Contractile mechanisms in diabetes-related erectile dysfunction.
Penile tumescence (erection) and detumescence (return to the flaccid state) are regulated by a complex neurophysiological process involving the relaxation and contraction, respectively, of smooth muscle (SM) within the two corpus cavernosum (CC) of the penis. Failure of the above SM-mediated process to function properly results in the inability to obtain an erection sufficient for sexual satisfaction and has been termed erectile dysfunction (ED). It is predicted that an estimated 322 million men worldwide will have ED by the year 2025 and, relevant to this review article, is that roughly 50% of men with diabetes also have ED. Furthermore, one of the largest classes of nonresponders to oral phosphodiesterase V (PDE5) inhibitors (the predominant pharmacological treatment for organic ED) are diabetics. This review article examines the current knowledge about the contractile pathways that fine-tune SM tone with particular emphasis on vascular SM including corpus cavernosum smooth muscle (CCSM). The role of the contractile apparatus, SM myosin phosphorylation/dephosphorylation pathways, calcium "sensitization" and "desensitization" pathways and the main neurotransmitters/modulators responsible for regulating CCSM contraction are outlined along with how they are modified or potentially may be modified in response to diabetes. The overall hypothesis generated from this review is that an increased CCSM tone, resulting from an enhancement of contractile mechanisms, may contribute to the higher than average nonresponse rate of diabetic men to PDE5 inhibitors. Knowledge gained from this review will hopefully lead to the generation of drugs that specifically target CCSM contractile pathways which may prove to have therapeutic usefulness in treating ED in diabetics either alone or in combination with existing PDE5 inhibitors.
Disanto
Michael E
ME
Albert Einstein College of Medicine, 744 Forchheimer Building, 1300 Morris Park Avenue, Bronx, NY 10461, USA. mdisanto@aecom.yu.edu
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D048909:Diabetes Complications / Q000503:physiopathology*; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000453:epidemiology / Q000209:etiology*; D006801:Humans; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000098:blood supply / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects
D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human