It is estimated that, on average, 50% of the 10 million men with diabetes mellitus (DM) have erectile dysfunction (ED) with both Type 1 and Type 2 DM nearly equally associated with ED. Although efficacious orally active PDE5 inhibitors have been developed to treat ED, a large percentage of diabetic men (with estimates as high as 50%) remain refractory to this therapy. The specific hypothesis of this proposal is that an increased corpus cavernosum smooth muscle (CCSM) basal tone and inability to properly relax the CCSM in diabetes-induced ED is mediated by SM calcium sensitization via inhibition of smooth muscle myosin phosphatase (SMMP) activity. Specifically, to address this hypothesis, we will examine the expression and regulation of molecules that either directly or indirectly regulate SMMP activity and the roles that they play in """"""""calcium sensitization/desensitization"""""""" pathways will be elucidated. Using CCSM from Type- I and Type II diabetic rats, patients with ED, as well as cultured CCSM cells, our hypothesis will be addressed by accomplishing the following specific aims: 1) To determine, using both Type I and Type II rat models of diabetes a) the precise correlation between diabetes and ED, b) whether there is an increased expression/activity of the """"""""calcium-sensitizing"""""""" enzyme Rho-kinase, three well-established ROK regulators (RhoA, endothelin and sphingosine-1-phosphate) and/or the SMMP inhibitory protein CPI-17 in diabetic animals, and the correlation of these changes with ED and c) if there is a simultaneous downregulation of molecules that promote the """"""""calcium desensitization"""""""" of smooth muscle (namely PKG-1 and telokin), 2) To determine a) whether similar alterations in the expression/activity of """"""""calcium sensitization/desensitization""""""""- associated molecules that occur in response to experimentally-induced diabetes can be induced in isolated CCSM cells (e.g. high glucose, high insulin, exogenous Et-1, etc.) and b) the ability of pharmacological inhibition of """"""""calcium sensitization"""""""" molecules or plasmid-mediated overexpression of """"""""calcium desensitization"""""""" molecules to prevent, attenuate or reverse ED and the mechanisms for these effects and 3) To determine, using human CCSM specimens routinely isolated from men undergoing penile surgery to treat ED, whether alterations in the """"""""calcium sensitization/desensitization"""""""" pathways in the rat translate to diabetic humans with ED. The data obtained by the completion of the studies described above should provide keen and novel insight into the molecular mechanism for diabetes-induced ED and also establish which """"""""calcium sensitization/desensitization"""""""" pathways may serve as attractive molecular therapeutic targets for the treatment of ED. Moreover, since similar changes in """"""""calcium sensitization"""""""" pathways are beginning to emerge in diabetic vascular SM, knowledge gained from these studies may have implications in diabetes- induced pathologies beyond the urogenital system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK077116-03S1
Application #
8043845
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Rankin, Tracy L
Project Start
2010-04-27
Project End
2011-04-26
Budget Start
2010-04-27
Budget End
2011-04-26
Support Year
3
Fiscal Year
2010
Total Cost
$99,600
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Urology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Zhang, Xinhua; Kanika, Nirmala D; Melman, Arnold et al. (2012) Smooth muscle myosin expression, isoform composition, and functional activities in rat corpus cavernosum altered by the streptozotocin-induced type 1 diabetes. Am J Physiol Endocrinol Metab 302:E32-42
Aydin, Memduh; Wang, Hong Zhan; Zhang, Xinhua et al. (2012) Large-conductance calcium-activated potassium channel activity, as determined by whole-cell patch clamp recording, is decreased in urinary bladder smooth muscle cells from male rats with partial urethral obstruction. BJU Int 110:E402-8
Zhang, Xinhua; Seftel, Allen; DiSanto, Michael E (2011) Blebbistain, a myosin II inhibitor, as a novel strategy to regulate detrusor contractility in a rat model of partial bladder outlet obstruction. PLoS One 6:e25958
Zhang, Xin-Hua; Melman, Arnold; Disanto, Michael E (2011) Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? J Sex Med 8:1865-79
Zhang, Xinhua; Kuppam, Dwaraka Srinivasa R; Melman, Arnold et al. (2011) In vitro and in vivo relaxation of urinary bladder smooth muscle by the selective myosin II inhibitor, blebbistatin. BJU Int 107:310-7
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Chua, Rowena G; Calenda, Giulia; Zhang, Xinhua et al. (2009) Testosterone regulates erectile function and Vcsa1 expression in the corpora of rats. Mol Cell Endocrinol 303:67-73
Zhang, Xin-Hua; Aydin, Memduh; Kuppam, Dwaraka et al. (2009) In vitro and in vivo relaxation of corpus cavernosum smooth muscle by the selective myosin II inhibitor, blebbistatin. J Sex Med 6:2661-71