The outward transport of catecholamines mediated by uptake2 of the rat heart

The efflux of 3H-catecholamines from the extra-neuronal tissue of the rat heart was analysed (after inhibition of vesicular and neuronal uptake, monoamine oxidase and catechol-O-methyl transferase). In most experiments, hearts were first loaded with a tracer concentration of a 3H-catecholamine and then washed out. For all four catecholamines [3H-(+/-)-isoprenaline, 3H-(+/-)-adrenaline, 3H-(-)-noradrenaline, and 3H-dopamine] the loading period resulted in virtually the same distribution pattern: most of the radioactivity distributed into "compartment III". However, the rate constants for efflux from compartment III increased in the order 3H-(-)-noradrenaline less than 3H-dopamine less than 3H-(+/-)isoprenaline = 3H-(+/-)-adrenaline. O-methyl-isoprenaline (OMI, a potent inhibitor of uptake2) caused a concentration-dependent and partial inhibition of the efflux of all 3H-catecholamines; its IC50 (half-maximal inhibition of OMI-sensitive efflux) was very close to that for half-maximal inhibition of inward transport by uptake2. It is concluded that there is not only (OMI-resistant) diffusional efflux of 3H-catecholamines, but also (OMI-sensitive) outward transport of 3H-catecholamines. The contribution by each of these processes to total efflux differed considerably from one 3H-catecholamine to the next. U-0521 (the COMT inhibitor used in this study) inhibited the OMI-sensitive efflux of 3H-noradrenaline with an IC50 of about 100 mumol/l. However, no inhibitory effect was found for 10 mumol/l U-0521. During the wash-out period (see above) various unlabelled substrates of uptake2 were added to the perfusion fluid at a concentration equalling 2 X Km.(ABSTRACT TRUNCATED AT 250 WORDS)