Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.685100
Title: A comparison of the electrophysiological properties of sodium channels in cardiomyocytes of the rat pulmonary vein and atrium
Author: Hutchison, Laura
ISNI:       0000 0004 5923 9614
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2016
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Abstract:
Atrial fibrillation isthe most common cardiac arrhythmia, currently affecting up to one million people in the UK. Clinical studies have demonstrated that ectopic activity originating from the cardiomyocyte sleeve which surrounds the pulmonary vein (PV), is an important cause of atrial fibrillation. However, the underlying mechanisms for this ectopic activity remain unclear. Recent studies have proposed that sodium channels in the PV cardiomyocytes play a role. Thus, the aim of this thesis was to determine the distribution of the Na+ channel isoforms, as well as examine their characteristics in the rat PV and for comparative purposes the properties of the Na+ channel isoforms in the left atrium (LA), using a number of complimentary techniques. Furthermore, the arrhythmogenic activity in the PV and LA was investigated with the use of Anemonia sulcata toxin II (ATX-II), a substance that is frequently used as a pro-arrhythmic toxin. Microelectrode recordings revealed that there was no significant difference in the electrically evoked action potentials in the rat PV and LA tissues. Subsequent voltage clamp experiments on single isolated cardiomyocytes demonstrated that the INa current density, activation and inactivation properties were also similar between the PV and LA. However, the use of the selective Na⁺ channel blocker tetrodotoxin (TTX), to distinguish between Na⁺ channel subtypes, revealed a 20% contribution of the TTX-sensitive INa to the total INa in PV cardiomyocytes, with the current activated at more depolarised potentials compared to the TTX-resistant INa. In contrast, there was no evidence of the TTX-sensitive INa in LA cardiomyocytes. Although, inhibition of the TTX-sensitive Na⁺ channels had no effect on the action potential of the PV and LA, a small, but significant, reduction in the contractile response of both tissues was observed. Arrhythmogenic activity in the form of spontaneous contractions, spontaneous action potentials (which for the purpose of this thesis are used to define contractions or action potentials that occur after treatment of the tissue with ATX-II, and which are independent of electrical stimulation), and early afterdepolarisations (EADs) were induced in both PV and LA tissues in the presence of ATX-II, which is known to enhance the INaL. This ATX-II induced arrhythmogenic activity was not affected by block of TTX-sensitive Na⁺ channels alone, but was abolished by inhibition of both TTX-sensitive and TTX-resistant Na⁺ channels, highlighting the dependence of this arrhythmogenic activity on Na⁺ channels. In addition, suppression of the ATX-II induced arrhythmogenic activity using the calcium/calmodulin-dependent protein kinase II (CaMKII) blocker, KN-93, or the Na⁺/Ca2⁺ exchanger (NCX) inhibitor, ORM-10103, demonstrated the involvement of CaMKII and the NCX in ATX-II induced spontaneous activity. Thus, the excitability of cells from both the PV and LA is influenced by both the direct and indirect action of Na⁺ influx through the action of ATX-II.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.685100  DOI: Not available
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