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


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-infused 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 microg/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.


CONCLUSIONS
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.
Peng
Jie
J
Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
Wang
Yang-Kai
YK
Wang
Li-Gang
LG
Yuan
Wen-Jun
WJ
Su
Ding-Feng
DF
Ni
Xin
X
Deng
Xiao-Ming
XM
Wang
Wei-Zhong
WZ
D000200:Action Potentials; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage*; D007150:Immunohistochemistry; D007263:Infusions, Parenteral; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007550:Isothiuronium / Q000008:administration & dosage / Q000031:analogs & derivatives; D007668:Kidney / Q000294:innervation; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000201:enzymology; D009433:Neural Inhibition / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013564:Sympathetic Nervous System / Q000187:drug effects*; D013565:Sympatholytics / Q000008:administration & dosage*; D013997:Time Factors
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D013565:Sympatholytics; D007550:Isothiuronium; D009569:Nitric Oxide; C043482:moxonidine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C027744:S-methylisothiopseudouronium