Nitric oxide-cyclic GMP pathway with some emphasis on cavernosal contractility.
Nitric oxide (NO) is formed from the conversion of L-arginine by nitric oxide synthase (NOS), which exists in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). nNOS is expressed in penile neurons innervating the corpus cavernosum, and eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium. NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine-3',5'-monophosphate (cGMP) and, finally, to calcium depletion from the cytosolic space and cavernous smooth muscle relaxation. The effects of cGMP are mediated by cGMP dependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDE). Thus, cGMP effect depends on the expression of a cell-specific cGMP-receptor protein in a given cell type. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decreased erectile function in men and a number of animal models of penile erection. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated smooth muscle relaxation. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Development of pharmacologic agents with this effect has closely paralleled the emerging science.
Ghalayini
I F
IF
Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan. ibrahim@ghalayini.com
D006152:Cyclic GMP / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology; D007172:Erectile Dysfunction / Q000188:drug therapy / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000502:physiology; D008297:Male; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010413:Penis / Q000098:blood supply / Q000294:innervation; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D010727:Phosphoric Diester Hydrolases / Q000502:physiology; D011494:Protein Kinases / Q000378:metabolism
D007473:Ion Channels; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D011494:Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006162:Guanylate Cyclase; D006152:Cyclic GMP