Abstract
Sphingosine 1-phosphate (S1P) is the natural ligand for a specific G protein-coupled receptors. In endothelial cells, S1P has been shown to modulate the activity of the endothelial nitric-oxide synthase (eNOS) through phosphorylation operated by Akt. Nitric oxide (NO) produced by neuronal nitric-oxide synthase and eNOS plays a central role in triggering and maintaining penile erection. This study has assessed the possibility of a similar cross-talk between eNOS and S1P in human corpus cavernosum and whether this interaction is connected to penile vascular response. Quantitative reverse transcription-polymerase chain reaction demonstrated the presence of S1P1, S1P2, and S1P3 receptors in both the human corpus cavernosum (HCC) and the penile artery. S1P on its own did not relax or contract HCC strips, but on the other hand, incubation with S1P (0.1 μM) caused a 6-fold increase in relaxation induced by a subliminal dose of acetylcholine. This effect is dependent upon eNOS activation through an Akt-dependent phosphorylation, as demonstrated by pharmacological modulation with l-nitroarginine methyl ester and wortmannin and by Western blot studies. In human tissue, S1P seems to be the possible candidate for the activation of the eNOS calcium-independent pathway. This pathway may represent a new therapeutic area of intervention in erectile dysfunction (ED) to develop a way to selectively promote NO production at the endothelial level. This approach could also be used to enhance phosphodiesterase 5 therapy in patients with ED that are poor responders, such as in the case of diabetes.
Footnotes
-
doi:10.1124/jpet.105.093419.
-
ABBREVIATIONS: ED, erectile dysfunction; S1P, sphingosine 1-phosphate; NO, nitric oxide; eNOS, endothelial nitric-oxide synthase; SNP, sodium nitroprusside; HCC, human corpus cavernosum; l-NAME, l-nitroarginine methyl ester; EDG, endothelial differentiation gene; PI3K, phosphatidylinositol 3-kinase; Akt, serine/threonine kinase or protein kinase B; nNOS, neuronal nitric-oxide synthase; ACh, acetylcholine; PE, phenylephrine; PGE, prostaglandin E; LY294002, 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride.
- Received July 28, 2005.
- Accepted October 14, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|