beta-adrenoceptor subtypes involved in myocardial preconditioning and postconditioning.

Penson, Peter Edward. 2009. beta-adrenoceptor subtypes involved in myocardial preconditioning and postconditioning. PhD Thesis, Cardiff University.

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Abstract

Ischaemia and reperfusion in the heart leads to necrotic cell death (infarction) and contractile dysfunction (stunning). Ischaemic preconditioning (non-lethal periods of ischaemia prior to a longer ischaemic episode) and postconditioning (modified reperfusion) both reduce infarct size and are thought to act via activation of reperfusion injury salvage kinase (RISK) pathways to prevent the opening of the mitochondrial permeability transition pore (MPTP) at reperfusion. Catecholamines are released centrally and locally during myocardial ischaemia and activate adrenoceptors. This investigation was concerned with the roles of beta-adrenoceptor activation in preconditioning and postconditioning. Studies utilising isolated paced atrial and ventricular tissues demonstrated that preconditioning against stunning could be achieved by ischaemic preconditioning, or pre-treatment of tissues with isoprenaline, a beta-adrenoceptor agonist. Both forms of protection were blocked by propranolol, a beta-adrenoceptor antagonist. Postconditioning was not protective in this model. A Langendorff model of regional ischaemia was used to determine effects of beta-adrenoceptor agonists and antagonists on infarct size. In this model, ischaemic postconditioning was blocked by timolol, a non-selective p-adrenoceptor antagonist. Formoterol, a beta2-adrenoceptor agonist, given at reperfusion, mimicked postconditioning. The non-selective adrenoceptor agonist, adrenaline, when applied at reperfusion, worsened reperfusion contracture but had no effect on infarct size. The application of a selective beta1-adrenoceptor antagonist (CGP-20712A) at reperfusion led to a reduction of infarct size whereas beta2 (ICI-118,551) and beta3 (SR-59230A) antagonists had the opposite effect. If the results are replicable in man in vivo they would be of clinical relevance because a commonly used class of drugs (beta-adrenoceptor antagonists) have the potential to abrogate the protection of postconditioning. Another widely available class of drugs (beta-adrenoceptor agonists) can have cardioprotective effects at reperfusion.

Item Type:	Thesis (PhD)
Status:	Unpublished
Schools:	Pharmacy
Subjects:	R Medicine > RS Pharmacy and materia medica
ISBN:	9781303196911
Funders:	British Heart Foundation
Date of First Compliant Deposit:	30 March 2016
Last Modified:	19 Mar 2016 23:30
URI:	https://orca.cardiff.ac.uk/id/eprint/54502

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