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This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/R181    most recent 00173.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Werner, M. E. Articles by Nelson, M. T. PubMed PubMed Citation Articles by Werner, M. E. Articles by Nelson, M. T.

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