Investigation into the effects of specific muscarinic acetylcholine receptor antagonists on the myocardium in pre-clinical conditions of ischaemia reperfusion injury and oxidative stress model*


Khan, J. (2015) Investigation into the effects of specific muscarinic acetylcholine receptor antagonists on the myocardium in pre-clinical conditions of ischaemia reperfusion injury and oxidative stress model*. Unpublished PhD Thesis. Coventry: Coventry University


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Abstract

Muscarinic acetylcholine receptors (mAChRs) are G-protein coupled receptors that mediate various actions of Acetylcholine (ACh) in the central nervous system and peripheral nervous system. In mammals, five distinct mAChR subtypes (M1-M5) have been recognised with the M2 subtype being predominantly present in the heart. The mAChR antagonists are routinely used for the treatment of various pathophysiological conditions including respiratory conditions. However, it has been postulated that mAChR antagonists may increase morbidity and mortality in chronic obstructive pulmonary disorder (COPD) and asthma patients with underlying cardiovascular disease, raising concerns regarding the cardiovascular safety of these agents. The current study was therefore undertaken to investigate the effects of individual mAChR antagonists in the setting of myocardial ischaemia reperfusion injury and oxidative stress models. We also investigated whether the inhibition of the mitochondrial permeability transition pore (MPTP) with cyclosporine-A (CsA) in the presence and absence of individual mAChR antagonists provided protection against ischaemia reperfusion injury. Furthermore, we also aimed to investigate the intracellular signalling pathway associated with mAChRs antagonists mediated myocardial injury under the stress conditions. Langendorff results showed that the non-selective M1-M3 mAChR antagonist, ipratropium bromide, the M2 mAChR antagonist, AF-DX 116 and the M3 mAChR antagonist, DAU 5884 significantly increased the infarct size to risk ratio of the heart in conditions of ischaemia and reperfusion. Detrimental effects of AF-DX 116 and DAU 5884 were abrogated by co-treatment of these drugs with mAChR agonist, acetylcholine (ACh) and/or CsA. Cell viability data of isolated cardiac myocytes revealed that AF-DX 116 and DAU 5884 caused a concentration dependent decrease in the viability of cardiac myocytes as well as causing a reduction in the time taken to depolarisation and hypercontracture under oxidative stress. AF-DX 116 and DAU 5884 significantly increased the levels of p-SAPK/JNK and decreased the levels of p-Akt and p-ERK. In addition, ACh and CsA showed to activate p-Akt and p-ERK. To conclude, the data suggest that AF-DX 116 and DAU 5884 caused cardiotoxicity at cellular, tissue and protein level in conditions of ischaemia reperfusion injury and oxidative stress. Furthermore, inhibition of the mitochondrial transition pore with CsA protected against the AF-DX 116 and DAU 5884 induced injury via activation of the pro-survival proteins, p-Akt and p-ERK.



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Item TypeThesis (PhD)
TitleInvestigation into the effects of specific muscarinic acetylcholine receptor antagonists on the myocardium in pre-clinical conditions of ischaemia reperfusion injury and oxidative stress model*
Authors Khan, J.
Uncontrolled Keywordsmuscarinic acetylcholine, myocardium in pre-clinical conditions of ischaemia reperfusion injury, oxidative stress model
Departments Centre for Applied Biological and Exercise Sciences (ABES)
Faculty of Health and Life Sciences
Publisher statementSome materials have been removed from this thesis due to third party copyright. Pages where material has been removed are clearly marked in the electronic version. The unabridged version of the thesis can be viewed at the Lanchester Library, Coventry University.
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Deposited on 21-Mar-2016 in Research - Coventry.
Last modified on 24-Mar-2021

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