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


OBJECTIVE
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.


METHODS
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.
Nangle
Matthew R
MR
School of Medical Sciences, University of Aberdeen, Aberdeen, Scotland, UK.
Cotter
Mary A
MA
Cameron
Norman E
NE
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D018783:Impotence, Vasculogenic / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D051379:Mice; D009599:Nitroprusside / Q000494:pharmacology; D009930:Organic Chemicals / Q000494:pharmacology / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010410:Penile Erection / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000187:drug effects / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology
D001786:Blood Glucose; D009930:Organic Chemicals; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D009599:Nitroprusside; D010656:Phenylephrine; C502278:GPI 15427; D011065:Poly(ADP-ribose) Polymerases; D000109:Acetylcholine