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TMEM16A is implicated in the regulation of coronary flow and is altered in hypertension
Author(s) -
Askew Page Henry R.,
Dalsgaard Thomas,
Baldwin Samuel N.,
Jepps Thomas A.,
Povstyan Oleksandr,
Olesen Søren P.,
Greenwood Iain A.
Publication year - 2019
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14598
Subject(s) - cardiology , coronary arteries , medicine , contractility , artery , coronary circulation , myocardial infarction , coronary artery disease , vascular smooth muscle , perfusion , myocyte , chloride channel , blood flow , smooth muscle , biology , microbiology and biotechnology
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. Ca 2+ ‐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 Ca 2+ ‐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, T16A inh ‐A01, and Ani9 attenuated 5‐HT/U46619‐induced contractions. MONNA and T16A inh ‐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.