Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease.
OBJECTIVE
We sought to demonstrate non-angiotensin converting enzyme (ACE) dependent angiotensin II (AII) generating pathways in resistance arteries from patients with chronic heart failure (CHF).


BACKGROUND
Non-ACE dependent AII generation occurs in resistance arteries from normal volunteers. Inhibition of non-ACE dependent AII generation may have therapeutic potential in CHF.


METHODS
Resistance arteries were dissected from gluteal biopsies from patients with coronary heart disease (CHD) and preserved left ventricular function and from patients with CHF. Using wire myography, concentration response curves to angiotensin I (AI) and AII were constructed in the presence of 1) vehicle, 2) chymostatin [an inhibitor of chymase], 3) enalaprilat, and 4) the combination of chymostatin and enalaprilat.


RESULTS
In resistance arteries from patients with CHD, the vasoconstrictor response to AI was not inhibited by either inhibitor alone (chymostatin [p > or = 0.05] or enalaprilat [p > or = 0.05]) but was significantly inhibited by the combination (p < 0.001). In arteries from patients with CHF, AI responses were inhibited by enalaprilat (p < 0.05) but not by chymostatin alone (p > 0.05). The combination ofchymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p < or = 0.01).


CONCLUSIONS
Non-ACE dependent AII generating pathways exist in resistance arteries from patients with both CHF and CHD. In resistance arteries from patients with CHD, inhibition of either the ACE or chymase pathway alone has no effect on AII generation, and both pathways must be blocked before the vasoconstrictor action of AI is inhibited. In CHF, blockade of ACE results in marked inhibition of responses to AI, but this is enhanced by coinhibition of chymase. These studies suggest that full suppression of the renin-angiotensin system cannot be achieved by ACE inhibition alone and provide a rationale for developing future therapeutic strategies.
Petrie
M C
MC
Clinical Research Initiative in Heart Failure, University of Glasgow, Scotland, United Kingdom.
Padmanabhan
N
N
McDonald
J E
JE
Hillier
C
C
Connell
J M
JM
McMurray
J J
JJ
D000109:Acetylcholine / Q000494:pharmacology; D000368:Aged; D000787:Angina Pectoris / Q000503:physiopathology*; D000803:Angiotensin I / Q000378:metabolism / Q000494:pharmacology; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D001920:Bradykinin / Q000494:pharmacology; D053818:Chymases; D015773:Enalaprilat / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects
D000806:Angiotensin-Converting Enzyme Inhibitors; D009842:Oligopeptides; D000804:Angiotensin II; D000803:Angiotensin I; C002101:chymostatin; D007703:Peptidyl-Dipeptidase A; D012697:Serine Endopeptidases; D053818:Chymases; D015773:Enalaprilat; D019808:Losartan; D000109:Acetylcholine; D001920:Bradykinin