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.
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 language | English |
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Pages (from-to) | 3396-3403 |
Number of pages | 8 |
Journal | The Journal of Sexual Medicine |
Volume | 7 |
Issue number | 10 |
Early online date | 26 Apr 2010 |
DOIs | |
Publication status | Published - Oct 2010 |
Keywords
- diabetes and erectile dysfunction
- endothelial dysfunction
- diabetic neuropathy
- oxidative stress
- peroxynitrite
- poly(ADP-ribose) polymerase (PARP)