The role of the small conductance calcium-activated potassium channel in the rabbit atrial and ventricular action potential

Dobi, Sara (2021) The role of the small conductance calcium-activated potassium channel in the rabbit atrial and ventricular action potential. PhD thesis, University of Glasgow.

Abstract

Background: Small conductance potassium channels (SK) channels have been shown to participate specifically in atrial repolarisation, modulating action potential duration (APD). Atrial arrhythmias, including AF have been associated with overexpression of SK channels where they are thought to contribute to APD abnormalities. Their role in the ventricular electrophysiology remains controversial with limited evidence of their function.
Purpose: This study aimed to reveal the role of the SK channel in the AP of atrial and ventricular muscle in healthy and AF susceptible hearts. Additionally, the sensitivity of the SK channel to [Ca2+]i was investigated using low extracellular [Ca2+] and intracellular [Ca2+]-buffers.
Methods: Electrophysiological measurements of APs and [Ca2+] were made using optical techniques in enzymatically digested cardiomyocytes and isolated rabbit hearts. The specific SK channel blocker, ICAGEN was used to investigate the contribution of the current to the APD. [Ca2+]i was altered in two ways: (1) lowering extracellular [Ca2+] to 0.3mM and (2) chelating intracellular Ca2+ by incubating in 20µM BAPTA-AM.
Results: Pharmacological block of SK channels in tissue preparations caused a significant increase in APD by ~30% and 40% prolongation of APD50 and APD75/90 respectively at 10min drug perfusion in atrial muscle. No response to ICAGEN was observed in the ventricle. Atrial APs in low extracellular [Ca2+] retained a significant ICAGEN-sensitivity causing comparable prolongation to that seen in 1.8mM [Ca2+]. However, buffering [Ca2+]i with BAPTA abolished the drug effect with no significant APD prolongation in either cells or tissue. No APD prolongation occurred in response to ICAGEN in both the atrium and ventricle of AF-susceptible hearts from a heart failure (HF) model.
Conclusion: Using ICAGEN as a tool to probe SK channel activity, the data suggests that SK channels have an atrial-specific function in repolarisation in the normal rabbit. From the response to BAPTA loading, the channels appeared sensitive to local (possibly dyadic) [Ca2+] rather than global [Ca2+]i. The role of the channel in disease remains unclear with no evident contribution to AP repolarisation in an AF-susceptible rabbit model.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Atrial Fibrillation, AF, SK channel, calcium, intracellular calcium, isolated atrial cardiomyocytes, 1.8mM calcium, whole heart.
• Subjects: Q Science > Q Science (General); Q Science > QP Physiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Funder's Name: European Commission (EC)
• Supervisor's Name: Smith, Professor Godfrey
• Date of Award: 2021
• Embargo Date: 22 April 2022
• Depositing User: Dr Sara Dobi
• Unique ID: glathesis:2021-82128
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 28 Apr 2021 08:28
• Last Modified: 28 Apr 2021 08:29
• Thesis DOI: 10.5525/gla.thesis.82128
• URI: https://theses.gla.ac.uk/id/eprint/82128