| Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice. | |
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MedLine Citation:
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PMID: 20456626 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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INTRODUCTION: Activation of the DNA repair enzyme, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), in response to hyperglycemia-driven oxidative/nitrosative stress, may be an important mechanism in the development of vascular and neural complications in diabetes mellitus. However, a role for PARP in diabetic erectile dysfunction (ED) has not been demonstrated. AIM: To assess whether treatment with a novel PARP-1 inhibitor, GPI 15427, could improve neurovascular dysfunction in corpus cavernosum (CC) from diabetic mice. METHODS: Diabetes was induced by streptozotocin in male MF1 mice; duration was 6 weeks. Intervention GPI 15427 treatment (20mg/kg/day intraperitoneal [i.p.]) was given for 2 weeks following 4 weeks of untreated diabetes. CC strips were mounted in aerated organ baths for measurement of pharmacological or electrical stimulation-evoked changes in smooth muscle tension. MAIN OUTCOME MEASURES: Contractile responses to noradrenergic stimulation and to pharmacological agents stimulating endothelium-dependent and -independent relaxation, and nerve-mediated relaxations against a background precontraction. RESULTS: Contractions in response to phenylephrine or activation of noradrenergic nerves were not significantly altered by diabetes. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted CC was approximately 28% reduced by diabetes: GPI 15427 treatment completely corrected this diabetic deficit. Similarly, maximal nitric oxide (NO)-mediated endothelium-dependent and -independent relaxations to acetylcholine and sodium nitroprusside, against phenylephrine precontraction, were attenuated approximately 37% and 23% by diabetes, respectively. These deficits were completely reversed by PARP-1 inhibition. Furthermore, GPI 15427 corrected a modest diabetic deficit in sensitivity to nitroprusside (EC(50) reduced by 0.14 log units); a similar trend was observed for acetylcholine-induced relaxation. CONCLUSIONS: GPI 15427 treatment provides marked benefits for NO-dependent neurovascular function in diabetic mouse CC. Therefore, PARP-1 inhibition may be worthy of further investigation for diabetes-associated ED. |
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Authors:
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Matthew R Nangle; Mary A Cotter; Norman E Cameron |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: The journal of sexual medicine Volume: 7 ISSN: 1743-6109 ISO Abbreviation: J Sex Med Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-29 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101230693 Medline TA: J Sex Med Country: United States |
Other Details:
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Languages: eng Pagination: 3396-403 Citation Subset: IM |
Copyright Information:
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© 2010 International Society for Sexual Medicine. |
Affiliation:
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School of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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