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DEVELOPMENTAL PHYSIOLOGY AND PREGNANCY

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

¹Division of Cardiovascular and Endocrine Sciences, School of Medicine, University of Manchester, Manchester, United Kingdom; ²Department of Physiology, School of Medicine, University of Maryland, Baltimore, Maryland; ³Section of Neurobiology, University of Texas at Austin, Austin, Texas; and ⁴Department of Pharmacology, College of Medicine, University of Vermont, Burlington, Vermont

Submitted 7 March 2008 ; accepted in final form 4 May 2008

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 BK_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_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_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_Ca channels. At concentrations >1 µM, sildenafil caused relaxations independent of inhibition of sGC or BK_Ca channels. Sildenafil did not affect the enhanced force oscillations that were induced by the loss of BK_Ca 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 BK_Ca channels, and loss of BK_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