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1 Division of Urology, University of Pennsylvania, Philadelphia, PA, USA
2 Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA
3 Division of Urology, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathobiology, University of Pennsylvania, Philadelphia, PA, USA
* To whom correspondence should be addressed. E-mail: mdisanto{at}mail.med.upenn.edu.
Increased cyclic GMP (cGMP), induced by nitric oxide (NO) release, is crucial for corpus cavernosum smooth muscle (CCSM) relaxation within the penis. This CCSM relaxation (necessary for penile erection) is impaired in men with erectile dysfunction (ED), especially those men with diabetes. One of the effector proteins for cGMP is cGMP-dependent protein kinase-1 (PKG-1). PKG-1 knockout mice exhibit detrusor overactivity [Am J Physiol 179:R1112, 2000] and, more relevant to this study, ED [PNAS, 97:2349, 2000], suggesting an in vivo role for PKG-1 in urogenital smooth muscle relaxation. In the current study, using normal rabbit CCSM, Western blot analysis revealed high expression of PKG-1 at levels almost equivalent to aorta (previously shown to have high PKG-1 expression) and that the two known alternatively spliced isoforms of PKG-1 (
and 
) are expressed in nearly equal amounts in the CCSM. However, in response to alloxan-induced diabetes, there was a significant decrease in expression of both PKG-1 isoforms at the mRNA and protein levels as determined by Real-Time RT-PCR and Western blotting, respectively, but with the PKG-1 isoform expression decreased to a greater extent. Moreover, diabetes was associated with significantly decreased PKG-1 activity of CCSM in vitro. Immunofluorescence microscopy revealed a diabetes-associated decrease in PKG-1 in the CCSM cells. In conclusion, our results demonstrate for the first time a significant downregulation of PKG-1 expression associated with decreased PKG-1 activity in the CCSM in response to diabetes. Furthermore, these results suggest a mechanistic basis for the decreased efficacy of phosphodiesterase V (PDE5) inhibitors in treating diabetic patients with ED.
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