Hypercontractility and impaired sildenafil relaxations in the [BK.sub.Ca] channel deletion model of erectile dysfunction

Erectile dysfunction (ED) can be elicited by a variety of pathogenic factors, particularly impaired formation of and responsiveness to nitric oxide (NO) and the down-stream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large-conductance, [Ca.sup.2+]-activated potassium ([BK.sub.Ca]) channel. In our previous report (42), we demonstrated that deletion of the [BK.sub.Ca] channel in mice induced force oscillations and led to reduced nerve-evoked relaxations and ED. In the current study, we used this ED model to explore the role of the [BK.sub.Ca] channel in the NO/sGC/PKGI pathway. Electrical field stimulation (EFS)-induced contractions of corpus cavernosum smooth muscle strips were significantly enhanced in the absence of [BK.sub.Ca] channel function. In strips precontracted with phenylephrine, EFS-induced relaxations were converted to contractions by inhibition of sGC, and this was further enhanced by loss of BK channel function. Sildenafil-induced relaxations were decreased to a similar extent by inhibition of sGC or [BK.sub.Ca] channels. At concentrations > 1 [micro]M, sildenafil caused relaxations independent of inhibition of sGC or [BK.sub.Ca] channels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of [BK.sub.Ca] channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent [Ca.sup.2+] channels (VDCCs). These results suggest that therapeutically relevant concentrations of sildenafil act through cGMP and [BK.sub.Ca] channels, and loss of [BK.sub.Ca] channel function leads to hypercontractility, which depends on VDCCs and cannot be modified by the cGMP pathway. smooth muscle; calcium-activated potassium channel; mouse