Submitted on March 7, 2008
Accepted on May 4, 2008
Hyper-contractility and impaired sildenafil relaxations in the BKCa channel deletion model of erectile dysfunction
Matthias E Werner1*, Andrea L. Meredith2, Richard W. Aldrich3, and Mark T Nelson4
1 Division of Cardiovascular and Endocrine Science, University of Manchester, Manchester, United Kingdom
2 Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
3 Section of Neurobiology, University of Texas at Austin, Austin, Texas, United States
4 Department of Pharmacology, University of Vermont, Burlington, Vermont, United States; Division of Cardiovascular and Endocrine Science, University of Manchester, Manchester, Lancashire, United Kingdom
* To whom correspondence should be addressed. E-mail: Matthias.Werner{at}manchester.ac.uk.
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), cGMP-dependent protein kinase I (PKGI). One important target of PKGI in smooth muscle is the large conductance, calcium-activated potassium (BKCa) channel. In our previous report (40), we demonstrated that deletion of the BKCa channel in mice induced force oscillations, 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 soluble guanylyl cyclase (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 greater than 1 µM, sildenafil caused relaxations independent of inhibition of sGC or BKCa channels. Sildenafil did not affect the enhanced force oscillations which were induced by the loss of BKCa channel function. Yet, these oscillations could be completely eliminated by blocking L-type voltage-dependent calcium 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 hyper-contractility which depends on VDCCs and can not be modified by the cGMP pathway.
