1,1′-Diisopropyl-2,4′-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines

Abstract

1,1'-Diisopropyl-2,4'-cyanine (disprocynium24), a potent inhibitor of the extraneuronal monoamine transport system (uptake2), was previously shown to reduce the clearance of catecholamines from plasma not only by blocking uptake2 but presumably also by blocking organic cation transport. To provide more direct evidence for the latter conclusion, the present study was carried out in anaesthetized rabbits. It aimed at determining the effect of disprocynium24 on the renal excretion of catecholamines which is known to be, at least in part, a consequence of organic cation transport in the kidney. To this end, the plasma clearance due to renal excretion (Cl(u)) of endogenous as well as infused 3H-labelled adrenaline, noradrenaline and dopamine was determined for 60-min periods of urine collection in rabbits treated either with disprocynium24 (270 nmol kg(-1) i.v. followed by i.v. infusion of 80 nmol kg(-1) min(-1)) or vehicle. Two groups of animals were studied: group I (monoamine oxidase and catechol-O-methyltransferase intact) and group II (monoamine oxidase and catechol-O-methyltransferase inhibited). A third group of animals with intact monoamine oxidase and catechol-O-methyltransferase was used to study the effect of disprocynium24 on the glomerular filtration rate (as determined by measuring the plasma clearance of inulin). In vehicle controls, Cl(u) of endogenous adrenaline, noradrenaline and dopamine was 7.2, 5.2 and 153.6 ml kg(-1) min(-1), respectively, in group I and 10.4, 7.0 and 134.3 ml kg(-1) min(-1), respectively, in group II. Similar control values of Cl(u) were obtained for infused 3H-adrenaline and 3H-noradrenaline, but not for infused 3H-dopamine; Cl(u) of 3H-dopamine (4.9 ml kg(-1) min(-1) in group I and 15.4 ml kg(-1) min(-1) in group II) was considerably smaller than Cl(u) of endogenous dopamine, indicating that most of the dopamine in urine (i.e., 98% in group I and 92% in group II) was derived from the kidneys rather than from the circulation. By contrast, only about one quarter of the noradrenaline in urine (32% in group I and 24% in group II) and none of the urinary adrenaline were of renal origin. In both groups, disprocynium24 markedly reduced the Cl(u) of endogenous catecholamines (by 72-90%) and of infused 3H-catecholamines (by 49-69%). Moreover, it preferentially inhibited the renal excretion of those components of urinary dopamine and noradrenaline which were derived from the kidney. Therefore, disprocynium24 inhibits the tubular secretion of catecholamines and, hence, organic cation transport in the kidney. This conclusion was substantiated by the observation that disprocynium24 did not alter the glomerular filtration rate.

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

“…This figure fits in with the present results that reveal a K i of 5.1 nmol/liter of disprocynium24 for the inhibition of dopamine transport by OCT2. Interestingly enough, disprocynium24 does not only block tubular secretion of dopamine but induces marked spill-over of renal dopamine into the systemic circulation (24). This finding is compatible with the concept that dopamine from proximal tubule cells is normally secreted by OCT2 through the apical plasma membrane into the lumen of the tubule.…”

“…In the anesthetized rabbit, intravenous treatment with disprocynium24 grossly reduces tubular secretion of dopamine (24). Renal proximal and distal tubule cells express the dopaminesynthesizing enzyme L-aromatic amino acid decarboxylase (25), and proximal tubule cells are known to form and secrete substantial amounts of dopamine (26).…”

Both stimulatory and inhibitory effects of dietary 5-hydroxytryptophan and tyrosine are found on urinary excretion of serotonin and dopamine in a large human population

“…The uncoupling of neurotransmitter excretion from the ingestion of precursors for the neurotransmitter is most likely caused by the degradation of blood-borne neurotransmitter in the kidney 8,9. Most of the serotonin or dopamine found in the urine is synthesized in the kidney 9–12.…”

“…Most of the serotonin or dopamine found in the urine is synthesized in the kidney 9–12. Therefore, the excreted neurotransmitters must be synthesized in the kidneys and escape reabsorption into the blood in order to be excreted in the urine.…”

Eukaliuric natriuresis and diuresis in response to disprocynium24: studies on the tubular site of action

“…Alternatively, DP24 could indirectly affect renal function, e.g., through affecting circulating catecholamines (Eisenhofer et al 1996;Friedgen et al 1996;Graefe et al 1997). We observed that application of DP24-containing artificial tubular fluid (ATF) into the first surface loop of the proximal tubule under free-flow conditions significantly increased the rise in early distal tubular fluid, sodium ion and potassium ion delivery as compared to application of vehicle-containing ATF; a response similar to that described with systemic application of DP24 in the first series.…”