MODULATION OF LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY SELECTIVE ALPHA-ADRENERGIC AND BETA-ADRENERGIC DRUGS IN MICE

In a previous study we demonstrated that mice pretreated with the highly selective alpha(2)-adrenoceptor antagonist CH-38083 showed blunting of the tumor necrosis factor-alpha (TNF-alpha) response induced by bacterial lipopolysaccharide (LPS). In the present study, the effect of a selective block of alpha(2)-adrenoreceptors and the role of the sympathetic nervous system (SNS) in the regulation of LPS-induced TNF-alpha production was explored further using different selective adrenoceptor antagonists and agonists. While adrenalectomy did not prevent the effect of CH-38083, the block of the sympathetic transmission by chlorisondamine fully abolished the inhibitory effect of CH-38083 on LPS-induced TNF-alpha production, suggesting that the effect of the alpha(2)-adrenoceptor blocking agent is corticosteroid-independent, but it requires intact sympathetic activity. Since the selective block of alpha(2)-adrenoceptors results in an increased sympathetic activity and an increase of the release of noradrenaline (NA) in both the central and the peripheral nervous systems, and in our experiments propranolol, a non-selective beta-adrenoceptor antagonist, and atenolol, a selective antagonist of beta(1)-adrenoceptors, prevented the effect of alpha(2)-adrenoceptor blockade by CH-38083 of the TNF-alpha response induced by LPS, it seems likely that the excessive stimulation by NA of beta(1)-adrenoceptors is responsible for this action. The role of beta-adrenoceptors and endogenous catecholamines is further substantiated by the finding 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, decreased it. Additionally, it was shown that prazosin, an alpha(1)- and alpha(2B)-adrenoceptor antagonist, reduced LPS-induced TNF-alpha production. However, L-phenylephrine, a selective alpha(1)-adrenoceptor agonist, was not able to modulate the TNF-alpha response following LPS challenge. Our findings that alpha- and beta-adrenoceptor antagonists are able to decrease or increase, respectively, the TNF-alpha response elicited by LPS indicate that SNS, through release of endogenous catecholamines, is involved in vivo in the regulation of LPS-induced TNF-alpha production. In this process, the beta-adrenoceptor-mediated events seems 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 of catecholamines on alpha(2)-adrenoceptors. It is suggested that the fine-tuning of TNF-alpha release exerted by SNS in vivo might be particularly important during immunological and non-immunological stress, when the concentration of catecholamines is increased in the close proximity of TNF-alpha-secreting cells, which are known to possess adrenoceptors.