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Title: An investigation into the role of TMEM16A in the coronary vasculature
Author: Page, Henry Askew
ISNI:       0000 0004 7427 1364
Awarding Body: St George's, University of London
Current Institution: St George's, University of London
Date of Award: 2017
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Introduction: Failure of coronary blood vessels to adequately supply cardiac myocytes with oxygen underlies ischaemic heart disease and ultimately myocardial infarction. Therefore, it is important to determine the factors that regulate coronary blood flow. Activation of Ca2+-activated chloride channels depolarises vascular smooth muscle cells sufficiently to cause Ca2+ influx through voltage-dependent channels and contraction of the cell. TMEM16A is the main molecular candidate for these channels. Hypothesis: TMEM16A is expressed in rat coronary arteries where it regulates vascular smooth muscle contraction. In coronary arteries from hypertensive rats the level of expression, and function of TMEM16A is altered. Methods: Quantitative polymerase chain reaction and immunodetection techniques assessed TMEM16A expression. Whole-cell patch clamp techniques were used to measure currents from freshly isolated rat coronary artery vascular smooth muscle cells (VSMCs). Wire myography and Langendorff perfused heart setup assessed coronary artery contractility and coronary blood flow respectively. Microelectrode impalement of rat coronary artery segments were combined with wire myography for membrane potential measurements. Results: TMEM16A was identified at mRNA and protein levels in rat coronary artery smooth muscle and TMEM16A-specific blockers attenuated the vasoconstricting effects of U46619 and 5-HT. These pharmacological agents also reduced the membrane depolarising effects of U46619 in sharp microelectrode studies and enhanced coronary flow in Langendorff set-ups. TMEM16A transcript was increased in coronary arteries from spontaneously hypertensive rats while the sensitivity to U46619 and 5HT was also increased in these vessels. This increased sensitivity was diminished in the presence of a novel TMEM16A inhibitor. Conclusion: TMEM16A is expressed in rat coronary arteries, where chloride is essential for optimal contraction and novel inhibitors of TMEM16A drastically effect vascular function. The expression of TMEM16A, contractility, and sensitivity to novel inhibitors of TMEM16A are all altered in coronary arteries from hypertensive rats.
Supervisor: Greenwood, Iain A. ; Olesen, Soren-Peter Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available