Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone
Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone
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DOI：
10.1161/circresaha.117.312380
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发表时间：
2018-02-16
影响因子：
20.1
通讯作者：
Ravichandran, Kodi S.
中科院分区：
文献类型：
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作者：
Good, Miranda E.;Chiu, Yu-Hsin;Ravichandran, Kodi S.
理论基础：顽固性高血压是一种原因不明的主要健康问题。螺内酯是一种有效的降压药，特别是对难治性高血压患者，被世界卫生组织视为基本药物。虽然螺内酯可以作用于盐皮质激素受体(MR；NR3C2)，但越来越多的证据表明螺内酯的MR非依赖性作用。目的：在这里，我们详细介绍了一项出人意料的发现，即Panx1(Pannin 1)通道可能是螺内酯的相关体内靶点。方法和结果：首先，我们在无偏倚小分子筛选中确定螺内酯是Panx1的有效抑制剂，并通过电生理分析证实了这一点。接下来，螺内酯抑制小鼠和高血压人小动脉的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，螺内酯显著降低血压，这依赖于血管平滑肌细胞Panx1的表达，而不依赖于NR3C2。然而，这种作用仅限于类固醇MR拮抗剂，因为非类固醇MR拮抗剂未能降低血压。结论：这些数据为基于Panx1抑制的难治性高血压提供了新的治疗方法。
Rationale: 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.Objective: Here, we detail the unexpected discovery that Panx1 (pannexin 1) channels could be a relevant in vivo target of spironolactone.Methods and Results: 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 alpha-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.Conclusions: These data suggest new therapeutic modalities for resistant hypertension based on Panx1 inhibition.