EFFECT OF RESERPINE ON FEBRILE RESPONSES INDUCED BY PYROGENIC SUBSTANCES

Abstract

Although there are many reports as to the hypothermic effect of reserpine (1-5), the exact mechanism of this action appears to be undecided. Recently, the action of reserpine has been found to be associated with the depletion of 5-hydroxytryptamine (5-HT) or catecholamine in the brain and the direct action of the alkaloid itself would be, if any, fairly negligible (6-12). After monoamine oxidase inhibitors had been introduced to pharmacology their effects were also studied on the reserpine action by many authors (13-20). Tyramine is known to have a pyrogenic action. Bachtold and Pletscher (21) demonstrated that rabbits pretreated with iproniazid exhibited a marked hyperthermia by the subsequently administered tyramine, phenylethylamine, 5-HT or reserpine. Horita (22) and Horita and Gogerty (23) showed that the pyrogenic activity of 5-hydroxytryptophane, a possible precursor of 5-HT, was greatly enhanced by pretreatment with either iproniazid or beta-phenylisopropylhydrazine (PIH). In addition, Horita (22) has found that preliminary treatment of rabbits with PIH produced a marked excitation and hyperthermia with subsequent administration of reserpine. Such “reserpine reversal” was also observed between iproniazid and reserpine except in a few cases (19-21, 23). Kroneberg et al. (24) have shown that the pyrogenic effect of E. coli lipopolysaccharide (LPS), purified by the method of Westphal et al. (25) is inhibited by pretreatment with reserpine and that the fever thus inhibited reappeared when iproniazid is given. Going (26) has confirmed this finding and has reported the augmentation of febrile responses of animals to bacterial pyrogens by pretreatment with iproniazid. These interesting results may indicate that biogenic amines such as 5-HT or catecholamines could play an important role in the pyrogenic activity of bacterial pyrogens. The question remains whether the bacterial endotoxins injected intravenously in animals gain access to the brain by crossing the blood-brain barrier or it is possible that the bacterial endotoxin may not have a direct action on the thermoregulatory center, and that the active principle transferrable across the blood-brain barrier may be some of the products, derived from bacterial endotoxins. Another possibility involves a substance in the animal body produced secondarily to the effect of bacterial pyrogens. This, in substance, covers the two theories on pyrogenic effects of bacterial pyrogens, i.e., ‘endogenous pyrogen’ (27-31) and ‘endogenous serum pyrogen’ (32-34). The present paper deals with a study of the possible relationship between the biogenic amine and the pyrogenic effects of several substances, bacterial as well as chemical in origin. An attempt was also made to elucidate whether these substances cross the bloodbrain barrier and whether they have a direct effect on the thermoregulatory center in brain or not.