From the Experimental Research Laboratory, Division of Cardiology,
University of Louisville, Louisville, Ky.
Correspondence to Roberto Bolli, MD, Division of Cardiology, University of Louisville, Louisville, KY 40292. E-mail rbolli{at}louisville.edu
Background—Despite intense
investigation, the effector of the infarct-limiting protection observed
during the late phase of ischemic preconditioning (PC) remains
unknown. The goal of this study was to test the hypothesis that late PC
against myocardial infarction is mediated by the activity of nitric
oxide synthase (NOS).
Methods and Results—Conscious rabbits underwent a 30-minute
coronary occlusion followed by 3 days of reperfusion. In group
I (control group, n=10), infarct size (tetrazolium staining) averaged
56.8±5.3% of the risk region, which was decreased to 27.6±2.5%
(P<0.05) in rabbits preconditioned 24 hours earlier
with a sequence of six 4-minute occlusion/4-minute reperfusion cycles
(group II, n=10). When preconditioned rabbits were given the
nonselective NOS inhibitor
N
Conclusions—Taken together, these results indicate that in the
conscious rabbit, the infarct-sparing effect of the late phase of
ischemic PC is mediated by the activity of NOS and suggest that
the specific isoform primarily responsible for this cardioprotective
phenomenon is iNOS. Thus, NO appears to be a pivotal component of the
pathophysiological cascade of late PC.
© 1998 American Heart Association, Inc.
Basic Science Reports
Nitric Oxide Synthase Is the Mediator of Late Preconditioning Against Myocardial Infarction in Conscious Rabbits
-nitro-L-arginine (L-NA, 13
mg/kg IV [group III, n=8]) or the selective iNOS
inhibitor aminoguanidine (AG, 150 mg/kg SC [group V,
n=7]) before the 30-minute occlusion, the protective effect of late PC
was completely abrogated; that is, infarct size (59.9±4.5% and
65.8±3.3%, respectively) was similar to that measured in the control
group. Measurements of systolic wall thickening
(sonomicrometry) demonstrated that L-NA and AG also abolished the
improved recovery of myocardial function effected by late PC in group
II. When rabbits were given L-NA or AG without prior PC (group IV
[n=8] and group VI [n=6], respectively), infarct size did not
differ from that observed in controls (53.8±4.3% and 59.8±4.3%,
respectively), demonstrating that L-NA and AG do not increase the
extent of cell death in nonpreconditioned
myocardium.
Key Words: nitric oxide • ischemia • reperfusion • myocardial infarction
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F. Jung, L. A. Palmer, N. Zhou, and R. A. Johns Hypoxic Regulation of Inducible Nitric Oxide Synthase via Hypoxia Inducible Factor-1 in Cardiac Myocytes Circ. Res., February 18, 2000; 86(3): 319 - 325. [Abstract] [Full Text] [PDF]
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B. Dawn, Y.-T. Xuan, Y. Qiu, H. Takano, X.-L. Tang, P. Ping, S. Banerjee, M. Hill, and R. Bolli Bifunctional Role of Protein Tyrosine Kinases in Late Preconditioning Against Myocardial Stunning in Conscious Rabbits Circ. Res., December 3, 1999; 85(12): 1154 - 1163. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, S. Huang, X. Cao, X.-L. Tang, R. C. X. Li, Y.-T. Zheng, Y. Qiu, A. Clerk, P. Sugden, et al. PKC-dependent activation of p46/p54 JNKs during ischemic preconditioning in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1771 - H1785. [Abstract] [Full Text] [PDF]
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K. Baghelai, L. J. Graham, A. S. Wechsler, and E. R. Jakoi Phenylephrine induces delayed cardioprotection against necrosis without amelioration of stunning Ann. Thorac. Surg., October 1, 1999; 68(4): 1219 - 1224. [Abstract] [Full Text] [PDF]
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Y. Guo, W. K. Jones, Y.-T. Xuan, X.-L. Tang, W. Bao, W.-J. Wu, H. Han, V. E. Laubach, P. Ping, Z. Yang, et al. The late phase of ischemic preconditioning is abrogated by targeted disruption of the inducible NO synthase gene PNAS, September 28, 1999; 96(20): 11507 - 11512. [Abstract] [Full Text] [PDF]
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P. Ping, J. Zhang, Y.-T. Zheng, R. C. X. Li, B. Dawn, X.-L. Tang, H. Takano, Z. Balafanova, and R. Bolli Demonstration of Selective Protein Kinase C–Dependent Activation of Src and Lck Tyrosine Kinases During Ischemic Preconditioning in Conscious Rabbits Circ. Res., September 17, 1999; 85(6): 542 - 550. [Abstract] [Full Text] [PDF]
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A. Rizvi, X.-L. Tang, Y. Qiu, Y.-T. Xuan, H. Takano, A. K. Jadoon, and R. Bolli Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H874 - H884. [Abstract] [Full Text] [PDF]
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R. D Rakhit, R. J Edwards, and M. S Marber Nitric oxide, nitrates and ischaemic preconditioning Cardiovasc Res, August 15, 1999; 43(3): 621 - 627. [Full Text] [PDF]
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C. S.R. Baker, O. Rimoldi, P. G. Camici, E. Barnes, M. R. Chacon, T. Y. Huehns, D. O. Haskard, J. M. Polak, and R. J.C. Hall Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases Cardiovasc Res, August 15, 1999; 43(3): 685 - 697. [Abstract] [Full Text] [PDF]
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K. Stambaugh, G. T. Elliott, K. A. Jacobson, and B. T. Liang Additive Effects of Late Preconditioning Produced By Monophosphoryl Lipid A and the Early Preconditioning Mediated By Adenosine Receptors and KATP Channel Circulation, June 29, 1999; 99(25): 3300 - 3307. [Abstract] [Full Text] [PDF]
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Y.-T. Xuan, X.-L. Tang, S. Banerjee, H. Takano, R. C. X. Li, H. Han, Y. Qiu, J.-J. Li, and R. Bolli Nuclear Factor-{kappa}B Plays an Essential Role in the Late Phase of Ischemic Preconditioning in Conscious Rabbits Circ. Res., May 14, 1999; 84(9): 1095 - 1109. [Abstract] [Full Text] [PDF]
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P. Ping, H. Takano, J. Zhang, X.-L. Tang, Y. Qiu, R. C. X. Li, S. Banerjee, B. Dawn, Z. Balafonova, and R. Bolli Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits : A Signaling Mechanism for Both Nitric Oxide–Induced and Ischemia-Induced Preconditioning Circ. Res., March 19, 1999; 84(5): 587 - 604. [Abstract] [Full Text] [PDF]
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Y. Guo, W.-J. Wu, Y. Qiu, X.-L. Tang, Z. Yang, and R. Bolli Demonstration of an early and a late phase of ischemic preconditioning in mice Am J Physiol Heart Circ Physiol, October 1, 1998; 275(4): H1375 - H1387. [Abstract] [Full Text] [PDF]
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T. C. Zhao, M. M. Taher, K. C. Valerie, and R. C. Kukreja p38 Triggers Late Preconditioning Elicited by Anisomycin in Heart: Involvement of NF-{kappa}B and iNOS Circ. Res., November 9, 2001; 89(10): 915 - 922. [Abstract] [Full Text] [PDF]
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