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 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.

Conclusions: These data suggest new therapeutic modalities for resistant hypertension based on Panx1 inhibition.

中文翻译：

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Pannexin 1通道作为抗高血压药物螺内酯新奇和意义的意外新目标

理由：抵抗性高血压是主要的健康问题，原因不明。螺内酯是一种有效的降压药，特别是对于顽固性高血压患者，世界卫生组织认为螺内酯是必不可少的药物。尽管螺内酯可以作用于盐皮质激素受体（MR; NR3C2），但是螺内酯的MR独立作用的证据越来越多。

目的：在这里，我们详细介绍了意想不到的发现，即Panx1（pannexin 1）通道可能是螺内酯的体内相关靶标。

方法和结果：首先，我们在无偏小分子筛选中确定了螺内酯是Panx1的有效抑制剂，这已通过电生理分析得到了证实。接下来，螺内酯抑制小鼠和高血压人的小动脉中的α-肾上腺素血管收缩，这种作用依赖于平滑肌Panx1，但不依赖于MR NR3C2。最后，螺内酯可急剧降低血压，这取决于Panx1的平滑肌细胞表达，而与NR3C2无关。但是，此作用仅限于甾体MR拮抗剂，因为非甾体MR拮抗剂无法降低血压。

结论：这些数据提示了基于Panx1抑制作用的抗高血压药物的新治疗方法。