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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 17, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp202
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Sympathoinhibitory mechanism of moxonidine: role of the inducible nitric oxide synthase in the rostral ventrolateral medulla

Jie Peng1,2,{dagger}, Yang-Kai Wang1,{dagger}, Li-Gang Wang1, Wen-Jun Yuan1,3, Ding-Feng Su1, Xiao-Ming Deng2,* and Wei-Zhong Wang1,4,*

1 Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
2 Department of Anesthesiology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China
3 Department of Neurobiology and Physiology, Ningxia Medical University, Yinchuan 750004, China
4 Key Laboratory of Molecular Neurobiology, Ministry of Education, Second Military Medical University, Shanghai 200433, China

* Correspondence: Dr. Wei-Zhong Wang, Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China. Tel/Fax: 86-21-81870982; Email: wangwz68{at}hotmail.com; or Dr. Xiao-Ming Deng, Department of Anesthesiology, Changhai Hospital, 168 Changhai Road, Shanghai 200433, China; Email: deng_x{at}yahoo.com

Aims: The central antihypertensive drug moxonidine lowers blood pressure (BP) through stimulating an imidazoline receptor within the rostral ventrolateral medulla (RVLM). Nitric oxide (NO) generated by the inducible NO synthase (iNOS) in the RVLM has been suggested to be involved in tonic sympathetic inhibition. The aim of this study was to determine the role of NO generated by iNOS in mediating moxonidine-induced cardiovascular inhibition in rats.

Methods and results: In anaesthetized rats, the cardiovascular response to local or systemic injection of moxonidine was observed after treatment with the selective iNOS inhibitor S-methylisothiourea (SMT) in the brain. Using immunohistochemical staining and western blot techniques, the protein expression of iNOS in the RVLM was measured in the moxonidine-infusion rats. Intracerebroventricular (ICV) injection of SMT (1-100 nmol) dose-dependently attenuated the moxonidine (20 nmol, ICV)-induced decrease in BP and heart rate. Prior injection of SMT (20 and 200 pmol) into the RVLM also dose-dependently prevented the decrease in BP and renal sympathetic nerve activity evoked by RVLM microinjection of moxonidine (5 nmol) or intravenous injection of moxonidine (50 µg/kg). We further found that expression of iNOS protein following chronic ICV infusion of moxonidine (20 nmol, 2 weeks) is selectively upregulated in the RVLM but not in the nucleus tractus solitarius.

Conclusion: The present data suggest that an NO mechanism generated by iNOS in the RVLM plays an important role in mediating the sympathetic inhibition of the centrally acting drug moxonidine.

KEYWORDS Centrally acting drug; imidazoline receptor; nitric oxide; blood pressure; microinjection

Time for primary review: 29 Days

{dagger} The first two authors contribute equally to this work


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