DISPROCYNIUM24, A NOVEL INHIBITOR OF THE EXTRANEURONAL MONOAMINE TRANSPORTER, HAS POTENT EFFECTS ON THE INACTIVATION OF CIRCULATING NORADRENALINE AND ADRENALINE IN CONSCIOUS RAT

The role of extraneuronal uptake in terminating the actions of catecho lamines has been difficult to evaluate in vivo, largely because of lac k of suitable inhibitors. The compound, 1,1'-diisopropyl-2,4'-cyanine iodide or disprocynium24 (D24), is a novel inhibitor of extraneuronal uptake with a high degree of potency in vitro. This study examined the actions of D24 on the inactivation and metabolism of circulating nora drenaline and adrenaline in conscious rats. Animals received i.v. infu sions of H-3-labelled noradrenaline and adrenaline, and their extraneu ronal O-methylated metabolites, normetanephrine and metanephrine. Plas ma concentrations of endogeneous and H-3-labelled catecholamines and m etanephrines were measured before and after D24. D24 caused large incr eases in plasma concentrations of noradrenaline and adrenaline, effect s due to both decreases in their plasma clearances and increases in th eir rates of release into plasma, Plasma concentrations of normetaneph rine and metanephrine also increased due to their decreased clearance from plasma. Increased release of normetanephrine into plasma did not contribute to increased plasma concentrations of normetanephrine. In f act, the contribution of extraneuronal O-methylation to noradrenaline clearance decreased substantially after D24. The data indicate that D2 4 is a potent inhibitor of the extraneuronal catecholamine transporter in vivo and that this process contributes importantly to the removal of circulating catecholamines and their O-methylated amine metabolites . Increased release of noradrenaline into plasma may reflect an increa se in the proportion of transmitter that escapes from sites of release into the circulation. However, increased adrenaline release indicates that the drug also causes sympathoadrenal. activation.