Published Online
on May 20, 2002

A more recent version of this article appeared on June 11, 2002

This Article Full Text (PDF) All Versions of this Article: 105/23/2785    most recent 01.CIR.0000017433.90061.2Ev1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nikolaidis, L. A. Articles by Shannon, R. P. Search for Related Content PubMed Articles by Nikolaidis, L. A. Articles by Shannon, R. P. Related Collections Congestive ACE/Angiotension receptors Heart failure - basic studies Myocardial cardiomyopathy disease Coronary circulation Endothelium/vascular type/nitric oxide

Submitted on January 29, 2002
Revised on March 20, 2002
Accepted on March 21, 2002

Angiotensin-Converting Enzyme Inhibitors Improve Coronary Flow Reserve in Dilated Cardiomyopathy by a Bradykinin-Mediated, Nitric Oxide--Dependent Mechanism

Lazaros A. Nikolaidis MD, Aaron Doverspike MS, Rhonda Huerbin LVT, Teresa Hentosz BS, and Richard P. Shannon MD^*

From the Cardiovascular Research Institute, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pa.

^* To whom correspondence should be addressed. E-mail: rshannon{at}wpahs.org.

Background—ACE inhibitors have been used extensively in heart failure, where they induce systemic vasodilatation. ACE inhibitors have also been shown to reduce ischemic events after myocardial infarction, although their mechanisms of action on the coronary circulation are less well understood. The purpose of the present study was to determine the effects and the mechanism of action of the ACE inhibitor enalaprilat and the AT₁ antagonist losartan on regional myocardial perfusion and coronary flow and vasodilator reserve in conscious dogs with pacing-induced dilated cardiomyopathy (DCM).

Methods and Results—Twenty-seven conscious, chronically instrumented dogs were studied during advanced stages of dilated cardiomyopathy, which was induced by rapid pacing. Enalaprilat (1.25 mg IV) improved transmural distribution (endocardial/epicardial ratio) at rest (baseline, 0.91±0.11; enalaprilat, 1.02±0.07 mL/min per g; P<0.05) and during atrial pacing (baseline, 0.82±0.11; enalaprilat, 0.98±0.07; P<0.05). Enalaprilat also restored subendocardial coronary flow reserve (CFR) (baseline CFR, 1.89±0.11; enalaprilat CFR, 2.74±0.33; P<0.05) in DCM. These effects were abolished by pretreatment with the NO synthase inhibitor nitro-L-arginine. The effects were recapitulated by the bradykinin₂ receptor agonist cereport but not by the AT₁ antagonist losartan.

Conclusions—The ACE inhibitor enalaprilat improves transmural myocardial perfusion at rest and after chronotropic stress and restores impaired subendocardial coronary flow and vasodilator reserve in DCM. The effects of enalaprilat were bradykinin mediated and NO dependent and were not recapitulated by losartan. These data suggest beneficial effects of ACE inhibitors on the coronary circulation in DCM that are not shared by AT₁ receptor antagonists.

Key words: angiotensin • bradykinin • nitric oxide • cardiomyopathy • microcirculation

This article has been cited by other articles:

				M. White, H. Ross, S. Levesque, L. Whittom, G. B Pelletier, N. Racine, S. Meloche, and L. Voisin Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant Ann. Pharmacother., May 1, 2009; 43(5): 831 - 839. [Abstract] [Full Text] [PDF]

				B. I. Levy, E. L. Schiffrin, J.-J. Mourad, D. Agostini, E. Vicaut, M. E. Safar, and H. A.J. Struijker-Boudier Impaired Tissue Perfusion: A Pathology Common to Hypertension, Obesity, and Diabetes Mellitus Circulation, August 26, 2008; 118(9): 968 - 976. [Full Text] [PDF]

				N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]

				L. A. Nikolaidis, I. Poornima, P. Parikh, M. Magovern, Y.-T. Shen, and R. P. Shannon The Effects of Combined Versus Selective Adrenergic Blockade on Left Ventricular and Systemic Hemodynamics, Myocardial Substrate Preference, and Regional Perfusion in Conscious Dogs With Dilated Cardiomyopathy J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1871 - 1881. [Abstract] [Full Text] [PDF]

				T. Unger and Jun Li The role of the renin-angiotensin-aldosterone system in heart failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1_suppl): S7 - S10. [Abstract] [PDF]

				C. Pizzi, O. Manfrini, F. Fontana, and R. Bugiardini Angiotensin-Converting Enzyme Inhibitors and 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase in Cardiac Syndrome X: Role of Superoxide Dismutase Activity Circulation, January 6, 2004; 109(1): 53 - 58. [Abstract] [Full Text] [PDF]

				D. Tonduangu, L. Hittinger, B. Ghaleh, P. Le Corvoisier, L. Sambin, S. Champagne, T. Badoual, F. Vincent, A. Berdeaux, B. Crozatier, et al. Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs Circulation, January 6, 2004; 109(1): 114 - 119. [Abstract] [Full Text] [PDF]

				R. Chen, M. Iwai, L. Wu, J. Suzuki, L.-J. Min, T. Shiuchi, T. Sugaya, H.-W. Liu, T.-X. Cui, and M. Horiuchi Important Role of Nitric Oxide in the Effect of Angiotensin-Converting Enzyme Inhibitor Imidapril on Vascular Injury Hypertension, October 1, 2003; 42(4): 542 - 547. [Abstract] [Full Text] [PDF]

				P. L. Hooper Diabetes, Nitric Oxide, and Heat Shock Proteins Diabetes Care, March 1, 2003; 26(3): 951 - 952. [Full Text] [PDF]