Hypercontractility and impaired sildenafil relaxations in the BK Ca channel deletion model of erectile dysfunction

Mark Nelson, Matthias E. Werner, Andrea L. Meredith, Richard W. Aldrich, Mark T. Nelson

    Research output: Contribution to journalArticlepeer-review


    Erectile dysfunction (ED) can be elicited by a variety of pathogenic factors, particularly impaired formation of and responsiveness to nitric oxide (NO) and the downstream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large-conductance, Ca2+-activated potassium (BK Ca) channel. In our previous report (42), we demonstrated that deletion of the BKCa 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 BKCa 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 BKCa 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 BKCa channels. At concentrations >1 μM, sildenafil caused relaxations independent of inhibition of sGC or BKCa channels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of BKCa channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent Ca2+ channels (VDCCs). These results suggest that therapeutically relevant concentrations of sildenafil act through cGMP and BKCa channels, and loss of BKCa channel function leads to hypercontractility, which depends on VDCCs and cannot be modified by the cGMP pathway. Copyright © 2008 the American Physiological Society.
    Original languageEnglish
    Pages (from-to)R181-R188
    JournalAJP: Regulatory, Integrative and Comparative Physiology
    Issue number1
    Publication statusPublished - Jul 2008


    • Calcium-activated potassium channel
    • Mouse
    • Smooth muscle


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