Testosterone Restores Diabetes-Induced Erectile Dysfunction and Sildenafil Responsiveness in Two Distinct Animal Models of Chemical Diabetes

Authors

Errata

This article is corrected by:

  1. Errata: ERRATUM Volume 3, Issue 3, 573, Article first published online: 20 April 2006

Mario Maggi, MD, Andrology Unit, Department of Clinical Physiopathology, University of Florence, V.le G. Pieraccini, 6, 50139 Florence, Italy. Tel: (+39) 0554271415; Fax: (+39) 0554271413; E-mail: m.maggi@dfc.unifi.it

ABSTRACT

Introduction.  Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED).

Aim.  To investigate the role of hypogonadism on phosphodiesterase type 5 (PDE5) expression and sildenafil responsiveness in diabetes.

Methods.  Two different models of experimental diabetes were used: (i) alloxan-induced diabetic rabbit; and (ii) streptozotocin (STZ)-induced diabetic rat. In both experimental models, animals were separated into three groups: control, diabetic, diabetic supplemented with testosterone (T) enanthate. Rabbits were used for “in vitro” experiments. Conversely, each rats group was further subdivided: no further treatment or acute sildenafil dosing (25 mg/kg, 1 hour before “in vivo” electrical stimulation [ES]).

Main Outcome Measure.  Erectile capacity was evaluated either by “in vitro” contractility study (alloxan-induced diabetic rabbit) and “in vivo” evaluation of erectile response elicited by ES of cavernous nerve (STZ-induced diabetic rats). Also endothelial nitric oxide synthase, neural nitric oxide synthase (nNOS), and PDE5 protein (Western blot) and mRNA (quantitative real-time reverse transcriptase polymerase chain reaction [RT-PCR]) expression were measured in rat penile samples of each group.

Results.  In both models, hypogonadism was observed, characterized by reduced T and atrophy of androgen-dependent accessory glands. T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to “in vitro” (acetylcholine, rabbit) or “in vivo” (ES, rat) relaxant stimuli, along with nNOS expression, which was reduced (P < 0.05) in STZ rats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both “in vitro” nitric oxide donor (NCX 4040) relaxant effect (rabbit) and “in vivo” ES-induced erection (rat). PDE5 was reduced in diabetic STZ rats (P < 0.05) and normalized by T. In STZ rats, sodium nitroprusside (SNP) intracavernous injection induced a more sustained erection than in control rats, which was no further enhanced by sildenafil. T substitution normalized both hyper-responsiveness to SNP and sildenafil efficacy.

Conclusion.  In two models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates sensitivity to relaxant stimuli and responsiveness to sildenafil. Zhang X-H, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, Forti G, and Maggi M. Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. J Sex Med 2006;3:253–266.

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