Study of the cholinergic system in the heart and its potential pharmacological targeting

Abstract : Introduction: The results of current research suggest that acetylcholine has a protective role during heart failure and atrial or ventricular fibrillation. Cholinesterases (ChE) control the level of acetylcholine and thus play an important role in the cholinergic system of the heart. However, detail information about these enzymes in the heart is still missing. The aim of this thesis was to provide a complex study of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the heart, specifically of their activities, molecular forms and precise localization. Methods: Mutant mice with lack of ChE or their anchoring proteins, ColQ and PRiMA, were used. AChE and BChE activities in heart compartments were determined by 2-step Ellman’s method, developed by us. Molecular forms of ChE were determined in 5-20 % sucrose gradients and localized in the hearts filled with gelatin and in the cryosections by activity staining method and by immunohistochemistry. Nerve and endothelial cells were identified using specific markers. Basic heart morphology was studied in the transversal sections stained with hematoxyline and eosine. Results and conclusion: The highest AChE activity was determined in the atria, the lowest activity in the left ventricle and septum. In all compartments, PRiMA AChE and ColQ AChE were observed. Both anchored forms were distributed epicardially on the heart base, co-localized with intracardiac neurons. PRiMA AChE formed a subtle branching in the proximity of intracardiac neurons. The lack of AChE anchored forms led to significantly lower cardiomyocyte diameter. The BChE activity was higher than that of AChE. The highest BChE activity was detected in the left ventricle and septum. Amphiphilic monomers were the predominant form of BChE in the heart. In myocardium, the staining of BChE activity was diffused, while in epicardium it co-localized with a single intracardiac neuron. In this work, we have provided a complex study of ChE in heart. Our results could help in the design of new, more effective pharmacotherapy, which may reduce morbidity and mortality of the patients with various heart diseases.
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Dominika Dingová. Study of the cholinergic system in the heart and its potential pharmacological targeting. Neuroscience. Université Sorbonne Paris Cité; Univerzita Komenského (Bratislava), 2015. English. ⟨NNT : 2015USPCB021⟩. ⟨tel-01266053⟩

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