The mechanism of alpha2-adrenergic inhibition of sympathetic ganglionic transmission.
Alpha2-adrenergic agonists produce analgesia and reduce hemodynamic stress through central and peripheral mechanisms, but the effect of adrenergic agonists on pre- and postganglionic sites has not yet been clarified. In this study, we examined the effects of dexmedetomidine (DMT), an alpha2-agonist, on neural conduction and neurotransmitter release in sympathetic ganglia. The stellate ganglia from 48 mongrel dogs were isolated, desheathed, and superfused with Krebs' solution. Compound action potentials were evoked, and chromatography was used to detect acetylcholine released by preganglionic stimulation in the presence or absence of DMT. To further elucidate the mechanism of alpha2 effects, DMT was applied in combination with the alpha2-antagonist atipamezole (AT) or the imidazoline antagonist idazoxan (ID). In other experiments, DMT was applied in the presence of exogenous nicotinic stimulation with 1,1-dimethyl-4-phenylpiperazinium iodide or muscarinic stimulation with (+)cis-dioxolane. DMT dose-dependently inhibited synaptic transmission with a 50% effective dose of 71.6 (26.0-174.3) microM. Neurotransmitter release was reduced 25% by 70 microM DMT during low-frequency (0.4 Hz) stimulation, but this effect was abolished at higher frequency (5 Hz) stimulation. AT but not ID blocked the inhibitory action of DMT. DMT inhibited the excitatory postsynaptic response to exogenous muscarinic stimulation but not nicotinic stimulation. These results indicate that alpha2-receptor activation depresses ganglionic transmission through postsynaptic inhibition of muscarinic stimulation, although reduction of neurotransmitter release through a presynaptic autofeedback mechanism is also involved.


CONCLUSIONS
This article provides novel insights into the mechanism of drug action of alpha2-receptor agonists in the sympathetic ganglia of dogs by directly measuring the relative contribution of pre- and postganglionic receptors. Our study indicates that the central sympatholytic effects of alpha2-adrenoceptor stimulation are augmented by peripheral inhibition of ganglionic transmission.
McCallum
J B
JB
Department of Anesthesiology, The Medical College of Wisconsin and the Zablocki Veterans Administration Medical Center, Milwaukee 53226, USA. mccallum@mcw.edu
Boban
N
N
Hogan
Q
Q
Schmeling
W T
WT
Kampine
J P
JP
Bosnjak
Z J
ZJ
D000109:Acetylcholine / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D004285:Dogs; D005260:Female; D005728:Ganglia, Sympathetic / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D020926:Medetomidine; D009638:Norepinephrine / Q000494:pharmacology; D013233:Stellate Ganglion / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D020926:Medetomidine; D000109:Acetylcholine; D009638:Norepinephrine