Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 99, Issue 6, Pages 4061-4066Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.052712499
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Funding
- NIDA NIH HHS [DA00074, K05 DA000074, P50 DA000266, DA-00266] Funding Source: Medline
- NIDDK NIH HHS [DK02568] Funding Source: Medline
- NIMH NIH HHS [R01 MH018501, MH-18501, R37 MH018501] Funding Source: Medline
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In the penis, nitric oxide (NO) can be formed by both neuronal NO synthase and endothelial NOS (eNOS). eNOS is activated by viscous drag/shear stress in blood vessels to produce NO continuously, a process mediated by the phosphatidylinositol 3-kinase (P13-kinase)/Akt pathway. Here we show that P13-kinase/Akt physiologically mediates erection. Both electrical stimulation of the cavernous nerve and direct intracavernosal injection of the vasorelaxant drug papaverine cause rapid increases in phosphorylated (activated) Akt and eNOS. Phosphorylation is diminished by wortmannin and LY294002, inhibitors of P13-kinase, the upstream activator of Akt. The two drugs also reduce erection. Penile erection elicited by papaverine is reduced profoundly in mice with targeted deletion of eNOS. Our findings support a model in which rapid, brief activation of neuronal NOS initiates the erectile process, whereas P13-kinase/Akt-dependent phosphorylation and activation of eNOS leads to sustained NO production and maximal erection.
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