The effects of testosterone and dihydrotestosterone on endothelial nitric oxide synthase activity.

L. GOGLIA; V. TOSI; S. GARIBALDI; C. BALDACCI; P. MANNELLA; S. PISANESCHI; M.S. GIRETTI; M.I. FLAMINI; A.M. SANCHEZ; A.R. GENAZZANI; T. SIMONCINI

March 5-8, Venezia, Italy

Congreso; 13th World Congress on Human Reproduction.; 2009

Testosterone has been considered detrimental to the cardiovascular system, however, this is controversial. In the present study, we tested the effects of testosterone (T) and its metabolite, dihydrotestosterone (DHT), on endothelial nitric oxide synthase (eNOS) activity and on nitric oxide (NO) release. Our results show that at low concentrations (10-9 M), treatment with both T and DHT for 30 min rapidly increases eNOS activity as well as NO release. Flutamide blocks these actions. Intriguingly, the estrogen receptor antagonist, ICI 182,780 also inhibits eNOS activity and NO production enhanced by T but not by DHT. Both T and DHT induce a rapid phosphorylation of mitogen-activated protein kinase and Akt. The addition of the phosphatidylinositol-3 kinase (PI3K) inhibitor, wortmannin, and of the mitogen activated protein kinase kinase (MEK) inhibitor, PD98059, prevent T- or DHT-dependent eNOS activation and NO release, suggesting that PI3K/Akt and ERK1/2 are important mediators. However, at high concentration (10-8-10-6 M), these two compounds lead to a decreased eNOS activity and NO production. Testosterone and DHT function differently on human endothelial cells depending on their concentration. At the lower concentration, they may be cardio protective by regulating eNOS activity, NO production while at higher concentrations, they may have deleterious effects.