Nitric oxide plays a major role in oxygen-derived free radical generation in defibrillation and reperfusion injury; nitric oxide reacts with the superoxide radical to form peroxynitrite, which is toxic in itself and also forms further strongly oxidizing species resembling the hydroxyl radical. By limiting nitric oxide availability, nitric oxide synthase inhibitors may limit this process and ameliorate defibrillation/ reperfusion toxicity. Magnesium also has a role to play: it can also limit oxygen-derived free radical generation via its actions as a """"""""physiologic calcium antagonist"""""""", which include limiting the formation and release of endothelial-derived nitric oxide. The combination of NO synthase inhibitors and magnesium may be particularly effective. We will emphasize the direct detection of ascorbate radical to examine a series of testable hypotheses. Our overall hypotheses that the nitric oxide/superoxide/peroxynitrite pathway is a major source of free radicals that contribute to both defibrillation and reperfusion injury. Modulation of nitric oxide will alter bury from defibrillation and ischemia-reperfusion. The specific, testable hypotheses are: 1) Nitric oxide synthase inhibitors, by limiting the NO available to react with superoxide (forming peroxynitrite), reduce free radical generation and thereby ameliorate defibrillation and reperfusion injury. This preserves left ventricular function after defibrillation and/or reperfusion (i.e., less """"""""stunning""""""""). 2) Conversely, NO donors (SIN-1), by providing more NO substrate to react with superoxide and form toxic peroxynitrite, will increase free radical generation after defibrillation and/or reperfusion, worsening left ventricular function. 3) Magnesium, which we have already shown to reduce free radical generation in reperfusion injury, will be similarly cardioprotective in ameliorating defibrillation injury, reducing radical generation and deserving ventricular function. 4) The combination of nitric oxide synthase inhibitors and magnesium, which alter two different mechanisms/pathways to limit free radical generation, will be especially cardioprotective, ameliorating defibrillation and reperfusion injury.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL053284-07
Application #
6389389
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Dunn, Rosalie
Project Start
1995-07-01
Project End
2003-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
7
Fiscal Year
2001
Total Cost
$178,149
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Clark, Craig B; Zhang, Yi; Martin, Sean M et al. (2004) The nitric oxide synthase inhibitor N(G)-nitro-L-arginine decreases defibrillation-induced free radical generation. Resuscitation 60:351-7
Zhang, Yi; Davies, Loyd R; Martin, Sean M et al. (2003) The nitric oxide donor S-nitroso-N-acetylpenicillamine (SNAP) increases free radical generation and degrades left ventricular function after myocardial ischemia-reperfusion. Resuscitation 59:345-52
Zhang, Yi; Davies, Loyd R; Martin, Sean M et al. (2003) Magnesium reduces free radical concentration and preserves left ventricular function after direct current shocks. Resuscitation 56:199-206
Zhang, Yi; Davies, Loyd R; Coddington, William J et al. (2003) Open-chest epicardial ""surgical"" defibrillation: biphasic versus monophasic waveform shocks. Pacing Clin Electrophysiol 26:711-8
Zhang, Yi; Ramabadran, R S; Boddicker, Kimberly A et al. (2003) Triphasic waveforms are superior to biphasic waveforms for transthoracic defibrillation: experimental studies. J Am Coll Cardiol 42:568-75
Clark, Craig B; Zhang, Yi; Martin, Sean M et al. (2003) The nitric oxide synthase inhibitor N(G)-nitro-L-arginine decreases defibrillation-induced free radical generation. Resuscitation 57:101-8
Oltman, Christine L; Clark, Craig B; Kane, Neal L et al. (2003) Coronary vascular dysfunction associated with direct current shock injury. Basic Res Cardiol 98:406-15
Clark, Craig B; Zhang, Yi; Davies, L Ray et al. (2002) Transthoracic biphasic waveform defibrillation at very high and very low energies: a comparison with monophasic waveforms in an animal model of ventricular fibrillation. Resuscitation 54:183-6
Zhang, Yi; Clark, Craig B; Davies, L Ray et al. (2002) Body weight is a predictor of biphasic shock success for low energy transthoracic defibrillation. Resuscitation 54:281-7
Karlsson, G; Zhang, Y; Davies, L R et al. (2001) Does electrode polarity alter the energy requirements for transthoracic biphasic waveform defibrillation? Experimental studies. Resuscitation 51:77-81

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