Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes.
BACKGROUND
Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED).


OBJECTIVE
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]).


METHODS
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.


CONCLUSIONS
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
Xin-Hua
XH
Andrology Unit, Department of Clinical Physiopathology, Center of Research, Transfer and High Education, University of Florence, Florence, Italy.
Filippi
Sandra
S
Morelli
Annamaria
A
Vignozzi
Linda
L
Luconi
Michaela
M
Donati
Silvia
S
Forti
Gianni
G
Maggi
Mario
M
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000496:Alloxan; D000818:Animals; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D007006:Hypogonadism / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D010879:Piperazines / Q000008:administration & dosage* / Q000494:pharmacology; D011687:Purines; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013311:Streptozocin; D013450:Sulfones; D013739:Testosterone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D013739:Testosterone; D013311:Streptozocin; D000496:Alloxan; C004648:testosterone enanthate; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat