© 2002 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Nitric oxide as a mediator of delayed pharmacological (A1 receptor triggered) preconditioning; is eNOS masquerading as iNOS?
The Hatter Institute and Centre for Cardiology (Division of Medicine), University College London Medical School, Department of Cardiology, University College London Hospitals, Grafton Way, London WC1E 6DB, UK
* Corresponding author, The Hatter Institute for Cardiovascular Studies, Department of Academic Cardiology, University College Hospital, Gower Street, London WC1E 6AU, UK. Tel.: +44-20-7380-9888; fax: +44-20-7388-5095 hatter-institute{at}ucl.ac.uk
Background: Nitric oxide (NO), synthesised from the inducible isoform of nitric oxide synthase (iNOS), is implicated in mediating second window of protection (SWOP)/delayed ischemic preconditioning. However the role of NO and iNOS in delayed pharmacological protection remains unclear and is the subject of this investigation. Methods: To test the hypothesis that iNOS is necessary for delayed pharmacological preconditioning, the adenosine A1 receptor agonist, 2-chloro N6 cyclopentyl adenosine (CCPA) (25 µg/kg i.v.) or saline was administered to wild type (WT) or iNOS gene knockout mice (KO). Twenty-four hours later, the hearts were isolated, Langendorff perfused and subjected to 35 min ischemia/30 min reperfusion prior to infarct size determination. Results: WT and KO control hearts had identical infarct sizes of 37±3% and 37±2%, respectively. CCPA significantly reduced infarct size in WT hearts to 22±2% and also, unexpectedly, in KO hearts (27±2%). This protection was abrogated with the non-specific NOS inhibitor, N
nitro L-arginine methyl ester (L-NAME, 100 µM), and could be mimicked in naïve hearts with the NO donor, donor S-nitroso N-acetyl DL penicillamine (SNAP, 1 µM). Delayed protection appeared to be mediated by NO synthesis in both WT and KO hearts. Additional studies using Western blot analysis demonstrated endothelial NOS (eNOS) upregulation and increased NOx release in both WT and KO hearts. Conclusions: This is the first study to demonstrate a role for eNOS in delayed A1 receptor triggered (pharmacological) preconditioning, potentially representing a new pharmacological target for protecting the ischemic heart.
KEYWORDS Adenosine; Nitric oxide; Infarction; Preconditioning
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Y. Ye, Y. Lin, S. Manickavasagam, J. R. Perez-Polo, B. C. Tieu, and Y. Birnbaum Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice Am J Physiol Heart Circ Physiol, December 1, 2008; 295(6): H2436 - H2446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ye, J. D. Martinez, R. J. Perez-Polo, Y. Lin, B. F. Uretsky, and Y. Birnbaum The role of eNOS, iNOS, and NF-{kappa}B in upregulation and activation of cyclooxygenase-2 and infarct size reduction by atorvastatin Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H343 - H351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Merla, Y. Ye, Y. Lin, S. Manickavasagam, M.-H. Huang, R. J. Perez-Polo, B. F. Uretsky, and Y. Birnbaum The central role of adenosine in statin-induced ERK1/2, Akt, and eNOS phosphorylation Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1918 - H1928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. P. Taylor, M. E. Olsen, and J. W. Starnes Improved postischemic function following acute exercise is not mediated by nitric oxide synthase in the rat heart Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H601 - H607. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Atar, Y. Ye, Y. Lin, S. Y. Freeberg, S. P. Nishi, S. Rosanio, M.-H. Huang, B. F. Uretsky, J. R. Perez-Polo, and Y. Birnbaum Atorvastatin-induced cardioprotection is mediated by increasing inducible nitric oxide synthase and consequent S-nitrosylation of cyclooxygenase-2 Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1960 - H1968. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Feron and J.-L. Balligand Caveolins and the regulation of endothelial nitric oxide synthase in the heart Cardiovasc Res, March 1, 2006; 69(4): 788 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Guo, A. B. Stein, W.-J. Wu, X. Zhu, W. Tan, Q. Li, and R. Bolli Late preconditioning induced by NO donors, adenosine A1 receptor agonists, and {delta}1-opioid receptor agonists is mediated by iNOS Am J Physiol Heart Circ Physiol, November 1, 2005; 289(5): H2251 - H2257. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Lasley, B. J. Keith, G. Kristo, Y. Yoshimura, and R. M. Mentzer Jr. Delayed adenosine A1 receptor preconditioning in rat myocardium is MAPK dependent but iNOS independent Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H785 - H791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Xu, S.-S. Park, R. A. Mueller, R. C. Bagnell, C. Patterson, and P. G. Boysen Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes Cardiovasc Res, March 1, 2005; 65(4): 803 - 812. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Birnbaum, Y. Ye, S. Rosanio, S. Tavackoli, Z.-Y. Hu, E. R. Schwarz, and B. F. Uretsky Prostaglandins mediate the cardioprotective effects of atorvastatin against ischemia-reperfusion injury Cardiovasc Res, February 1, 2005; 65(2): 345 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Yamasowa, S. Shimizu, T. Inoue, M. Takaoka, and Y. Matsumura Endothelial Nitric Oxide Contributes to the Renal Protective Effects of Ischemic Preconditioning J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 153 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, C. Yin, L. Xi, and R. C. Kukreja Opening of Ca2+-activated K+ channels triggers early and delayed preconditioning against I/R injury independent of NOS in mice Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2070 - H2077. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Murphy Primary and Secondary Signaling Pathways in Early Preconditioning That Converge on the Mitochondria to Produce Cardioprotection Circ. Res., January 9, 2004; 94(1): 7 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. YELLON and J. M. DOWNEY Preconditioning the Myocardium: From Cellular Physiology to Clinical Cardiology Physiol Rev, October 1, 2003; 83(4): 1113 - 1151. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Arnaud, D. Godin-Ribuot, S. Bottari, A. Peinnequin, M. Joyeux, P. Demenge, and C. Ribuot iNOS is a mediator of the heat stress-induced preconditioning against myocardial infarction in vivo in the rat Cardiovasc Res, April 1, 2003; 58(1): 118 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Bell and D. M. Yellon Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway J. Am. Coll. Cardiol., February 5, 2003; 41(3): 508 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M Bell, H. L Maddock, and D. M Yellon The cardioprotective and mitochondrial depolarising properties of exogenous nitric oxide in mouse heart Cardiovasc Res, February 1, 2003; 57(2): 405 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Mentzer Jr., M. S. Jahania, and R. D. Lasley Myocardial Protection Card. Surg. Adult, January 1, 2003; 2(2003): 413 - 438. [Full Text]
|
|