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TMEM16A is Implicated in the Regulation of Coronary Flow and is Altered in Hypertension.

Askew Page, H; Dalsgaard, T; Baldwin, S; Jepps, T; Povstyan, O; Olesen, SP; Greenwood, IA (2019) TMEM16A is Implicated in the Regulation of Coronary Flow and is Altered in Hypertension. BRITISH JOURNAL OF PHARMACOLOGY. ISSN 0007-1188 https://doi.org/10.1111/bph.14598
SGUL Authors: Greenwood, Iain Andrew

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Abstract

Background and purpose Coronary artery disease leads to ischaemic heart disease and ultimately myocardial infarction. Thus is it important to determine the factors that regulate coronary blood flow. Ca2+‐activated chloride channels contribute to the regulation of arterial tone; however, their role in coronary arteries is unknown. The aim of this study was to investigate the expression and function of the main molecular correlate of Ca2+‐activated chloride channels, TMEM16A, in rat coronary arteries. Experimental approach We performed mRNA and protein analysis, electrophysiological studies of coronary artery myocytes, and functional studies of coronary artery contractility and coronary perfusion, using novel inhibitors of TMEM16A. Furthermore, we assessed whether any changes in expression and function occurred in coronary arteries from spontaneously hypertensive rats. Key Results TMEM16A was expressed in rat coronary arteries. The TMEM16A‐specific inhibitor, MONNA, hyperpolarised the membrane potential by ‐22.1mV in U46619, (p=0.0017). MONNA, T16Ainh‐A01, and Ani9 attenuated 5HT/U46619‐induced contractions, and MONNA and T16Ainh‐A01 also increased coronary flow in Langendorff perfused rat heart preparations (p=<0.0001 for both drugs). TMEM16A mRNA was increased in coronary artery smooth muscle cells from spontaneously hypertensive rats (SHR), and U46619/5HT were more potent in arteries from SHRs (5HT EC50 in Wistars was 207±56 nM, versus 51±16 nM in SHRs, n=12 and n=13 respectively, p<0.05). MONNA diminished this increased sensitivity to U46619 and 5HT. Conclusions and Implications In conclusion TMEM16A is a key regulator of coronary blood flow and is implicated in altered contractility of coronary arteries from SHRs.

Item Type: Article
Additional Information: This is the peer reviewed version of the following article: Askew Page HR, Dalsgaard T, Baldwin SN, et al. TMEM16A is Implicated in the Regulation of Coronary Flow and is Altered in Hypertension. Br J Pharmacol. 2019, which has been published in final form at https://doi.org/10.1111/bph.14598. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Keywords: 1115 Pharmacology And Pharmaceutical Sciences, Pharmacology & Pharmacy
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: BRITISH JOURNAL OF PHARMACOLOGY
ISSN: 0007-1188
Dates:
DateEvent
2 February 2019Published Online
5 January 2019Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
6553Novo Nordisk Foundation DenmarkUNSPECIFIED
MR/K019074/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PG/14/57/30992British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
URI: http://openaccess.sgul.ac.uk/id/eprint/110620
Publisher's version: https://doi.org/10.1111/bph.14598

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