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dc.creatorWerner, Matthias E.en
dc.creatorMeredith, Andrea L.en
dc.creatorAldrich, Richard W.en
dc.creatorNelson, Mark T.en
dc.date.accessioned2014-12-15T17:10:21Zen
dc.date.available2014-12-15T17:10:21Zen
dc.date.issued2007-07-25en
dc.identifier.citationWerner, Matthias E., Andrea L. Meredith, Richard W. Aldrich, and Mark T. Nelson. “Hyper-Contractility and Impaired cGMP Signaling in the BKCa Channel Deletion Model of Erectile Dysfunction.” BMC Pharmacology 7, no. Suppl 1 (July 25, 2007): P65. doi:10.1186/1471-2210-7-S1-P65.en
dc.identifier.urihttp://hdl.handle.net/2152/27867en
dc.descriptionMatthias E. Werner is with the Division of Cardiovascular and Endocrine Science, School of Medicine, University of Manchester, Manchester M13 9NT, UK -- Andrea L. Meredith is with the Department of Physiology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA -- Richard W. Aldrich is with the Section of Neurobiology, 1 University Station C7000, The University of Texas at Austin, Austin, TX 78712, USA -- Mark T. Nelson is with the Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405, USAen
dc.description.abstractErectile dysfunction (ED) is frequently elicited by a multiplicity of pathogenic factors, predominantly by impaired formation of and responsiveness to nitric oxide (NO) and the downstream effectors soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI). In smooth muscle, one important target of PKGI is the large conductance, calcium-sensitive potassium (BKCa) channel, which upon activation hyperpolarizes the smooth muscle cell membrane, causing relaxation. In our earlier report [1], we demonstrated that ablation of the gene, encoding for the pore-forming α subunit of the BKCa channel in mice (Slo-/-) induced an increase of corpus cavernosum smooth muscle (CCSM) force oscillations, led to reduced nerve-evoked relaxations and ED. In our current work, we used this ED model to explore the role of the BKCa channel in the NO/cGMP pathway. Electrical field stimulation (EFS)-induced contractions of CCSM strips from Slo-/- mice demonstrated a 53% increase that could be reduced by sildenafil similar to levels observed in strips from wild-type (Slo+/+) mice. In Slo-/- strips precontracted with phenylephrine (PE), SNP and sildenafil induced relaxations, which were diminished by 10% and 7% over Slo+/+, respectively. Neither SNP nor sildenafil was able to reduce 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). The latter results indicate that loss of BKCa channel leads to ED and hyper-contractility likely due to instability of membrane potential which activates VDCCs. Moreover, since the relaxing effects of SNP and sildenafil were reduced in Slo-/-, the ED phenotype in our BKCa channel deletion model could also be the consequence of an impaired NO/cGMP signaling pathway.en
dc.description.sponsorshipen
dc.language.isoEnglishen
dc.publisherBMC Pharmacologyen
dc.rightsAdministrative deposit of works to UT Digital Repository: This works author(s) is or was a University faculty member, student or staff member; this article is already available through open access at http://www.biomedcentral.com. The public license is specified as CC-BY: http://creativecommons.org/licenses/by/4.0/. The library makes the deposit as a matter of fair use (for scholarly, educational, and research purposes), and to preserve the work and further secure public access to the works of the University.en
dc.subjectErectile dysfunctionen
dc.subjectprotein kinase I (PKGI)en
dc.subjectsmooth muscleen
dc.titleHyper-contractility and impaired cGMP signaling in the BKCa channel deletion model of erectile dysfunctionen
dc.typeOtheren
dc.description.departmentNeuroscienceen
dc.description.catalogingnoteMatthias.Werner@manchester.ac.uken
dc.identifier.Filename1471-2210-7-S1-P65en
dc.identifier.doidoi:10.1186/1471-2210-7-S1-P65en


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