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.
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 diabeticrat. 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 diabeticrats). 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 STZrats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both "in vitro" nitric oxidedonor (NCX 4040) relaxant effect (rabbit) and "in vivo" ES-induced erection (rat). PDE5 was reduced in diabeticSTZrats (P < 0.05) and normalized by T. In STZrats, 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.
Authors: Carol A Podlasek; John Mulhall; Kelvin Davies; Christopher J Wingard; Johanna L Hannan; Trinity J Bivalacqua; Biljana Musicki; Mohit Khera; Nestor F González-Cadavid; Arthur L Burnett Journal: J Sex Med Date: 2016-08 Impact factor: 3.802
Authors: Elizabeth Yohannes; Jinsook Chang; Moses T Tar; Kelvin P Davies; Mark R Chance Journal: Mol Cell Proteomics Date: 2009-12-10 Impact factor: 5.911
Authors: R González-Corrochano; Jm La Fuente; P Cuevas; A Fernández; Mx Chen; I Sáenz de Tejada; J Angulo Journal: Br J Pharmacol Date: 2013-05 Impact factor: 8.739