Published Online
on March 22, 2004

A more recent version of this article appeared on April 20, 2004

This Article Full Text (PDF) All Versions of this Article: 109/15/1886    most recent 01.CIR.0000124231.98250.A8v1 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ziolo, M. T. Articles by Bers, D. M. Search for Related Content PubMed PubMed Citation Articles by Ziolo, M. T. Articles by Bers, D. M. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Medline Plus Health Information Heart Failure Related Collections Calcium cycling/excitation-contraction coupling Heart failure - basic studies Endothelium/vascular type/nitric oxide

Submitted on April 9, 2002
Revised on December 30, 2003
Accepted on January 7, 2004

Myocyte Nitric Oxide Synthase 2 Contributes to Blunted -Adrenergic Response in Failing Human Hearts by Decreasing Ca²⁺ Transients

Mark T. Ziolo PhD, Lars S. Maier MD, Valentino Piacentino III PhD, Julie Bossuyt PhD, DVM, Steven R. Houser PhD, and Donald M. Bers PhD^*

From the Department of Physiology, Loyola University Medical Center, Maywood, Ill (M.T.Z., L.S.M., J.B., D.M.B.), and the Cardiovascular Research Group, Department of Physiology, Temple University School of Medicine, Philadelphia, Pa (V.P., S.R.H.). Dr Maier is now at the Department of Cardiology, Georg-August-University, Goettingen, Germany.

^* To whom correspondence should be addressed. E-mail: dbers{at}lumc.edu.

Background--Human heart failure (HF) usually exhibits blunted response to -adrenergic receptor (AR) stimulation. Here, we examined whether expression of nitric oxide synthase-2 (NOS2, or inducible NOS) contributes to this loss of inotropic reserve in human HF.

Methods and Results--Failing human hearts were obtained at transplantation. Contraction and [Ca²⁺]_i measurements were performed in isolated cardiac myocytes and trabeculae. In HF myocytes and muscle, isoproterenol (ISO), a -AR agonist, led to small inotropic and lusitropic responses. Specific inhibition of NOS2 by aminoguanidine (AG) or L-NIL dramatically increased the ISO-induced inotropy and lusitropy, such that the ISO+AG response in HF approached that seen with ISO alone in nonfailing human myocytes or muscles. Ca²⁺ transient data directly paralleled these results, indicating that altered cellular Ca²⁺ handling is responsible. In nonfailing human hearts, NOS2 inhibition had no effects. In addition, NOS2 inhibition also had no effect in 30% of failing hearts, but in these myocytes and muscles, the ISO response alone was similar to that of nonfailing hearts. In line with these functional findings, NOS2 protein expression measured by Western blotting was induced in HF when AG/L-NIL had a functional effect but not when AG/L-NIL had no effect on contractility and Ca²⁺ transients.

Conclusions--NOS2 expression strongly limited ISO-induced increases in contraction, twitch [Ca²⁺]_i, and lusitropy in trabeculae and isolated myocytes from failing human hearts. Thus, the -AR hyporesponsiveness in human HF is mediated in large part by NO (or related congeners) produced within cardiac myocytes via NOS2.

Key words: myocytes • receptors, adrenergic, beta • calcium • heart failure • nitric oxide synthase

This article has been cited by other articles:

				M. J. Kohr, H. Wang, D. G. Wheeler, M. Velayutham, J. L. Zweier, and M. T. Ziolo Targeting of phospholamban by peroxynitrite decreases {beta}-adrenergic stimulation in cardiomyocytes Cardiovasc Res, January 15, 2008; 77(2): 353 - 361. [Abstract] [Full Text] [PDF]

				A. Maffei, A. Di Pardo, R. Carangi, P. Carullo, R. Poulet, M. T. Gentile, C. Vecchione, and G. Lembo Nebivolol Induces Nitric Oxide Release in the Heart Through Inducible Nitric Oxide Synthase Activation Hypertension, October 1, 2007; 50(4): 652 - 656. [Abstract] [Full Text] [PDF]

				K. Kawai, T. Kawai, J. T. Sambol, D.-Z. Xu, Z. Yuan, F. J. Caputo, C. D. Badami, E. A. Deitch, and A. Yatani Cellular mechanisms of burn-related changes in contractility and its prevention by mesenteric lymph ligation Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2475 - H2484. [Abstract] [Full Text] [PDF]

				N. Burkard, A. G. Rokita, S. G. Kaufmann, M. Hallhuber, R. Wu, K. Hu, U. Hofmann, A. Bonz, S. Frantz, E. J. Cartwright, et al. Conditional Neuronal Nitric Oxide Synthase Overexpression Impairs Myocardial Contractility Circ. Res., February 16, 2007; 100(3): e32 - e44. [Abstract] [Full Text] [PDF]

				J. Steppan, S. Ryoo, K. H. Schuleri, C. Gregg, R. K. Hasan, A. R. White, L. J. Bugaj, M. Khan, L. Santhanam, D. Nyhan, et al. Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism PNAS, March 21, 2006; 103(12): 4759 - 4764. [Abstract] [Full Text] [PDF]

				S. Mak, C. B. Overgaard, and G. E. Newton Effect of vitamin C and L-NMMA on the inotropic response to dobutamine in patients with heart failure Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2424 - H2428. [Abstract] [Full Text] [PDF]

				M. T. Ziolo, J. L. Martin, J. Bossuyt, D. M. Bers, and S. M. Pogwizd Adenoviral Gene Transfer of Mutant Phospholamban Rescues Contractile Dysfunction in Failing Rabbit Myocytes With Relatively Preserved SERCA Function Circ. Res., April 29, 2005; 96(8): 815 - 817. [Abstract] [Full Text] [PDF]