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(Circulation. 2004;110:2476-2483.)
© 2004 American Heart Association, Inc.

Molecular Cardiology

In Situ Akt Phosphorylation in the Nucleus Tractus Solitarii Is Involved in Central Control of Blood Pressure and Heart Rate

Hsiao-Ning Huang, MS; Pei-Jung Lu, PhD; Wan-Chen Lo, MS; Chia-Hui Lin, MS; Michael Hsiao, DVM, PhD; Ching-Jiunn Tseng, MD, PhD

From the Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.

Reprint requests to Ching-Jiunn Tseng, MD, PhD, Department of Medical Education and Research, Kaohsiung Veterans General Hospital 386-Ta-Chung 1st Rd, Kaohsiung, Taiwan. E-mail cjtseng{at}isca.vghks.gov.tw

Received July 20, 2004; revision received July 26, 2004; accepted July 29, 2004.

Background— Previously, we have shown that nitric oxide (NO) plays a significant role in central cardiovascular regulation and modulates the baroreflex in the nucleus tractus solitarii (NTS) of rats. NO production is mediated by activation of NO synthase (NOS). Insulin signaling was involved in controlling peripheral blood pressure via the activation of endothelial NOS. Here, we investigated whether the insulin signal transduction pathway is involved in controlling central cardiovascular effects.

Methods and Results— Insulin was injected into NTS of urethane-anesthetized male Wistar-Kyoto (WKY) rats. Unilateral microinjection (60 nL) of insulin (100 IU/mL) into the NTS produced prominent depressor and bradycardic effects in 8- and 16-week-old WKY rats. In addition, pretreatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the NOS inhibitor L-NAME into the NTS caused attenuation of the cardiovascular response evoked by insulin in either 8- or 16-week-old WKY rats. Western blot analysis showed a significant increase (2.6±0.4-fold; P<0.05) in Akt phosphorylation after insulin injection, whereas LY294002 abolished the insulin-induced effects. In situ Akt phosphorylation was found in NTS by immunohistochemistry analysis after injection of insulin. This in situ Akt phosphorylation was abolished significantly after injection of LY294002.

Conclusions— Take together, these results suggest that the insulin-PI3K-Akt-NOS signaling pathway may play a significant role in central cardiovascular regulation.

Key Words: insulin • enzymes • nitric oxide synthase

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