Enhancement of both EDHF and NO/cGMP pathways is necessary to reverse erectile dysfunction in diabetic rats.
OBJECTIVE
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.
Angulo
Javier
J
Instituto de Medicina Sexual, Fundación para la Investigación y el Desarollo en Andrología, Madrid, Spain. jangulo@ibercom.com
Cuevas
Pedro
P
Gabancho
Sonia
S
Gonzalez-Corrochano
Rocio
R
Videla
Sebastian
S
Saenz de Tejada
Iñigo
I
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D001685:Biological Factors / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D003920:Diabetes Mellitus; D007172:Erectile Dysfunction / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009434:Neural Pathways / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use*; D011687:Purines; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use*
D001685:Biological Factors; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; C022994:cyclic GMP-binding protein; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat