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Cardioprotective actions of bradykinin in the normal and hypertrophied myocardium.

Ebrahim, Zaileen; (2001) Cardioprotective actions of bradykinin in the normal and hypertrophied myocardium. Doctoral thesis (Ph.D.), University College London. Green open access

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Abstract

Very few therapeutic modalities are beneficial in the treatment of acute myocardial infarction. However, the phenomenon of ischaemic preconditioning (IPC) reduces cell necrosis and therefore, may offer protection against ischaemia-reperfusion injury. Bradykinin has been implicated in IPC as a trigger of this protective phenomenon. The protective effects of both IPC and bradykinin are largely under-investigated in models of chronic myocardial hypertrophy. Furthermore, the kallikrein-kinin system is thought to be implicated in hypertension, indeed studies have demonstrated that levels of bradykinin are attenuated in hypertension. Therefore, the aim of this thesis was to further elucidate the cardioprotective actions of bradykinin in both the normal and hypertrophied myocardium. In preliminary experiments, the deoxycorticosterone acetate (DOCA)-salt rat was used to represent a mild model of left ventricular hypertrophy (LVH) associated with short term hypertension. Although IPC was found to reduce infarct size in the DOCA-salt rat hearts subjected to ischaemic-reperfusion injury, bradykinin induced cardioprotection was impaired in these hearts. Drugs that inhibit bradykinin degradation, namely, angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) inhibitors can be used therapeutically to augment bradykinin levels. Previous studies have demonstrated that ACE inhibitors can potentiate a subthreshold preconditioning stimulus, however, it is not known whether dual ACE and NEP inhibition also potentiates IPC. It was found that the dual ACE and NEP inhibitor, omapatrilat, analogous to captopril, augmented a subthreshold IPC stimulus via activation of the bradykinin B2 receptor. In contrast to captopril, omapatrilat also evoked protection when administered directly (ie, in the absence of preconditioning ischaemia), an effect also dependent upon 82 receptor activation. The effects of IPC in chronic myocardial hypertrophy associated with long term hypertension were investigated. IPC evoked protection in hearts isolated from young and middle aged SHR and normotensive age matched, WKY rats. However, IPC did not protect the ageing SHR/WKY rat hearts. Therefore, the combination of ageing and long standing hypertrophy interfere with the occurrence of IPC. In an attempt to raise bradykinin levels, captopril was used in conjunction with the IPC protocol. However, no protection was observed in hearts isolated from the ageing SHR. In contrast, modest protection was seen in age matched WKY rat hearts. In the normal myocardium, it was found that bradykinin administered just prior to reperfusion also induced cardioprotection possibly via activation of the PIS kinase pathway. However, the protective effect of bradykinin at reperfusion could not be duplicated in the ageing SHR myocardium. Even though numerous studies have demonstrated that bradykinin elicits classical preconditioning, its role in delayed preconditioning remains elusive. The final set of experiments in this thesis investigated whether bradykinin triggers delayed preconditioning. It was found that a bradykinin bolus given 24 hours prior to infarction triggered protection, an effect dependent upon the generation of nitric oxide. The work contained in this thesis confirms the cardioprotective potential of bradykinin and bradykinin modifying drugs in normal myocardium. However, the impairment of cardioprotective pathways in hypertensive myocardium was a consistent finding of these studies and therefore requires further investigation.

Type: Thesis (Doctoral)
Qualification: Ph.D.
Title: Cardioprotective actions of bradykinin in the normal and hypertrophied myocardium.
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis Digitised by Proquest.
URI: https://discovery.ucl.ac.uk/id/eprint/10120979
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