Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress

Yoshikuni Kimura, Yoshitaka Hirooka, Yoji Sagara, Koji Ito, Takuya Kishi, Hiroaki Shimokawa, Akira Takeshita, Kenji Sunagawa

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or β-galactosidase (Adβgal) were transfected into the RVLM in Wistar-Kyoto (WKY) rats. Blood pressure and heart rate were monitored using a radiotelemetry system. iNOS expression in the RVLM was confirmed by immunohistochemical staining or Western blot analysis. Mean arterial pressure significantly increased from day 6 to day 11 after AdiNOS transfection, but did not change after Adβgal transfection. Urinary norepinephrine excretion was significantly higher in AdiNOS-transfected rats than in Adβgal-transfected rats. Microinjection of aminoguanidine or S-methylisothiourea, iNOS inhibitors, or tempol, an antioxidant, significantly attenuated the pressor response evoked by iNOS gene transfer. The levels of thiobarbituric acid-reactive substances, a marker of oxidative stress, were significantly greater in AdiNOS-transfected rats than in Adβgal-transfected rats. Dihydroethidium fluorescence in the RVLM was increased in AdiNOS-transfected rats. In addition, nitrotyrosine- positive cells were observed in the RVLM only in AdiNOS-transfected rats. Intracisternal infusion of tempol significantly attenuated the pressor response and the increase in the levels of thiobarbituric acid-reactive substances induced by AdiNOS transfection. These results suggest that overexpression of iNOS in the RVLM increases blood pressure via activation of the sympathetic nervous system, which is mediated by an increase in oxidative stress.

Original languageEnglish
Pages (from-to)252-260
Number of pages9
JournalCirculation research
Volume96
Issue number2
DOIs
Publication statusPublished - Feb 4 2005

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Nitric Oxide Synthase Type II
Adenoviridae
Galactosidases
Oxidative Stress
Hypertension
Transfection
Thiobarbituric Acid Reactive Substances
Blood Pressure
Inbred WKY Rats
Sympathetic Nervous System
Microinjections
Brain Stem
Norepinephrine
Arterial Pressure
Antioxidants
Heart Rate
Fluorescence
Western Blotting
Staining and Labeling
Genes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress. / Kimura, Yoshikuni; Hirooka, Yoshitaka; Sagara, Yoji; Ito, Koji; Kishi, Takuya; Shimokawa, Hiroaki; Takeshita, Akira; Sunagawa, Kenji.

In: Circulation research, Vol. 96, No. 2, 04.02.2005, p. 252-260.

Research output: Contribution to journalArticle

Kimura, Yoshikuni ; Hirooka, Yoshitaka ; Sagara, Yoji ; Ito, Koji ; Kishi, Takuya ; Shimokawa, Hiroaki ; Takeshita, Akira ; Sunagawa, Kenji. / Overexpression of inducible nitric oxide synthase in rostral ventrolateral medulla causes hypertension and sympathoexcitation via an increase in oxidative stress. In: Circulation research. 2005 ; Vol. 96, No. 2. pp. 252-260.
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AB - The present study examined the role of inducible nitric oxide synthase (iNOS) in the rostral ventrolateral medulla (RVLM) of the brain stem, where the vasomotor center is located, in the control of blood pressure and sympathetic nerve activity. Adenovirus vectors encoding iNOS (AdiNOS) or β-galactosidase (Adβgal) were transfected into the RVLM in Wistar-Kyoto (WKY) rats. Blood pressure and heart rate were monitored using a radiotelemetry system. iNOS expression in the RVLM was confirmed by immunohistochemical staining or Western blot analysis. Mean arterial pressure significantly increased from day 6 to day 11 after AdiNOS transfection, but did not change after Adβgal transfection. Urinary norepinephrine excretion was significantly higher in AdiNOS-transfected rats than in Adβgal-transfected rats. Microinjection of aminoguanidine or S-methylisothiourea, iNOS inhibitors, or tempol, an antioxidant, significantly attenuated the pressor response evoked by iNOS gene transfer. The levels of thiobarbituric acid-reactive substances, a marker of oxidative stress, were significantly greater in AdiNOS-transfected rats than in Adβgal-transfected rats. Dihydroethidium fluorescence in the RVLM was increased in AdiNOS-transfected rats. In addition, nitrotyrosine- positive cells were observed in the RVLM only in AdiNOS-transfected rats. Intracisternal infusion of tempol significantly attenuated the pressor response and the increase in the levels of thiobarbituric acid-reactive substances induced by AdiNOS transfection. These results suggest that overexpression of iNOS in the RVLM increases blood pressure via activation of the sympathetic nervous system, which is mediated by an increase in oxidative stress.

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