Spironolactone can act on pannexin1 channels in smooth muscle cells to regulate vasoconstriction and blood pressure

Using an unbiased screen for potential inhibitors of pannexin1 (Panx1) channels, we identified spironolactone, a potent anti-hypertensive, as being able to block Panx1 channels. This was especially interesting considering spironolactone has been considered a mineralcorticoid receptor (MR) antagonist. Initial confirmation of this result was obtained using electrophysiology, which showed that spironolactone could directly and effectively inhibit Panx1 channel activity without inhibiting other putative ATP release channels. Next, because we have previously demonstrated that Panx1 channels on smooth muscle cells (SMCs) can regulate α-adrenergic vasoconstriction and blood pressure, we hypothesized that spironolactone would also inhibit α-adrenergic vasoconstriction. Indeed, we found that spironolactone inhibited α-adrenergic vasoconstriction from resistance arteries isolated from hypertensive humans. This effect was also seen in C57Bl6 mice, mice lacking SMC MR, or mice lacking Panx1 in endothelial cells. Howe...