Poly(ADP-ribose) polymerase inhibition reverses nitregic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice

Matthew R Nangle, Mary A Cotter, Norman E Cameron

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

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 (20 mg/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 (EC50 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. Nangle MR, Cotter MA, and Cameron NE. Poly(ADP-ribose) polymerase inhibition reverses nitrergic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice. J Sex Med 2010;7:3396–3403.
Original languageEnglish
Pages (from-to)3396-3403
Number of pages8
JournalThe Journal of Sexual Medicine
Volume7
Issue number10
Early online date26 Apr 2010
DOIs
Publication statusPublished - Oct 2010

Keywords

  • diabetes and erectile dysfunction
  • endothelial dysfunction
  • diabetic neuropathy
  • oxidative stress
  • peroxynitrite
  • poly(ADP-ribose) polymerase (PARP)

Fingerprint Dive into the research topics of 'Poly(ADP-ribose) polymerase inhibition reverses nitregic neurovascular dysfunctions in penile erectile tissue from streptozotocin-diabetic mice'. Together they form a unique fingerprint.

  • Cite this