Patel, Vanlata Chhotabhai; (1996) The role of nitric oxide in ischaemia reperfusion injury in the rabbit heart. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: Nitric oxide (NO), synthesised by a constitutive enzyme from L-arginine, is a highly reactive species which is produced continuously by endothelial cells. NO maintains the coronary microcirculation in a state of active vasodilatation, prevents platelet and leucocyte adherence, and preserves physiological vascular impermeability, however, in excess NO may be injurious. This may be important during the early reactive hyperaemia after ischaemia, which is mediated by a substantial increase in NO release. Brief periods of ischaemia followed by reperfusion leads to an increased tolerance of the myocardium to a subsequent and sustained ischaemic insult, this phenomenon is termed ischaemic preconditioning (IP). The mechanism for IP in not clear, however, recent evidence appears to support an important primary role for adenosine released by ischaemic cells during the preconditioning period. Aims: This thesis examines some aspects of the role of nitric oxide in the myocardium and during ischaemia, reperfusion and its involvement in ischaemic preconditioning. Method: The experimental model studied was regional ischaemia followed by reperfusion both in the in situ and Langendorff perfused rabbit hearts. Infarct size was the endpoint assessed but haemodynamic parameters and several biochemical determinants of injury were also measured. The role of NO in ischaemia reperfusion injury was studied by the inhibition of L-arginine analogue which inhibits NO synthesis, Nitro-L-arginine methyl ester hydrochloride (L-NAME) was used. Results: Rabbit hearts pretreated with L-NAME were more resistant to injury than controls both in situ and isolated perfused hearts. When hearts were treated with both L-NAME and 8-p-sulfophenyl theophylline an adenosine receptor antagonist (SPT) the protection seen with L-NAME was abolished. Ischaemic preconditioning (IP) prior to sustained ischaemia and reperfusion reduced the infarct ratio both in situ and isolated hearts, this was not augmented by pretreatment with L-NAME. All protection due to IP was lost in hearts pretreated with SPT. We postulate that the protective effects of L-NAME is mediated largely by the release of adenosine. Conclusion: We have demonstrated that the infarct size limitation following inhibition of NO synthesis shares a common mechanism with that of IP and is dependent on the release of adenosine. These results have implications for the mechanisms of coronary autoregulation during ischaemia and reperfusion injury, when the physiological mechanisms are deranged.

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