A KCa2.2/2.3 opener reverses ET-1 induced NLRP3 activation in hypertensive mice

Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca 2+ -activated K + channels type 2.3 (K Ca 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating K Ca 2.2/2.3 channels reverses erectile dysfunction and ET-1-induced NLRP3 activation in hypertensive DOCA/salt mice. Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls. We measured blood pressure, intracavernous pressure (ICP), and corpus cavernosum (CC) contractility, and performed immunoblots for K Ca 2.3, caspase-1, and interleukin-1β (IL-1β). DOCA/salt mice showed impaired erectile function and increased IL-1β activity and K Ca 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the K Ca 2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation. NS13001 also restored decreased currents in endothelial cells exposed to ET-1. These findings establish that hypertension-induced erectile dysfunction involves an ET-1/membrane depolarization/NLRP3 inflammasome axis in corpus cavernosum endothelial cells, and that targeting endothelial K Ca 2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction. Abstract Figure Graphic abstract Overview of the K Ca 2.2/2.3 regulation on the ET-1-induced NLRP3 inflammasome activation in ECs. NLRP3 inflammasome activation in ECs depends on endothelin receptor B. On activation, NLRP3 recruits and forms a complex with ASC as well as procaspase 1. In the final step, the assembled inflammasome platform cleaves pro-caspase-1, and caspase-1 cleaves pro–IL-1β to activate IL-1β. NS13001 activates K Ca 2.2/2.3, which inhibits ET-1-induced NLRP3 activation. Apamin inhibits K Ca 2.2/2.3 opening. Bosentan directly inhibits ETB receptors in ECs, preventing the NLRP3 inflammasome activation.