Potent vasorelaxant activity of the TMEM16A inhibitor T16A inh ‐A01

作者：Alison Davis, Jian Shi, Harry A. T. Pritchard, Preet S. Chadha, Normand Leblanc, Georgios Vasilikostas, Zhen Yao, AS Verkman, Anthony P. Albert, Iain A. Greenwood · 发表于：British Journal of Pharmacology · 年份：2012 · DOI：10.1111/j.1476-5381.2012.02199.x · 被引用次数：88 · 研究领域：Ion channel regulation and function、Ion Channels and Receptors、Ion Transport and Channel Regulation

BACKGROUND AND PURPOSE: T16A(inh) -A01 is a recently identified inhibitor of the calcium-activated chloride channel TMEM16A. The aim of this study was to test the efficacy of T16A(inh) -A01 for inhibition of calcium-activated chloride channels in vascular smooth muscle and consequent effects on vascular tone. EXPERIMENTAL APPROACH: Single channel and whole cell patch clamp was performed on single smooth muscle cells from rabbit pulmonary artery and mouse thoracic aorta. Isometric tension studies were performed on mouse thoracic aorta and mesenteric artery as well as human abdominal visceral adipose artery. KEY RESULTS: In rabbit pulmonary artery myocytes T16A(inh) -A01 (1-30 μM) inhibited single calcium (Ca(2+) )-activated chloride (Cl(-) ) channels and whole cell currents activated by 500 nM free Ca(2+) . Similar effects were observed for single Ca(2+) -activated Cl(-) channels in mouse thoracic aorta, and in both cell types, channel activity was abolished by two antisera raised against TMEM16A but not by a bestrophin antibody. The TMEM16A potentiator, F(act) (10 μM), increased single channel and whole cell Ca(2+) -activated Cl(-) currents in rabbit pulmonary arteries. In isometric tension studies, T16A(inh) -A01 relaxed mouse thoracic aorta pre-contracted with methoxamine with an IC(50) of 1.6 μM and suppressed the methoxamine concentration-effect curve. T16A(inh) -A01 did not affect the maximal contraction produced by 60 mM KCl and the relaxant effect of 10 μM T16A(inh) -A...