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Modulation of neutrophil activity by nitric oxide during acute myocardial ischaemia and reperfusion
R M Egdell1, T Siminiak, D J Sheridan
1Academic Cardiology Unit, St. Mary's Hospital Medical School, London, United Kingdom.
Abstract:
Nitric oxide (NO) exerts an inhibitory effect on polymorphonuclear neutrophil (PMN) function, via a cyclic GMP-mediated mechanism, while PMNs are known to play an important role in myocardial ischaemia-reperfusion injury (MI-R). Since the major source of NO, vascular endothelium, becomes functionally impaired during MI-R, it is attractive to hypothesize that it is this loss of endothelial nitric oxide production that allows PMN adherence and activation. The studies reviewed here add substance to this hypothesis. Authentic NO, administered during MI-R both reduces myocardial necrosis and PMN accumulation, while basal NO release, as estimated by coronary artery ring responses to L-NAME, an NO synthase inhibitor, declines during reperfusion with a time-course mirrored by PMN adherence in the same preparation. Reduction in infarct size and decreased PMN accumulation can also be demonstrated with L-arginine and NO donors. Since endothelial dysfunction leads to PMN adherence and PMNs have been shown to contribute to endothelial dysfunction, it seems probable that a positive feedback loop is generated during MI-R, leading to the amplification of PMN activity and subsequent myocardial damage.
Insights
Nitric oxide (NO) loss during myocardial ischemia-reperfusion (MI-R) injury allows neutrophil activation, worsening heart damage. Restoring NO levels can reduce injury and neutrophil accumulation, suggesting a therapeutic target for MI-R.
Area of Science:
- Cardiovascular Research
- Immunology
- Biochemistry
Background:
- Polymorphonuclear neutrophils (PMNs) contribute to myocardial ischemia-reperfusion (MI-R) injury.
- Nitric oxide (NO) normally inhibits PMN function via cyclic GMP.
- Endothelial NO production is impaired during MI-R.
Purpose of the Study:
- To investigate the role of nitric oxide (NO) in modulating polymorphonuclear neutrophil (PMN) activity during myocardial ischemia-reperfusion (MI-R) injury.
- To determine if impaired endothelial NO production contributes to PMN adherence and activation in MI-R.
- To evaluate the therapeutic potential of NO administration in mitigating MI-R damage.
Main Methods:
- Review of studies investigating NO modulation of PMN function in the context of MI-R.
- Assessment of basal NO release using L-NAME, an NO synthase inhibitor, in coronary artery ring preparations during reperfusion.
- Administration of authentic NO, L-arginine, and NO donors during MI-R models.
Main Results:
- Administered NO reduced myocardial necrosis and PMN accumulation during MI-R.
- Basal NO release declined during reperfusion, paralleling increased PMN adherence.
- L-arginine and NO donors decreased infarct size and PMN accumulation.
Conclusions:
- Loss of endothelial NO production during MI-R facilitates PMN adherence and activation.
- A positive feedback loop between endothelial dysfunction and PMN activity amplifies myocardial damage in MI-R.
- NO administration represents a promising therapeutic strategy for reducing MI-R injury.