HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: 287/4/R950    most recent 00639.2003v1 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 ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (18) Citing Articles via Google Scholar Google Scholar Articles by Chang, S. Articles by DiSanto, M. E. Search for Related Content PubMed PubMed Citation Articles by Chang, S. Articles by DiSanto, M. E.

NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits

¹Division of Urology, ²Department of Pathobiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Submitted 31 October 2003 ; accepted in final form 10 June 2004

Increased guanosine 3',5'-cyclic monophosphate (cGMP), induced by nitric oxide 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 Regul Integr Comp Physiol 279: R1112–R1120, 2000) and, more relevant to this study, ED (Proc Natl Acad Sci USA 97: 2349–2354, 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 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, correlating with decreased CCSM relaxation. 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 inhibitors in treating diabetic patients with ED.

diabetes; erectile dysfunction; alloxan; isoforms; PDE5 inhibitors

This article has been cited by other articles:

				J. G. Lopez-Lopez, J. Moral-Sanz, G. Frazziano, M. J. Gomez-Villalobos, J. Flores-Hernandez, E. Monjaraz, A. Cogolludo, and F. Perez-Vizcaino Diabetes induces pulmonary artery endothelial dysfunction by NADPH oxidase induction Am J Physiol Lung Cell Mol Physiol, November 1, 2008; 295(5): L727 - L732. [Abstract] [Full Text] [PDF]

				B. Musicki and A. L. Burnett eNOS Function and Dysfunction in the Penis Experimental Biology and Medicine, February 1, 2006; 231(2): 154 - 165. [Abstract] [Full Text] [PDF]

				F. Hofmann, R. Feil, T. Kleppisch, and J. Schlossmann Function of cGMP-Dependent Protein Kinases as Revealed by Gene Deletion Physiol Rev, January 1, 2006; 86(1): 1 - 23. [Abstract] [Full Text] [PDF]