CONTROL OF THE BROWN FAT RESPIRATORY RESPONSE TO NORADRENALINE BY CATECHOL-O-METHYLTRANSFERASE

The possibility that O-methylation of noradrenaline (NA)tonormetanephrine (NM)by catechol-O-methyltransferase (COMT: EC 2.1 : 1.6) may limit the concentration of NA at the receptors, and therefore control the adrenergic response, was evaluated from measurements of both the respiratory rate (MO2) and the rate of NM formation (MNM) in brown adipose tissue from the rat. MO2 and its increase (MO2 response) induced in tissue slices by endogenous or exogenous NA were measured in a stop flow respirometer perfused with Krebs-Ringer bicarbonate medium. MNM was measured in identical tissue slices incubated in the same medium, from exogenous radiolabelled NA and endogenous S-adenosyl methionine. This rate was taken as the apparent activity of the COMT system. It reached maximum values of about 100 pmole/min/g wet wt and was cut down to blank value by tropolone, a specific inhibitor of COMT. For any given sustained NA stimulus, the MO2 response reached a steady-state value. MNM was constant during one hour at concentra tions of added NA up to 3 μM, and during 30 min at higher ones. The MO2 response was potentiated (100-200 per cent) through inhibition of COMT by 0.2 mM tropolone. This effect was only transitory, with a maximum at 30 min followed by a 100 per cent inhibition of the MO2 response to exogenous NA 60 to 90 min later. Exposure of the stimulated preparations to 5· 10-5 M DOPA, which competitively inhibits the extraneuronal uptake-COMT system and whose decarboxylation product competitively inhibits not only COMT but also the neuronal uptake (uptake 1), induces a sustained increase of the MO2 response. Under blockage of uptake 1 by desmethyl-imipramine (DMI) 10-6 M, potentiation of the MO2 response was quantitatively the same with tropolone as with DOPA, for both endogenous and exogenous NA stimuli, and it was sustained. Quantitative analysis of the data suggests that COMT can control the local NA concentration at the site of hormone receptor interaction, not only by the (NA) gradient to the COMT system as a sink, but also indirectly via active induction of neuronal uptake. Large metabolic responses to nanomolar (NA), observed only when both COMT and uptake 1 were blocked, suggested that such a control might be operative even under basal conditions. © 1979.