Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF.
Standard treatments for erectile dysfunction (ED) (i.e., PDE5 inhibitors) are less effective in diabetic patients for unknown reasons. Endothelium-dependent relaxation (EDR) of human corpus cavernosum (HCC) depends on nitric oxide (NO), while in human penile resistance arteries (HPRA) endothelium-derived hyperpolarizing factor (EDHF) and NO participate. Here we show that diabetes significantly reduced EDR induced by acetylcholine (ACh) in HCC and HPRA. Relaxation attributed to EDHF was also impaired in HPRA from diabetic patients. The PDE5 inhibitor, sildenafil (10nM), reversed diabetes-induced endothelial dysfunction in HCC, but not in HPRA. Calcium dobesilate (DOBE; 10 microM) fully reversed diabetes-induced endothelial dysfunction in HPRA by specifically potentiating the EDHF-mediated component of EDR. Impairment by diabetes of NO and EDHF-dependent responses precluded the complete recovery of endothelial function in HPRA by sildenafil. This could explain the poor clinical response to PDE5 inhibitors of diabetic men with ED and 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
Fundación para la Investigación y el Desarrollo en Andrología. 28304, Madrid, Spain. isdtejada@terra.es
Cuevas
Pedro
P
Fernández
Argentina
A
Gabancho
Sonia
S
Allona
Antonio
A
Martín-Morales
Antonio
A
Moncada
Ignacio
I
Videla
Sebastián
S
Sáenz de Tejada
Iñigo
I
D000109:Acetylcholine / Q000494:pharmacology; D001158:Arteries / Q000473:pathology / Q000503:physiopathology*; D001685:Biological Factors / Q000378:metabolism*; D002123:Calcium Dobesilate / Q000494:pharmacology; D048909:Diabetes Complications; D003920:Diabetes Mellitus / Q000473:pathology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D007172:Erectile Dysfunction / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D018783:Impotence, Vasculogenic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D010413:Penis / Q000098:blood supply / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D010879:Piperazines; D011687:Purines; D012016:Reference Values; D000068677:Sildenafil Citrate; D013314:Stress, Mechanical; D013450:Sulfones
D001685:Biological Factors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D002123:Calcium Dobesilate; D000068677:Sildenafil Citrate; D000109:Acetylcholine