GABAergic mechanism in the rostral ventrolateral medulla contributes to the hypotension of moxonidine.
OBJECTIVE
The depressor action of the centrally antihypertensive drug moxonidine has been attributed to activation of I(1)-imidazoline receptor in the rostral ventrolateral medulla (RVLM). The objective of this study was to determine the role of the γ-aminobutyric acid (GABA) mechanisms in the RVLM in mediating the effect of moxonidine in anaesthetized normotensive rats.


RESULTS
The relationship between the effects of microinjection or picoinjection of moxonidine and the functional state of GABA receptors at the level of the RVLM or pre-sympathetic neuron was determined. Microdialysis was performed to detect the effect of moxonidine on the release of GABA in the RVLM. Western blot analysis was carried out to test the effect of chronic intracerebroventricular injection of moxonidine on the protein expression of GABA receptors in the RVLM. Pre-treatment with the GABA(A) or GABA(B) receptor antagonist bicuculline (5 pmol) or CGP35348 (200 pmol), respectively, microinjected into the RVLM significantly attenuated the decrease in blood pressure and renal sympathetic nerve activity induced by moxonidine. In 22 moxonidine-sensitive pre-sympathetic neurons in the RVLM, picoinjection of bicuculline (100 fmol/5 nL) significantly attenuated the neuronal inhibition evoked by moxonidine (100 pmol/5 nL). The release of GABA in the RVLM was increased after intravenous moxonidine (50 μg/kg). Central infusion of moxonidine upregulated the protein expression of both GABA(A) and GABA(B) receptors in the RVLM.


CONCLUSIONS
The current data demonstrate that GABAergic mechanisms in the RVLM are responsible for the hypotension and sympathoinhibition of moxonidine.
Peng
Jun-Feng
JF
Department of Physiology, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China.
Wu
Zhao-Tang
ZT
Wang
Yang-Kai
YK
Yuan
Wen-Jun
WJ
Sun
Tao
T
Ni
Xin
X
Su
Ding-Feng
DF
Wang
Wei
W
Xu
Ming-Juan
MJ
Wang
Wei-Zhong
WZ
D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D058787:GABA-A Receptor Antagonists / Q000008:administration & dosage; D058788:GABA-B Receptor Antagonists / Q000008:administration & dosage; D006339:Heart Rate / Q000187:drug effects; D007022:Hypotension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D057967:Infusions, Intraventricular; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007668:Kidney / Q000294:innervation; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects* / Q000378:metabolism; D017551:Microdialysis; D008845:Microinjections; D009433:Neural Inhibition / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D000959:Antihypertensive Agents; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D007093:Imidazoles; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; C043482:moxonidine