Inhibition of brain epinephrine synthesis by 3,4-dichlorophenylethanolamine, a competitive substrate for norepinephrine N-methyltransferase

Abstract

3,4-Dichlorophenylethanolamine (DCPE) is a substrate for norepinephrine N-methyltransferase (NMT) from rat brain stem or from rabbit adrenal glands and competitively inhibits the methylation of (−)norepinephrine by NMT in vitro. The K i value for inhibition of rat brain NMT by DCPE was 6 × 10 −5 M. When DCPE was injected i.p. into rats at a dose of 50 mg/kg, epinephrine concentration in hypothalamus was reduced, although NMT activity measured in hypothalamic homogenates in vitro was not inhibited. The findings contrast in several ways to those with 8,9-dichloro-2,3,4,5-tetrahydro-1 H-2-benzazepine (LY134046), a competitive inhibitor of rat brain NMT with an in vitro K i of 2.4 × 10 −8 M. Although the potency of DCPE was 1/2500th that of LY134046 in vityro, it lowered hypothalamic epinephrine concentrations at similar doses in vivo. The NMT activity measured in vivo in homogenates of hypothalamic tissue from LY134046-treated rats was reduced by a greater percentage than was epinephrine concentration. The reduction of epinephrine concentration in vivo by DCPE may relate to its ability to be a substrate for NMT, which would result in conversion of S-adenosylmethionine (SAMe) to S-adenosylhomocysteine (SAH) in NMT-containing neurons. The resulting increase in the SAH/SAMe ratio may inhibit norepinephrine N-methylation, since SAH is a competitive inhibitor of NMT when SAMe is the variable substrate. This mechanism is similar to that suggested for the decrease in epinephrine concentration in rat brain following l-dopa injection. l-Dopa injection increases SAH and decreases SAMe concentration measured in hypothalamus, due presumably to extensive O-methylation of dopa and its decarboxylated metabolites. In contrast, SAH and SAMe concentrations in hypothalamus were not measurably altered after DCPE injection, a not-unexpected finding since SAH/SAMe changes would occur only in NMT-containing neurons, which make up a negligibly small percentage by weight of hypothalamic tissue. DCPE and other NMT substrates may be able to inhibit epinephrine synthesis in vivo as effectively as non-substrate, competitive inhibitors having much higher affinity for NMT because their N-methylation elevates SAH/SAMe ratios specifically within NMT-containing neurons.