Ij. Elenkov et al., MODULATION OF LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY SELECTIVE ALPHA-ADRENERGIC AND BETA-ADRENERGIC DRUGS IN MICE, Journal of neuroimmunology, 61(2), 1995, pp. 123-131
In a previous study we demonstrated that mice pretreated with the high
ly selective alpha(2)-adrenoceptor antagonist CH-38083 showed blunting
of the tumor necrosis factor-alpha (TNF-alpha) response induced by ba
cterial lipopolysaccharide (LPS). In the present study, the effect of
a selective block of alpha(2)-adrenoreceptors and the role of the symp
athetic nervous system (SNS) in the regulation of LPS-induced TNF-alph
a production was explored further using different selective adrenocept
or antagonists and agonists. While adrenalectomy did not prevent the e
ffect of CH-38083, the block of the sympathetic transmission by chlori
sondamine fully abolished the inhibitory effect of CH-38083 on LPS-ind
uced TNF-alpha production, suggesting that the effect of the alpha(2)-
adrenoceptor blocking agent is corticosteroid-independent, but it requ
ires intact sympathetic activity. Since the selective block of alpha(2
)-adrenoceptors results in an increased sympathetic activity and an in
crease of the release of noradrenaline (NA) in both the central and th
e peripheral nervous systems, and in our experiments propranolol, a no
n-selective beta-adrenoceptor antagonist, and atenolol, a selective an
tagonist of beta(1)-adrenoceptors, prevented the effect of alpha(2)-ad
renoceptor blockade by CH-38083 of the TNF-alpha response induced by L
PS, it seems likely that the excessive stimulation by NA of beta(1)-ad
renoceptors is responsible for this action. The role of beta-adrenocep
tors and endogenous catecholamines is further substantiated by the fin
ding that pretreatment of animals with propranolol alone resulted in a
dose-dependent increase of the TNF-alpha response induced by LPS, and
that isoproterenol, a non-selective beta-adrenoceptor agonist, decrea
sed it. Additionally, it was shown that prazosin, an alpha(1)- and alp
ha(2B)-adrenoceptor antagonist, reduced LPS-induced TNF-alpha producti
on. However, L-phenylephrine, a selective alpha(1)-adrenoceptor agonis
t, was not able to modulate the TNF-alpha response following LPS chall
enge. Our findings that alpha- and beta-adrenoceptor antagonists are a
ble to decrease or increase, respectively, the TNF-alpha response elic
ited by LPS indicate that SNS, through release of endogenous catechola
mines, is involved in vivo in the regulation of LPS-induced TNF-alpha
production. In this process, the beta-adrenoceptor-mediated events see
ms to play a pivotal role. Since the blockade of sympathetic activity
by chlorisondamine failed to affect LPS-induced TNF-alpha release, it
seems likely that, in vivo, the inhibitory effect of SNS on TNF-alpha
production, mediated via beta-adrenoceptors, is opposed by an effect o
f catecholamines on alpha(2)-adrenoceptors. It is suggested that the f
ine-tuning of TNF-alpha release exerted by SNS in vivo might be partic
ularly important during immunological and non-immunological stress, wh
en the concentration of catecholamines is increased in the close proxi
mity of TNF-alpha-secreting cells, which are known to possess adrenoce
ptors.