ORIGINAL RESEARCH—BASIC SCIENCE: Enhancement of Both EDHF and NO/cGMP Pathways Is Necessary to Reverse Erectile Dysfunction in Diabetic Rats

Authors

  • Javier Angulo PhD,

    Corresponding author
    1. Instituto de Medicina Sexual, Fundación para la Investigación y el Desarollo en Andrología, Madrid
    2. Departamento de Investigación, Hospital Ramón y Cajal, Madrid
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  • Pedro Cuevas MD, PhD,

    1. Departamento de Investigación, Hospital Ramón y Cajal, Madrid
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  • Sonia Gabancho,

    1. Instituto de Medicina Sexual, Fundación para la Investigación y el Desarollo en Andrología, Madrid
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  • Rocio Gonzalez-Corrochano BSc,

    1. Instituto de Medicina Sexual, Fundación para la Investigación y el Desarollo en Andrología, Madrid
    2. Departamento de Investigación, Hospital Ramón y Cajal, Madrid
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  • Sebastian Videla MD,

    1. Departamento de Investigación Clínica, Laboratorios Dr. Esteve, Barcelona, Spain
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  • Iñigo Saenz de Tejada MD

    1. Instituto de Medicina Sexual, Fundación para la Investigación y el Desarollo en Andrología, Madrid
    2. Departamento de Investigación, Hospital Ramón y Cajal, Madrid
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Javier Angulo, Instituto de Medicina Sexual, C/Ana Teresa 30-1st floor 28023–Aravaca, Madrid, Spain. Tel: 3491 7401692; Fax: 3491 7401694; E-mail: jangulo@ibercom.com

ABSTRACT

Aims and Methods.  Phosphodiesterase 5 (PDE5) inhibitors are less effective in the treatment of erectile dysfunction (ED) in diabetic men than in nondiabetic patients. We have evaluated the effects of sildenafil, a PDE5 inhibitor that enhances the nitric oxide (NO)/cGMP pathway, calcium dobesilate (DOBE), which potentiates endothelium-derived hyperpolarizing factor (EDHF)-mediated responses and the combination of both on erectile responses elicited by cavernosal nerve electrical stimulation (CNES) in a rat model of ED after 8 weeks of streptozotocin-induced diabetes.

Results.  After 8 weeks of diabetes, erectile responses to CNES were significantly decreased in diabetic animals compared with nondiabetic time controls. While intravenous administration of sildenafil (0.3 mg/kg) or DOBE (10 mg/kg), individually, enhanced erectile responses in nondiabetic rats (214.7 ± 34.1% and 268.5 ± 30.1% of control response at 1 Hz, respectively), each failed to significantly enhance erectile responses in diabetic rats. Only when administered in combination did DOBE and sildenafil markedly potentiate erectile responses in these animals (380.1 ± 88.6% of control response at 1 Hz), completely restoring erectile function.

Conclusions.  These findings emphasize the importance of NO/cGMP and EDHF pathways for normal erectile function. They also give support to the in vitro observation that diabetes impairs NO and EDHF-dependent responses, precluding the complete recovery of erectile function with PDE5 inhibitors and explaining the relatively poor clinical response of diabetic men with ED to PDE5 inhibition. Finally, our study suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men.

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