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.