# A KCa 2.2/2.3 Opener Reverses ET-1-Induced NLRP3 Activation in Hypertensive Mice Corpora Cavernosa

## TL;DR

A new treatment using a KCa channel opener reverses erectile dysfunction in hypertensive mice by reducing inflammation.

## Contribution

The study identifies a novel therapeutic strategy targeting KCa 2.2/2.3 channels to counteract ET-1-induced NLRP3 activation in hypertension-related erectile dysfunction.

## Key findings

- Hypertension in mice caused erectile dysfunction linked to NLRP3 inflammasome activation and reduced KCa 2.3 expression.
- Activating KCa 2.2/2.3 channels with NS13001 reversed erectile dysfunction and reduced ET-1-induced inflammation.
- NS13001 restored endothelial cell currents impaired by ET-1 exposure.

## Abstract

Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca2+-activated K+ channels type 2.3 (KCa 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating KCa 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 KCa 2.3, caspase-1, and interleukin-1β (IL-1β). DOCA/salt mice showed impaired erectile function and increased IL-1β activity and reduced KCa 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the KCa 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 KCa 2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction.