DIFFERENTIAL EFFECT OF SELECTIVE BLOCK OF ALPHA(2)-ADRENOCEPTORS ON PLASMA-LEVELS OF TUMOR-NECROSIS-FACTOR-ALPHA, INTERLEUKIN-6 AND CORTICOSTERONE INDUCED BY BACTERIAL LIPOPOLYSACCHARIDE IN MICE

The effect of selective block of alpha(2)-adrenoreceptors on plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and corticosterone induced by bacterial lipopolysaccharide (LPS) was investigated in mice using ELISA and RIA. It was found that the LPS-induced TNF-alpha response was significantly blunted in mice pretreated with CH-38083, a novel and highly selective alpha 2-adrenoreceptor antagonist (the alpha(2)/alpha(1) ratio is >2000). In contrast, LPS-induced increases in both corticosterone and IL-6 plasma levels were further increased by CH-38083. Since it has recently been shown that the selective block of alpha(2)-adrenoreceptors located on noradrenergic axon terminals resulted in an increase in the release of noradrenaline (NA), both in the central and peripheral nervous systems, and, in our experiments, that propranolol prevented the effect of alpha(2)-adrenoreceptor blockade on TNF-alpha plasma levels induced by LPS, it seems likely that the excessive stimulation by NA of beta-adrenoreceptors located on cytokine-secreting immune cells is responsible for this action. Since it is generally accepted that increased production of TNF-alpha is involved in the pathogenesis of inflammation and endotoxin shock on the one hand, and corticosterone and even IL-6 are known to possess antiinflammatory properties on the other hand, it is suggested that the selective block of alpha(2)-adrenoreceptors might be beneficial in the treatment of inflammation and/or endotoxin shock.