TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension

TY - JOUR

T1 - TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension

AU - Askew Page, Henry R

AU - Dalsgaard, Thomas

AU - Baldwin, Samuel N

AU - Jepps, Thomas A

AU - Povstyan, Oleksandr

AU - Olesen, Søren P

AU - Greenwood, Iain A

N1 - © 2019 The British Pharmacological Society.

PY - 2019/6

Y1 - 2019/6

N2 - BACKGROUND AND PURPOSE: Coronary artery disease leads to ischaemic heart disease and ultimately myocardial infarction. Thus, it is 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 (SHRs).KEY RESULTS: TMEM16A was expressed in rat coronary arteries. The TMEM16A-specific inhibitor, MONNA, hyperpolarised the membrane potential in U46619. MONNA, T16Ainh -A01, and Ani9 attenuated 5-HT/U46619-induced contractions. MONNA and T16Ainh -A01 also increased coronary flow in Langendorff perfused rat heart preparations. TMEM16A mRNA was increased in coronary artery smooth muscle cells from SHRs, and U46619 and 5-HT were more potent in arteries from SHRs than in those from normal Wistar rats. MONNA diminished this increased sensitivity to U46619 and 5-HT.CONCLUSIONS AND IMPLICATIONS: In conclusion, TMEM16A is a key regulator of coronary blood flow and is implicated in the altered contractility of coronary arteries from SHRs.

AB - BACKGROUND AND PURPOSE: Coronary artery disease leads to ischaemic heart disease and ultimately myocardial infarction. Thus, it is 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 (SHRs).KEY RESULTS: TMEM16A was expressed in rat coronary arteries. The TMEM16A-specific inhibitor, MONNA, hyperpolarised the membrane potential in U46619. MONNA, T16Ainh -A01, and Ani9 attenuated 5-HT/U46619-induced contractions. MONNA and T16Ainh -A01 also increased coronary flow in Langendorff perfused rat heart preparations. TMEM16A mRNA was increased in coronary artery smooth muscle cells from SHRs, and U46619 and 5-HT were more potent in arteries from SHRs than in those from normal Wistar rats. MONNA diminished this increased sensitivity to U46619 and 5-HT.CONCLUSIONS AND IMPLICATIONS: In conclusion, TMEM16A is a key regulator of coronary blood flow and is implicated in the altered contractility of coronary arteries from SHRs.

U2 - 10.1111/bph.14598

DO - 10.1111/bph.14598

M3 - Journal article

C2 - 30710335

SN - 0007-1188

VL - 176

SP - 1635

EP - 1648

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 11

ER -