From the Department of Molecular Physiology and Biophysics, Robert M. Berne Cardiovascular Research Center (M.E.G., J.T.B., L.J.D., A.W.L., B.E.I.), Department of Pharmacology (Y.-H.C., S.K.M., N.L., B.N.D., D.A.B.), Department of Microbiology, Immunology and Cancer Biology, the Center for Cell Clearance, and the Beirne B. Carter Center for Immunology Research (C.B.M., U.M.L., K.S.R.), and Division of Endocrinology (E.B.), University of Virginia School of Medicine, Charlottesville; Department of Biochemistry and Genetics, La Trobe University, Melbourne, Australia (I.K.H.P.); and Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.).
Circ Res. 2018 Feb 16;122(4):606-615. doi: 10.1161/CIRCRESAHA.117.312380. Epub 2017 Dec 13.
Resistant hypertension is a major health concern with unknown cause. Spironolactone is an effective antihypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization as an essential medication. Although spironolactone can act at the mineralocorticoid receptor (MR; NR3C2), there is increasing evidence of MR-independent effects of spironolactone.
Here, we detail the unexpected discovery that Panx1 (pannexin 1) channels could be a relevant in vivo target of spironolactone.
First, we identified spironolactone as a potent inhibitor of Panx1 in an unbiased small molecule screen, which was confirmed by electrophysiological analysis. Next, spironolactone inhibited α-adrenergic vasoconstriction in arterioles from mice and hypertensive humans, an effect dependent on smooth muscle Panx1, but independent of the MR NR3C2. Last, spironolactone acutely lowered blood pressure, which was dependent on smooth muscle cell expression of Panx1 and independent of NR3C2. This effect, however, was restricted to steroidal MR antagonists as a nonsteroidal MR antagonist failed to reduced blood pressure.
These data suggest new therapeutic modalities for resistant hypertension based on Panx1 inhibition.
耐药性高血压是一个病因不明的主要健康问题。螺内酯是一种有效的降压药物，特别是对耐药性高血压患者，世界卫生组织认为它是一种基本药物。尽管螺内酯可以在盐皮质激素受体（MR；NR3C2）上发挥作用，但越来越多的证据表明螺内酯具有 MR 非依赖性作用。
在这里，我们详细介绍了一个意想不到的发现，即 Panx1（连接蛋白 1）通道可能是螺内酯在体内的一个相关靶点。
首先，我们在一项无偏见的小分子筛选中发现螺内酯是 Panx1 的一种有效抑制剂，这一结果通过电生理分析得到了证实。其次，螺内酯抑制了来自小鼠和高血压患者的小动脉中的α-肾上腺素能血管收缩，这种作用依赖于平滑肌 Panx1，但不依赖于 MR NR3C2。最后，螺内酯可急性降低血压，这依赖于平滑肌细胞表达 Panx1，且不依赖于 NR3C2。然而，这种作用仅限于甾体 MR 拮抗剂，而非甾体 MR 拮抗剂不能降低血压。
这些数据表明，基于 Panx1 抑制的新的耐药性高血压治疗方法。
