Neurotransmitting substances and endotoxin respone in relation to hepatic enzyme induction.

Abstract

Since neurotransmission and selected enzymes of the serotonin/adrenalin pathway are altered during endotoxicosis, a variety of neurophilic drugs, some active on defined loci in the tryptophan-serotonin pathway, were evaluated for their ability to modify endotoxin lethality. Among the various putative neurotransmitters, only leucine had some sensitizing effect on endotoxin toxicity. If given prior, and not subsequent, to challenge, <i>p</i>-chlorophenyl-alanine (but not the other analogues) consistently lowered the LD<sub>50</sub> of endotoxin in mice and impaired cortisone proctection against endotoxic death. This effect could not be related to the possible increase in endogenous concentrations of tryptophan, as a result of inhibition of tryptophan hydroxylase by <i>p</i>-chlorophenylalanine (PCPA). Additionally, the endotoxin toxicity in normal mice could not be modified by the serotonin antagonists cyproheptadine and LSD-25. The inorganic mercurial HgCl<sub>2</sub> (but not its organic analoge <i>p</i>-chloromercuribenzoate), behaved like PCPA in its ability to modify the endotoxin lethality. These results are discussed in relation to hepatic enzyme induction and a common receptor-effector system possibly coordinating a variety of inter- and intra-cellular responses.