Response by Good et al to Letter Regarding Article, “Pannexin-1 Channels as an Unexpected New Target of the Antihypertensive Drug Spironolactone”

In our recent publication, we reported the discovery that spironolactone—an antihypertensive—is also a new Panx1 (pannexin 1) inhibitor. In addition, we found that spironolactone interferes with α1AR (α1 adrenoceptor)-mediated vasoconstriction of resistance vessels and acutely lowers blood pressure in mice; importantly, these effects require Panx1 channel expression in vascular smooth muscle cells but are independent of the MR (mineralocorticoid receptor)—the traditional target of spironolactone. Based on the accumulated evidence, we proposed that Panx1 is a novel target of spironolactone that, in combination with MR-dependent actions, may contribute to the beneficial blood pressure-lowering effects of spironolactone that are especially relevant for treatment of resistant hypertensive patients. We are pleased that Drs Wright and Angus recognize that this novel action adds to the well-accepted MR-dependent antihypertensive effects of spironolactone and that this unveils a potentially important mechanism with translational clinical implications. In addition, however, these authors raise some points of contention with our studies that can be summarized in 2 general arguments: (1) based on perceived differences with their own pharmacological reports, they insist that additional pharmacological studies are necessary to support the fundamental underlying mechanism (ie, that Panx1-mediated ATP release contributes to α1AR-mediated vasoconstriction) and (2) that spironolactone acts less potently at Panx1 than at MR and thus may require concentrations not achieved clinically. Below, we address both of these points. Despite the narrow focus of their argument on work involving a single Panx1 inhibitor (mefloquine)1 and a single P2X1 blocker (NF449),2 there is now substantial pharmacological and, importantly, genetic evidence supporting a role for Panx1-mediated ATP release in α1AR-mediated vasoconstriction. For Panx1, this …