Bell, Robert Midgley; (2001) The role of nitric oxide in myocardial ischaemia/reperfusion injury. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The management of acute myocardial infarction requires rapid restoration of blood flow to attenuate cell death. In recent years, the possibility of fortifying the myocardium against ischaemia/reperfusion injury has emerged with the identification of signalling pathways that promote cellular survival, modalities that include preconditioning and ischaemia/reperfusion injury salvage (IRIS). Preconditioning and IRIS are defined as the protection triggered by a stimulus either before the insult or upon reperfusion respectively. Nitric oxide has been implicated as a potential mediator of cell survival and cell death; whether the cell lives or dies may be critically dependent upon the synthesis of this second messenger. Therefore to determine the role of nitric oxide in the mediation/ protection from ischaemia/reperfusion injury, the aim of this thesis is to elucidate the role of nitric oxide in preconditioning and IRIS paradigms. In early ischaemic preconditioning, an immediate onset phase of protection after the preconditioning stimulus, nitric oxide was found to lower the preconditioning threshold significantly; in eNOS knockout animals, the ischaemic preconditioning threshold is at least twice that in eNOS wild type animals. Delayed pharmacological preconditioning, whereby transient adenosine A1 receptor activation with 2-chloro N6 cyclopentyl adenosine results in robust protection 24 hours later, was found to be dependent upon the synthesis of nitric oxide. Interestingly, whilst previous studies indicated that delayed ischaemic preconditioning was dependent upon the induction of the inducible isoform of nitric oxide synthase, this study implicates the endothelial nitric oxide synthase (eNOS) as having an important role in mediating the protection observed. IRIS is a novel form of myocardial protection that we have hypothesised is dependent upon the activation of a reperfusion injury salvage kinase (RISK) pathway to attenuate necrotic injury. To activate the RISK pathway we used bradykinin, which was found to trigger protection that was reliant upon the activity of eNOS. Exogenous nitric oxide was administered to hearts subjected to ischaemia/reperfusion injury. In this study, a clear dose-response relationship was found between the concentration of nitric oxide and myocardial protection that peaks at 2 μM. At higher concentrations, protection against ischaemic injury was lost. The protection mediated by nitric oxide was found to be closely linked to the opening of the mitochondrial ATP sensitive potassium channel (KATP), as indicated by studies in isolated mitochondria and in the whole heart subjected to ischaemia/reperfusion injury. Thus, this thesis provides evidence that (i) nitric oxide is involved in all facets of myocardial resistance to injury, (ii) eNOS is a far more important source of nitric oxide than previously thought, and (iii) nitric oxide has a concentration dependent influence upon infarct size, possibly via a direct action upon mitochondrial KATP channels.

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