Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

Abstract

The role of extraneuronal uptake in terminating the actions of catecholamines has been difficult to evaluate in vivo, largely because of lack 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 noradrenaline and adrenaline in conscious rats. Animals received i.v. infusions of 3H-labelled noradrenaline and adrenaline, and their extraneuronal O-methylated metabolites, normetanephrine and metanephrine. Plasma concentrations of endogeneous and 3H-labelled catecholamines and metanephrines were measured before and after D24. D24 caused large increases in plasma concentrations of noradrenaline and adrenaline, effects due to both decreases in their plasma clearances and increases in their rates of release into plasma. Plasma concentrations of normetanephrine 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 fact, the contribution of extraneuronal O-methylation to noradrenaline clearance decreased substantially after D24. The data indicate that D24 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 increase 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.

The Role of Advanced Glycation in Reduced Organic Cation Transport Associated with Experimental Diabetes

“…OCT-3 is the major cation transporter in the human kidney (Hayer-Zillgen et al, 2002). In addition, selective blockade of OCT-3 in rats results in increased plasma catecholamines and metanephrines (Eisenhofer et al, 1996). However, OCT-3 knockout mice seem to show no evidence of a monoamine imbalance (Zwart et al, 2001), possibly because of redundancy conferred through expression and/or activity of other cation transporters.…”

Transport of Monoamine Transmitters by the Organic Cation Transporter Type 2, OCT2

“…For this purpose, 293 OCT2r cells and 293 pcDNA3 cells were incubated with 100 nmol/liter 3 H-dopamine either in the absence or in the presence of 1 mol/liter decynium22. 3 H-dopamine accumulation increased almost linearly for about 10 min (Fig. 2).…”

“…3 and Table I). For comparison, the corresponding kinetic constants for specific 3 H-noradrenaline, 3 H-adrenaline, and 3 H-5-hydroxytryptamine uptake in 293 OCT2r cells were determined (Table I).…”

“…The use of a novel class of potent inhibitors of extraneuronal monoamine transport revealed that extraneuronal mechanisms contribute markedly to the inactivation of circulating catecholamines (3). The pharmacological characterization of extraneuronal monoamine transport in tissue culture suggests an unexpected but nevertheless close pharmacological relationship between extraneuronal monoamine transport and the secretion of organic cations through the apical plasma membrane of renal proximal tubule cells (4).…”

Impaired Activity of the Extraneuronal Monoamine Transporter System Known as Uptake-2 in Orct3/Slc22a3-Deficient Mice

“…The cyanine derivative disprocynium 24 (D24) was isolated as a highly potent uptake-2 inhibitor in vitro (23). However, the application of D24 in vivo to study uptake-2 was revealed to be limited, as it was shown previously that D24 blocks not only uptake-2 but also other transport mechanisms that clear catecholamines (8,11).…”