Down-regulation of K2.3 channels causes erectile dysfunction in mice.

Modulation of endothelial calcium-activated K channels has been proposed as an approach to restore arterial endothelial cell function in disease. We hypothesized that small-conductance calcium-activated K channels (K2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (K2.3 ) or down-regulation (K2.3 ) of the K2.3 channels and wild-type C57BL/6-mice (WT). QPCR revealed that K2.3 and K1.1 channels were the most abundant in mouse corpus cavernosum. K2.3 channels were found by immunoreactivity and electron microscopy in the apical-lateral membrane of endothelial cells in the corpus cavernosum. Norepinephrine contraction was enhanced in the corpus cavernosum of K2.3 versus K2.3 mice, while acetylcholine relaxation was only reduced at 0.3 µM and relaxations in response to the nitric oxide donor sodium nitroprusside were unaltered. An opener of K2 channels, NS309 induced concentration-dependent relaxations of corpus cavernosum. Mean arterial pressure was lower in K2.3 mice compared with WT and K2.3 mice. In anesthetized mice, cavernous nerve stimulation augmented in frequency/voltage dependent manner erectile function being lower in K2.3 mice at low frequencies. Our findings suggest that down-regulation of K2.3 channels contributes to erectile dysfunction, and that pharmacological activation of K2.3 channels may have the potential to restore erectile function.