Differences in Arylalkylamine N-Acetyltransferase Activity between Inflammatory Disease-Susceptible Lewis and -Resistant Fischer Rats

Lewis (LEW/N) and Fischer (F344/N) rats are histocompatible inbred strains characterized, respectively, by susceptibility and resistance to inflammatory disease. The susceptibility of LEW/N rats to inflammation has been associated with deficient corticotropin-releasing hormone (CRH), ACTH, and corticosterone responses to inflammatory stimuli, specifically attributed to a global impairment in hypothalamic CRH neuron function. In contrast to the LEW/N rats, F344/N rats demonstrate an intact hypothalamic-pituitary-adrenal (HPA) axis. Melatonin, a neurohormone initially isolated in the pineal gland, has been implicated with inhibition of the HPA axis. To investigate melatonin synthesis and secretion in LEW/N and F344/N rats, we examined the diurnal activity of pineal arylalkylamine N-acetyltransferase (NAT1), the rate-limiting enzyme in melatonin biosynthesis, which demonstrates circadian rhythmicity, as well as the diurnal levels of serum melatonin, in both strains. Arylamine N-acetyltransferase (NAT2), a related enzyme activity, thought not to be regulated in a circadian manner, was examined as a control of NAT1 activity. Pineal NAT1 activity peak was observed later and reached significantly higher levels in LEW/N than in F344/N rats. Serum melatonin levels reflected the circadian pattern of the NAT1 activity, without, however, showing any quantitative differences between the two strains. Time-course of pineal NAT1 activity response to beta-adrenergic stimulation was parallel in the two rat strains, whereas the magnitude of the response as greater in LEW/N than in F344/N rats. No circadian or major quantitative differences in NAT2 activity were found between the two strains. Size-exclusion HPLC chromatograms of NAT1 activity revealed similar patterns in both rat strains.(ABSTRACT TRUNCATED AT 250 WORDS)