Nitric oxide–cyclic GMP pathway with some emphasis on cavernosal contractility

Abstract

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 0 ,5 0 -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 cGMPreceptor 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.

Chuanxiongzine relaxes isolated corpus cavernosum strips and raises intracavernous pressure in rabbits

“…[7][8][9][10] Some drugs such as inhibitors of PDE 5 or other vasodilators, which can promote the relaxation of corpus cavernosum smooth muscle, can be potentially used to treat ED. [11][12][13][14][15][16][17][18][19] It has been shown that there are many Chinese traditional herbals that can enhance sexual activity. [20][21][22][23][24] Recently, there is an increasing interest in investigating their effective components.…”

Testosterone regulates smooth muscle contractile pathways in the rat prostate: emphasis on PDE5 signaling

“…On the other hand, decrease of free Ca 2ϩ in the sarcoplasm is caused mainly by the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP)/cGMP-dependent protein kinase-1 (cGKI)/phosphodiesterase 5 (PDE5) pathway, followed by calmodulin dissociation from myosin light-chain kinase, leading to SMM dephosphorylation and subsequent SM relaxation (20). This signaling pathway has been indentified in human prostate and colocalization of ␣-actin with cGMP, and cGKI supports the role of this pathway in regulating prostatic SM contractility (71).…”

L-DOPA inhibits nitric oxide-dependent vasorelaxation via production of reactive oxygen species in rat aorta

“…It is well know that nitric oxide (NO) is the major mediator of endothelium-dependent relaxation in aorta (15,21,22), which is formed from the conversion of L-arginine by nitric oxide synthase (NOS) in endothelium cell and released. This endothelium -derived NO stimulates the activity of soluble guanylate cyclase (sGC) in smooth muscle cells, leading to an increase in cyclic guanosine-3',5'-monophosphate (cGMP) and finally to calcium depletion from the cytosolic space and vascular smooth muscle relaxation (15,(21)(22)(23). Various agonists such as NE (noradrenaline), phenylephrine, 5HT can stimulate the release of NO from the endothelium during vasocontractile response to them (9).…”