Sam, Cynthia Laura Sandra (2013) Atrial myocyte physiology and pharmacology in health and disease. (PhD thesis), Kingston University, .
Abstract
Atrial fibrillation is the most common form of cardiac dysrhythmia in the world. According to the British Heart Foundation, about 1 million people in the UK are currently living with this condition and they are up to five times more likely to suffer a stroke than the rest of the population. Atrial fibrillation is the result of irregular spontaneous contractions of the atrial chambers of the heart separate to the contractions generated by the sino-atrial node activity. At a cellular level, pro-arrhythmogenic calcium handling has been observed upon the stimulation of atrial cells with the partial agonist CGP12177 at a novel low affinity beta1-AR (beta1L-AR). The aim of this thesis is to characterise the relationship between the morphology of the left and right atrial myocytes and the initial calcium release sites, and alterations in calcium handling protein phosphorylation state during cardiomyocyte contraction. We study how this relates to atrial arrhythmias via spontaneous calcium release activity in quiescent rat atrial myocytes by stimulating the propranolol-insensitive beta1-ARs using CGP12177. We aim to contribute towards understanding specific alterations at the cellular level in atrial myocytes during arrhythmias and heart failure (HF). Quiescent WKY rat left and right atrial cells were obtained from Langendorff perfusion of the whole heart and subsequent atrial cell isolation. Left atrial cells (13.6 [plus or minus] 0.3 urn) were wider on average compared to right atrial cells (9.9 [plus or minus] 0.25 um). Di-8ANEPPS stained cells confirmed networks of t-tubules in left atrial myocytes that facilitate t-tubular transportation of calcium during excitation contraction coupling. However no t-tubules were reported for right atrial myocytes presumably due to their narrower widths which are sufficient for calcium diffusion. Cardiac dysfunction results in cardiac proteins (sarco(endo)plasmic calcium ATP-ase (SERCA2a) protein, phospholamban (PLB) and ryanodine receptors (RyR2) having abnormal expressions. Western blotting studies have demonstrated high abundance of PLB and a tendency for lower abundance of SERCA2a in hypertensive and volume overload HF tissues as a result of the increased the workload on the heart and prolonged calcium release from the calcium store. Phosphorylated proteins of PLB in hypertensive tissues have lower population of beta-ARs and hence there is a reduction in the stimulation of these receptors in the heart. On the other hand, a deterioration of RyR2 of the sarcoplasmic reticulum leads to a reduced amount of calcium being stored in the calcium store and consequently contributes to a contractile deficit. This may eventually result in arrhythmias, commonly observed in people with HF. A pharmacological study of spontaneous calcium release (calcium sparks, wavelets and waves) using a series of cardioactive agents suggests pathways of pro-arrhythmogenic calcium release via the low affinity beta1-ARs. In particular, CGP12177 stimulating the ß1L-ARs of quiescent rat atrial myocytes has revealed that there may be a pro-arrhythmogenic pool of calcium in these atrial cells and a beta-blocker such as bupranolol may be efficient in supressing such stimulation as a therapeutic solution.
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