Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/29913
Title: Ischaemia/reperfusion injury and preconditioning in the human myocardium : the role of alpha 1 adrenoceptors and disease states
Authors: Loubani, Mahmoud
Award date: 2005
Presented at: University of Leicester
Abstract: The present studies have demonstrated that alpha1 -adrenoceptors play an important role in the ischaemia/reoxygenation-induced injury of the human atrial myocardium. They have shown that stimulation of alpha1-adrenoceptors with phenylephrine protects against injury whereas their blockade with prazosin is detrimental, both effects obtained in a dose-dependent manner. They have also shown that the effect of the stimulation or blockade of alpha1-adrenoceptors depends on the time of administration so that 1-adrenoceptors' stimulation is protective when given prior to ischaemia but detrimental when giving during ischaemia. On the contrary, alpha1-adrenoceptors' blockade is beneficial during ischaemia, detrimental during reoxygenation but has no significant effect prior to ischaemia. It appears that similar maximal protection can be obtained with alpha1-stimulation prior to ischaemia and with alpha1-blockade during ischaemia although the combination of the two does not induce additional protection. Furthermore, the protective effect of alpha1-stimulation prior to ischaemia is as potent as ischaemic preconditioning (IP). In this thesis, I have also demonstrated that protection with pharmacological preconditioning by activation of alpha1-adrenoreceptors or adenosine receptors is identical to that of IP in the human myocardium.;These studies have provided novel information to understand the underlying mechanism of protection by preconditioning of the human myocardium. They have shown that mitoKATP channels, PKC and p38MAPK are an integral part of the cellular signal transduction involved in this cardioprotection in which mitoKATP channels are placed upstream and p38MAPK is placed downstream of PKC.;The abolition of the ability of the human myocardium to be protected by ischaemic and pharmacological preconditioning without exacerbating the susceptibility to ischaemic injury when nicorandil, a mitoKATP channel opener and nitric oxide donor, was administered clinically was unexpected. I demonstrated that the likely cause of the failure to precondition the myocardium of patients on nicrorandil is the unresponsiveness of the mitoKATP channels since protection cannot be obtained with diazoxide, a specific mitoKchannel opener, but can be elicited by activation of PKC and p38MAPK that are downstream of mitoKATP channels in the signalling transduction cascade of preconditioning.;The sulfonylureas glibenclamide and gliclazide, that block KATP channels, have distinctive effects on IP. Thus, although glibenclamide abolished the protective effect of preconditioning even at 0.1 muM, gliclazide did at a higher concentration 30muM. The cardioprotection induced by diazoxide, which open mitoKATP channels was also abrogated by glibenclamide. However glibenclamide did not block the protective effect of activation of PKC and p38MAPK.
Links: http://hdl.handle.net/2381/29913
Type: Thesis
Level: Doctoral
Qualification: MD
Rights: Copyright © the author. All rights reserved.
Appears in Collections:Theses, Dept. of Cardiovascular Sciences
Leicester Theses

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