Our aim was to investigate the role of adrenoceptors in the modulation of in vivo interleukin-10 (IL-10) production in lipopolysaccharide (LPS)-treated mice. The effect of different adrenergic drugs on plasma concentration of IL-10 was measured by ELISA 90 min after LPS injection. Our results confirmed the involvement of beta-adrenoceptors since the beta-agonist isoproterenol significantly increased the IL-10 production in response to LPS stimulation, whereas the beta-antagonists propranolol decreased it. In contrast, the alpha2-agonists UK-14304, clonidine and xylazine significantly decreased the IL-10 plasma level, whereas the alpha2-antagonists CH-38083, prazosine and WB-4101 increased it. Our results provide the first in vivo evidence that, in addition to beta-adrenoceptors; alpha-adrenoceptors play also a very important role in the regulation of IL-10 production under endotoxaemic conditions.

01 Feb 2000·Journal of NeuroimmunologyQ3 · MEDICINE

Differential involvement of sympathetic nervous system and immune system in the modulation of TNF-α production by α2- and β-adrenoceptors in mice

Q3 · MEDICINE

Article

Author: Szelenyi, J. ; Vizi, E. S. ; Kiss, J. P.

In the present study, the regulation of tumor necrosis factor-alpha (TNF-alpha) production by alpha2- and beta-adrenoceptors located on noradrenergic nerve terminals and on macrophages was studied in endotoxaemic mice. We found that reduction of the sympathetic outflow by reserpine dramatically increased the lipopolysaccharide (LPS)-induced TNF-alpha production, demonstrating that the release of endogenous noradrenaline (NA), controlled by presynaptic alpha2-adrenoceptors, was a determinant factor in this model. By using alpha2- and beta-adrenergic drugs (clonidine, CH-38083, isoproterenol, propranolol) we provided the first in vivo evidence that, beside the dominance of neuronal alpha2- and macrophage beta-adrenoceptors, the alpha2-adrenoceptors on macrophages were also involved in the modulation of LPS-induced TNF-alpha production. Since adrenergic drugs are widely used in the clinical practice, our findings may have therapeutical implications.

01 Oct 1997·NeuroscienceQ3 · MEDICINE

Co-release of endogenous ATP and [3H]noradrenaline from rat hypothalamic slices: origin and modulation by α2-adrenoceptors

Q3 · MEDICINE

Article

Author: Sperlagh, B. ; Lajtha, A. ; Sershen, H. ; Vizi, E. S.

The release of endogenous ATP, measured by the luciferin-luciferase assay, and of [3H]noradrenaline from the in vitro superfused rat hypothalamic slices were studied. ATP and [3H]noradrenaline were released simultaneously during resting conditions and in response to low and high frequency field electrical stimulation; the release of both substances were frequency dependent between 2 Hz and 16 Hz. The stimulation-induced release of ATP and [3H]noradrenaline was diminished by more than 80% under Ca2+-free conditions. Tetrodotoxin inhibited the majority of the evoked release of both ATP and [3H]noradrenaline, however, it was less effective in reducing the release of [3H]noradrenaline, than that of ATP. Bilateral stereotaxic injection of 6-hydroxydopamine (4 microg/side) to the ventral part of the ventral noradrenergic bundle, originating from the A1 cell group in the brainstem, resulted in a 55% reduction of endogenous noradrenaline content of the hypothalamic slices, and the tritium uptake and the stimulation-evoked release of [3H]noradrenaline was also markedly reduced. While the basal release of ATP was not affected, the evoked release was diminished by 72% by this treatment. Perfusion of the slices with noradrenaline (100 microM) initiated rapid and continuous tritium release; on the other hand, it did not release any ATP. In contrast, 6 min perfusion of (-)nicotine and 1,1-dimethyl-4-phenyl-piperazinium iodide evoked parallel release of ATP and [3H]noradrenaline which was inhibited by the nicotinic receptor antagonist mecamylamine; 6-hydroxydopamine lesion of the ventral part of the ventral noradrenergic bundle did not affect the nicotine-evoked ATP and [3H]noradrenaline release. While CH 38083, a non subtype-selective alpha2-antagonist and BRL44408, the subtype-selective alpha2AD antagonist augmented the evoked release of [3H]noradrenaline, ARC239, a selective alpha2BC antagonist was without effect. In contrast, neither of the alpha2-antagonists significantly affected the evoked-release of ATP. In summary, we report here that endogenous ATP and [3H]noradrenaline are co-released stimulation-dependently from superfused rat hypothalamic slices. A significant part of the release of both compounds is derived from the nerve terminals, originating from the A1 catecholaminergic cell group of brainstem nuclei. Unlike that from the peripheral sympathetic transmission, noradrenaline and alpha1-adrenoceptor agonists were unable to promote the release of ATP. Conversely, parallel ATP and noradrenaline release could be induced by nicotine receptor activation, but this release does not originate from the same nerve endings. The evoked-release of [3H]noradrenaline is inhibited by endogenous noradrenaline via alpha2AD subtype of adrenoreceptors, while the release of ATP is not subject to this autoinhibitory modulation. In conclusion, our results support the view that ATP is involved in the neurotransmission in the hypothalamus, but the sources of the released ATP and noradrenaline seem to be not identical under different stimulatory and modulatory conditions.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Preclinical	HU	Chinoin Zrt.	-

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