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Growth Hormone Treatment Improves Markers of Systemic Nitric Oxide Bioavailability via Insulin-Like Growth Factor-I

Universitätsklinikum (T.T., F.F., J.B.), Medizinische Klinik I (Kardiologie), 97080 Würzburg, Germany; Universitätsklinikum (T.T., M.J.), Interdisziplinäres Zentrum für Klinische Forschung, Nachwuchsgruppe Cardiac Wounding and Healing, 97080 Würzburg, Germany; and Medizinische Hochschule Hannover (I.K., D.T., D.O.S.), Institut für Klinische Pharmakologie, D-30625 Hannover, Germany

Address all correspondence and requests for reprints to: Dr. med. Thomas Thum, Medizinische Klinik und Poliklinik I, Kardiologie, Universitätsklinikum, Bayerische Julius-Maximilians-Universität, Josef-Schneider Str. 2, 97080 Würzburg, Germany. E-mail: thum_t{at}klinik.uni-wuerzburg.de.

Context and Objective: Impaired nitric oxide (NO) bioavailability and low levels of circulating endothelial progenitor cells (EPC) are correlated to an increased risk for development of cardiovascular diseases. We investigated whether improved systemic NO bioavailability and increased levels of EPC after GH treatment are related and mediated by the IGF-I.

Design, Patients, and Results: Healthy middle-aged volunteers (n = 16) were treated for 10 d with recombinant human GH. Before and after GH treatment, we analyzed markers of NO bioavailability and EPC levels. GH treatment was responded by significant increases in plasma IGF-I levels. Urinary cGMP levels were increased and diastolic blood pressure reduced after GH treatment (P < 0.05). Likewise, plasma nitrate and nitrite levels were increased, whereas the NO synthase inhibitor asymmetric dimethylarginine was reduced. Correspondingly, IGF-I treatment increased expression of the asymmetric dimethylarginine-metabolizing enzyme dimethylarginie dimethylaminohydrolase-1 and dimethylarginie dimethylaminohydrolase-2 in cultured human endothelial cells. IGF-I levels correlated with cGMP concentrations (r = 0.51; P < 0.05). EPC numbers were increased after GH treatment and correlated with markers for NO bioavailability. These findings were also observed in mice treated with GH for 7 d. GH treatment additionally increased aortic endothelial NO synthase expression of mice. Importantly, blocking of the IGF-I receptor in vivo abolished the GH-mediated effects on markers of increased NO bioavailability.

Conclusions: GH treatment induced markers of increased NO bioavailability and enhanced circulating EPC numbers in healthy volunteers. Animal data demonstrate increased NO availability to be mediated via an increase in IGF-I plasma levels. Thus, GH treatment enhances systemic NO bioavailability via IGF-I and may be beneficial in certain cardiovascular diseases.

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