a serine proteinase that converts angiotensin (Ang) I to Ang II independent of angiotensin converting enzyme (ACE) in vitro. The effects of chymase on systemic hemodynamics and left ventricular function in vivo were studied in nine conscious baboons instrumented with a LV micromanometer and LV minor axis and wall thickness sonomicrometer crystal pairs. Measurements were made at baseline and after [Pro11DAla12] Ang I, a specific substrate for human chymase, was given in consecutive fashion as a 0.1 mg bolus, an hour-long intravenous infusion of 5 mg, a 3 mg bolus, and after 5 mg of an Ang II receptor antagonist. [Pro11DAla12]Ang I significantly increased LV systolic and diastolic pressure, LV end-diastolic and end systolic dimensions and the time constant of LV relaxation and significantly decreased LV fractional shortening and wall thickening. Administration of a specific Ang II receptor antagonist reversed all the hemodynamic changes. In separate studies, similar results were obtained in six of the baboons with ACE blockade (20 mg, intravenous captopril). Post-mortem studies indicated that chymase-like activity was widely distributed in multiple tissues. Thus, in primates, Ang I is converted into Ang II by an enzyme with chymase-like activity. This study provides the first in vivo evidence of an ACE-independent pathway for Ang II production.
Hoit
B D
BD
Division of Cardiology, University of Cincinnati Medical Center, Ohio 45267-0542, USA.
Shao
Y
Y
Kinoshita
A
A
Gabel
M
M
Husain
A
A
Walsh
R A
RA
D000803:Angiotensin I / Q000031:analogs & derivatives* / Q000378:metabolism; D000804:Angiotensin II / Q000096:biosynthesis* / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D016477:Artifacts; D002216:Captopril / Q000494:pharmacology; D053818:Chymases; D003243:Consciousness; D003971:Diastole / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007261:Infusions, Intra-Arterial; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D010215:Papio; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D013599:Systole / Q000187:drug effects; D014018:Tissue Distribution; D016277:Ventricular Function, Left / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; C087635:angiotensin I, Pro(11)-Ala(12)-; D000804:Angiotensin II; D000803:Angiotensin I; D002216:Captopril; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases