This Article Figures Only Full Text Full Text (PDF) 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 Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wittstein, I. S. Articles by Hare, J. M. Search for Related Content PubMed PubMed Citation Articles by Wittstein, I. S. Articles by Hare, J. M.

CLINICAL STUDY

Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy

^a Division of Cardiology, The Johns Hopkins Hospital, Baltimore, Maryland, USA

Manuscript received December 14, 2000; revised manuscript received April 19, 2001, accepted April 27, 2001.

Reprint requests and correspondence: Dr. Joshua M. Hare, The Johns Hopkins Hospital, 600 N. Wolfe Street, Carnegie 568, Baltimore, Maryland 21287
jhare{at}mail.jhmi.edu

OBJECTIVES

This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling.

BACKGROUND

The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure.

METHODS

The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N^G-monomethyl-L-arginine (L-NMMA, 5 mg/min).

RESULTS

In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 ± 8% (p < 0.001) and ventricular elastance (E_es) by 53 ± 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 ± 12% and E_es to –2 ± 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, E_es and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion.

CONCLUSIONS

Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   AT-1 = angiotensin-II receptor, type 1   DCM = dilated cardiomyopathy   +dP/dt = peak rate of rise of left ventricular pressure   Ea = arterial elastance   Ees = ventricular elastance   LVEDP = left ventricular end-diastolic pressure   LVEDV = left ventricular end-diastolic volume   L-NMMA = NG-monomethyl-L-arginine   NO = nitric oxide   NOS = nitric oxide synthase

This article has been cited by other articles:

				R. Bauer, V. Straub, A. Blain, K. Bushby, and G. A. MacGowan Contrasting effects of steroids and angiotensin-converting-enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy Eur J Heart Fail, May 1, 2009; 11(5): 463 - 471. [Abstract] [Full Text] [PDF]

				T. Ohta, N. Hasebe, S. Tsuji, K. Izawa, Y.-T. Jin, S. Kido, S. Natori, M. Sato, and K. Kikuchi Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2914 - H2921. [Abstract] [Full Text] [PDF]

				J. K. Bendall, T. Damy, P. Ratajczak, X. Loyer, V. Monceau, I. Marty, P. Milliez, E. Robidel, F. Marotte, J.-L. Samuel, et al. Role of Myocardial Neuronal Nitric Oxide Synthase-Derived Nitric Oxide in {beta}-Adrenergic Hyporesponsiveness After Myocardial Infarction-Induced Heart Failure in Rat Circulation, October 19, 2004; 110(16): 2368 - 2375. [Abstract] [Full Text] [PDF]

				W. J. Paulus and J. G. F. Bronzwaer Nitric oxide's role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H8 - H13. [Abstract] [Full Text] [PDF]

				D. A. Kass, J. G.F. Bronzwaer, and W. J. Paulus What Mechanisms Underlie Diastolic Dysfunction in Heart Failure? Circ. Res., June 25, 2004; 94(12): 1533 - 1542. [Abstract] [Full Text] [PDF]

				P.B. Massion, O. Feron, C. Dessy, and J.-L. Balligand Nitric Oxide and Cardiac Function: Ten Years After, and Continuing Circ. Res., September 5, 2003; 93(5): 388 - 398. [Abstract] [Full Text] [PDF]

				T. P. Cappola, L. Cope, A. Cernetich, L. A. Barouch, K. Minhas, R. A. Irizarry, G. Parmigiani, S. Durrani, T. Lavoie, E. P. Hoffman, et al. Deficiency of different nitric oxide synthase isoforms activates divergent transcriptional programs in cardiac hypertrophy Physiol Genomics, June 24, 2003; 14(1): 25 - 34. [Abstract] [Full Text] [PDF]

				W.-P. Qiu, Q. Hu, N. Paolocci, R. C. Ziegelstein, and D. A. Kass Differential effects of pulsatile versus steady flow on coronary endothelial membrane potential Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H341 - H346. [Abstract] [Full Text] [PDF]

				J. G. F. Bronzwaer, C. Heymes, C. A. Visser, and W. J. Paulus Myocardial fibrosis blunts nitric oxide synthase-related preload reserve in human dilated cardiomyopathy Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H10 - H16. [Abstract] [Full Text] [PDF]

				W. M Aartsen, M. P Schuijt, A.H.J. Danser, M. J.A.P Daemen, and J. F.M Smits The role of locally expressed angiotensin converting enzyme in cardiac remodeling after myocardial infarction in mice Cardiovasc Res, November 1, 2002; 56(2): 205 - 213. [Abstract] [Full Text] [PDF]

				J. G.F Bronzwaer, C. Zeitz, C. A Visser, and W. J Paulus Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart Cardiovasc Res, August 1, 2002; 55(2): 270 - 278. [Abstract] [Full Text] [PDF]

				T. Ignjatovic, F. Tan, V. Brovkovych, R. A. Skidgel, and E. G. Erdos Novel Mode of Action of Angiotensin I Converting Enzyme Inhibitors. DIRECT ACTIVATION OF BRADYKININ B1 RECEPTOR J. Biol. Chem., May 3, 2002; 277(19): 16847 - 16852. [Abstract] [Full Text] [PDF]

				W. J. Paulus, S. Frantz, and R. A. Kelly Nitric Oxide and Cardiac Contractility in Human Heart Failure: Time for Reappraisal Circulation, November 6, 2001; 104(19): 2260 - 2262. [Full Text] [PDF]