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
Mark C. Petrie, BSc, MB, ChB, MRCP*,
Neal Padmanabhan, MA, BM, BCh, MRCP ,
John E. McDonald, BSc, MB, ChB, MRCP* ,
Chris Hillier, BSc, PhD*,
John M. C. Connell, MD, FRCP and
John J. V. McMurray, BSc, MD, FRCP, FESC, FACC*
* Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, Scotland UK
Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland UK
Manuscript received August 4, 1999;
revised manuscript received November 8, 2000,
accepted December 13, 2000.
Reprint requests and correspondence: Dr. Neal Padmanabhan, Medical Research Council Blood Pressure Group, Department of Medicine and Therapeutics, Western Infirmary, University of Glasgow, Glasgow, United Kingdom, G11 6NT
np3n{at}clinmed.gla.ac.uk
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 and Acronyms
| | 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 |
|
This article has been cited by other articles:
|
|
|
|
 
M. Agirbasli, A. Cincin, and O. A Baykan
Short-term effects of angiotensin receptor blockers on blood pressure control, and plasma inflammatory and fibrinolytic parameters in patients taking angiotensin-converting enzyme inhibitors
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2008;
9(1):
22 - 26.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Seed, R. Gardner, J. McMurray, C. Hillier, D. Murdoch, R. MacFadyen, A. Bobillier, J. Mann, and T. McDonagh
Neurohumoral effects of the new orally active renin inhibitor, aliskiren, in chronic heart failure
Eur J Heart Fail,
November 1, 2007;
9(11):
1120 - 1127.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kobori, M. Nangaku, L. G. Navar, and A. Nishiyama
The Intrarenal Renin-Angiotensin System: From Physiology to the Pathobiology of Hypertension and Kidney Disease
Pharmacol. Rev.,
September 1, 2007;
59(3):
251 - 287.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Chandrashekhar and J. Narula
Exposing ACE up the Sleeve...
J. Nucl. Med.,
February 1, 2007;
48(2):
173 - 174.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Kohlstedt, C. Gershome, M. Friedrich, W. Muller-Esterl, F. Alhenc-Gelas, R. Busse, and I. Fleming
Angiotensin-Converting Enzyme (ACE) Dimerization Is the Initial Step in the ACE Inhibitor-Induced ACE Signaling Cascade in Endothelial Cells
Mol. Pharmacol.,
May 1, 2006;
69(5):
1725 - 1732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Fleming
Signaling by the Angiotensin-Converting Enzyme
Circ. Res.,
April 14, 2006;
98(7):
887 - 896.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. R. Marcy and T. L. Ripley
Aldosterone antagonists in the treatment of heart failure
Am. J. Health Syst. Pharm.,
January 1, 2006;
63(1):
49 - 58.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Demers, J. J. V. McMurray, K. Swedberg, M. A. Pfeffer, C. B. Granger, B. Olofsson, R. S. McKelvie, J. Ostergren, E. L. Michelson, P. A. Johansson, et al.
Impact of Candesartan on Nonfatal Myocardial Infarction and Cardiovascular Death in Patients With Heart Failure
JAMA,
October 12, 2005;
294(14):
1794 - 1798.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Zhou, L. C. Matavelli, H. Ono, and E. D. Frohlich
Superiority of combination of thiazide with angiotensin-converting enzyme inhibitor or AT1-receptor blocker over thiazide alone on renoprotection in L-NAME/SHR
Am J Physiol Renal Physiol,
October 1, 2005;
289(4):
F871 - F879.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. van der Harst, M. Volbeda, A. A. Voors, H. Buikema, S. Wassmann, M. Bohm, G. Nickenig, and W. H. van Gilst
Vascular Response to Angiotensin II Predicts Long-Term Prognosis in Patients Undergoing Coronary Artery Bypass Grafting
Hypertension,
December 1, 2004;
44(6):
930 - 934.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J.V. McMurray, M. A. Pfeffer, K. Swedberg, and V. J. Dzau
Which Inhibitor of the Renin-Angiotensin System Should Be Used in Chronic Heart Failure and Acute Myocardial Infarction?
