Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone

RATIONALE:Resistant hypertension is a major health concern with unknown etiology. Spironolactone is an effective anti-hypertensive drug, especially for patients with resistant hypertension, and is considered by the World Health Organization (WHO) as an 'essential' medication. Although spironolactone can act at the mineralocorticoid receptor (NR3C2), there is increasing evidence of mineralocorticoid receptor (MR)-independent effects of spironolactone. OBJECTIVE:Here, we detail the unexpected discovery that pannexin 1 (Panx1) 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 upon smooth muscle Panx1, but independent of the mineralocorticoid receptor NR3C2. Lastly, 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 non-steroidal MR antagonist failed to reduced blood pressure. CONCLUSIONS:These data suggest new therapeutic modalities for resistant hypertension based on Panx1 inhibition.