Okorie, M.; (2012) Mechanisms of ischaemic protection in humans. Doctoral thesis , UCL (University College London).

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Abstract

Reperfusion limits ischaemic tissue damage. Paradoxically, reperfusion can cause additional tissue injury and contribute to a composite phenomenon known as ischaemia reperfusion (IR) injury. Therapeutic interventions aimed at reducing IR injury have the potential to improve outcomes in the management of ischaemic conditions. Protective procedures such as ischaemic preconditioning (IPC), ischaemic postconditioning (PostC), remote preconditioning (RIPC) and remote postconditioning (RPostC) have all been shown in animals and humans to be effective in reducing IR injury. Experiments in this thesis sought to determine tractable aspects of the mechanisms underlying these protective phenomena with a view to validating potential pharmacological targets in humans. IR induced endothelial dysfunction in the forearm of healthy volunteers was characterised by vascular ultrasound and venous occlusion plethysmography. IPC, PostC, RIPC and RPostC all protected against IR-induced endothelial dysfunction. Oral inorganic nitrates in the form of beetroot juice or potassium nitrate (KNO3) also protected against endothelial IR injury. The magnitude of protection from IR injury was similar. The mechanism of PostC was investigated in detail. Protection by PostC was blocked by glibenclamide, a non selective KATP channel blocker, suggesting that activation of these potassium channels was necessary for PostC-induced ischaemic protection. Selectivity of KATP channels was evident because glimepiride (a selective KATP channel blocker) did not affect the protective effect of PostC. A role for the mitochondrial permeability transition pore (mPTP) was suggested by the effect of ciclosporin (blocker of the mPTP) to mimic PostC-induced protection. These aspects of the mechanism of PostC resemble previously identified mechanisms of IPC and RIPC in the human forearm. Studies were undertaken to explore the mechanism whereby protection spreads systemically. Systemic protection by RIPC from ischaemic injury to the endothelium was blocked by the opioid receptor antagonist, naloxone without any effect on protection conferred by IPC or RPostC These data implicate the opioid receptor pathway in the facilitation of RIPC, and is likely to involve a haematogenous mechanism. Conversely, the alpha adrenergic receptor antagonist phentolamine, blocked systemic protection from RPostC but had no effect on RIPC. This highlights a role of a component of the autonomic nervous system in the mediation of RPostC. Ischaemic protection in humans is mechanistically a complex process but results in this thesis contribute to the validation of pharmacological targets as a prelude to drug development.

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