Down-regulation of K Ca 2.3 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 (K _Ca 2.3 or SK3) contributes to erectile function. The research was performed in transgenic mice with overexpression (K _Ca 2.3 ^T/T(-Dox) ) or down-regulation (K _Ca 2.3 ^T/T(+Dox) ) of the K _Ca 2.3 channels and wild-type C57BL/6-mice (WT). QPCR revealed that K _Ca 2.3 and K _Ca 1.1 channels were the most abundant in mouse corpus cavernosum. K _Ca 2.3 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 K _Ca 2.3 ^T/T(+Dox) versus K _Ca 2.3 ^T/T(-Dox) 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 K _Ca 2 channels, NS309 induced concentration-dependent relaxations of corpus cavernosum. Mean arterial pressure was lower in K _Ca 2.3 ^T/T(-Dox) mice compared with WT and K _Ca 2.3 ^T/T(+Dox) mice. In anesthetized mice, cavernous nerve stimulation augmented in frequency/voltage dependent manner erectile function being lower in K _Ca 2.3 ^T/T(+Dox) mice at low frequencies. Our findings suggest that down-regulation of K _Ca 2.3 channels contributes to erectile dysfunction, and that pharmacological activation of K _Ca 2.3 channels may have the potential to restore erectile function.