Clinical study: heart failure
Angiotensin converting enzyme (ACE) and non-ACE dependent angiotensin II generation in resistance arteries from patients with heart failure and coronary heart disease

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Abstract

OBJECTIVES

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 ≥ 0.05] or enalaprilat [p ≥ 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 of chymostatin and enalaprilat markedly inhibited the response to AI (p < 0.001) to a greater degree than enalaprilat alone (p ≤ 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.

Abbreviations

ACE
angiotensin converting enzyme
ACh
acetylcholine
AI
angiotensin I
AII
angiotensin II
BK
bradykinin
CHD
coronary heart disease
CHF
chronic heart failure
KPSS
Kreb’s solution with KCl substituted for NaCl on an equimolar basis
LV
left ventricle, left ventricular
LVEF
left ventricular ejection fraction
NE
norepinephrine
RAAS
renin-angiotensin-aldosterone system

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Dr. Petrie was the recipient of a British Heart Foundation Junior Research Fellowship (FS/97031:1997), and Dr. Padmanabhan was the recipient of a Wellcome Trust Junior Research Fellowship. Also supported by the Medical Research Council (Programme Grants held by J.J.V.M. and J.M.C.C.) and the Chief Scientist Office of the Scottish Executive (project grant held jointly by J.J.V.M., J.M.C.C, N.P. and M.C.P.).