Circulation,
November 16, 2004;
110(20):
3281 - 3288.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. N. Gring and G. S. Francis
A hard look at angiotensin receptor blockers in heart failure
J. Am. Coll. Cardiol.,
November 2, 2004;
44(9):
1841 - 1846.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. L.M. Cruden, F. N. Witherow, D. J. Webb, K. A.A. Fox, and D. E. Newby
Bradykinin Contributes to the Systemic Hemodynamic Effects of Chronic Angiotensin-Converting Enzyme Inhibition in Patients With Heart Failure
Arterioscler Thromb Vasc Biol,
June 1, 2004;
24(6):
1043 - 1048.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A Doggrell and J. C Wanstall
Vascular chymase: pathophysiological role and therapeutic potential of inhibition
Cardiovasc Res,
March 1, 2004;
61(4):
653 - 662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Berl
Angiotensin-Converting Enzyme Inhibitors versus AT1 Receptor Antagonist in Cardiovascular and Renal Protection: The case for AT1 Receptor Antagonist
J. Am. Soc. Nephrol.,
January 1, 2004;
15(90010):
S71 - 76.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
M. A. Pfeffer, J. J.V. McMurray, E. J. Velazquez, J.-L. Rouleau, L. Kober, A. P. Maggioni, S. D. Solomon, K. Swedberg, F. Van de Werf, H. White, et al.
Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both
N. Engl. J. Med.,
November 13, 2003;
349(20):
1893 - 1906.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D B McKenzie and A J Cowley
Drug therapy in chronic heart failure
Postgrad. Med. J.,
November 1, 2003;
79(937):
634 - 642.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. R. Huang, W. Y. Chen, L. D. Truong, and H. Y. Lan
Chymase Is Upregulated in Diabetic Nephropathy: Implications for an Alternative Pathway of Angiotensin II-Mediated Diabetic Renal and Vascular Disease
J. Am. Soc. Nephrol.,
July 1, 2003;
14(7):
1738 - 1747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. W. Braith, R. M. Mills, C. S. Wilcox, G. L. Davis, J. A. Hill, and C. E. Wood
High-dose angiotensin-converting enzyme inhibition restores body fluid homeostasis in heart-transplant recipients
J. Am. Coll. Cardiol.,
February 5, 2003;
41(3):
426 - 432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. P. Jorde, T. Vittorio, S. D. Katz, P. C. Colombo, F. Latif, and T. H. Le Jemtel
Elevated Plasma Aldosterone Levels Despite Complete Inhibition of the Vascular Angiotensin-Converting Enzyme in Chronic Heart Failure
Circulation,
August 27, 2002;
106(9):
1055 - 1057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. A Sica
Review: The practical aspects of combination therapy with angiotensin receptor blockers and angiotensin-converting enzyme inhibitors
Journal of Renin-Angiotensin-Aldosterone System,
June 1, 2002;
3(2):
66 - 71.
[Abstract]
[PDF]
|
|
|
|
|
|
|
C. A. J. Farquharson and A. D. Struthers
Gradual reactivation over time of vascular tissue angiotensin I to angiotensin II conversion during chronic lisinopril therapy in chronic heart failure
J. Am. Coll. Cardiol.,
March 6, 2002;
39(5):
767 - 775.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns
Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide
Am J Physiol Heart Circ Physiol,
December 1, 2001;
281(6):
H2337 - H2365.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. McDonald, N. Padmanabhan, M. C. Petrie, C. Hillier, J. M.C. Connell, and J. J.V. McMurray
Vasoconstrictor Effect of the Angiotensin-Converting Enzyme-Resistant, Chymase-Specific Substrate [Pro11D-Ala12] Angiotensin I in Human Dorsal Hand Veins: In Vivo Demonstration of Non-ACE Production of Angiotensin II in Humans
Circulation,
October 9, 2001;
104(15):
1805 - 1808.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. McMurray
Angiotensin II receptor antagonists for the treatment of heart failure: what is their place after ELITE-II and Val-HeFT?
Journal of Renin-Angiotensin-Aldosterone System,
June 1, 2001;
2(2):
89 - 92.
[PDF]
|
|
|
|
