The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit

Friedgen, Bernd; Wölfel, Reinhard; Russ, Hermann; Schömig, Edgar; Graefe, Karl Heinz

doi:10.1007/bf00171058

Cited by 28 publications

(19 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1 B, C) revealed that the two drugs have similar pharmacokinetics characterized by short elimination halfqives (<10 rain) and very high plasma clearances (>150 ml kg -1 minq). The high plasma clearance of disprocynium24 obtained here from the AUC after a bolus injection (180 ml kg -1 min -1) was confirmed by Friedgen et al (1996) who found a value of 146 ml kg 1 rain q based on constant-rate infusions of the drug. The high plasma clearances of both drugs were in part due to drug accumulation in blood cells.…”

Section: Discussionsupporting

confidence: 53%

Pharmacokinetic and ?1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport

Russ

Friedgen

Konigs

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

1,1'-Diethyl-2,2'-cyanine (decynium22) and 1,1'-diisopropyl-2,4'-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monamine transporter. When given as i.v. bolus injections (4 mumol kg-1) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fall in diastolic blood pressure was 59% after decynium22 and 43% after disprocynium24 administration. The pharmacokinetics of decynium22 and disprocynium24 were similar; they were characterized by short half-lives for elimination (8.2 and 4.5 min, respectively) and very high plasma clearances (173 and 180 ml kg-1 min-1, respectively). The mechanism underlying the blood pressure-lowering effect of decynium22 was explored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA2 for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. In a membrane preparation from rat myocardium, decynium22 as well as disprocynium24 inhibited the specific binding of [125I]-2-[beta-(4-hydroxy-3-iodophenyl)-ethylaminomethyl]- tetralone (125I-HEAT), a selective ligand to alpha 1-adrenoceptors. The Ki's were 5.3 and 240 mumol l-1 for decynium22 and disprocynium24, respectively. The type of binding inhibition by decynium22 was competitive. It is concluded that the two inhibitors of extraneuronal monoamine transport decynium22 and disprocynium24 lower blood pressure by blocking alpha 1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and alpha 1-adrenoceptors clearly indicates that disprocynium24 is more suitable for studies designed to determine the role of extraneuronal monoamine transport in vivo. Considering its very fast elimination kinetics, disprocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.

show abstract

Section: Discussionsupporting

confidence: 53%

Pharmacokinetic and ?1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport

Russ

Friedgen

Konigs

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

View full text Add to dashboard Cite

show abstract

“…Uptake 2 is a sodium-and chloride-independent, low-affinity, high-capacity transport system initially described in heart, smooth muscle, and glandular cells (Iversen, 1965). Contrary to sodium-driven, high-affinity neuronal Uptake 1 , Uptake 2 can be inhibited by corticosteroids and O-methylated catecholamines as well as cyanin-related compounds (Trendelenburg, 1988;Friedgen et al, 1996;Wu et al, 1998). The main OCT subtypes (OCT1, OCT2, and OCT3) isolated these last few years in humans and rodents display pharmacological profiles that match these general characteristics (Grundemann et al, 1997(Grundemann et al, , 1998aBusch et al, 1998;Wu et al, 1998;Hayer-Zillgen et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

Vialou¹,

Amphoux²,

Zwart³

et al. 2004

J. Neurosci.

View full text Add to dashboard Cite

Organic cation transporters (OCTs) are carrier-type permeases known to participate in general detoxification functions in peripheral tissues. Previous in vitro studies have suggested that OCTs ensure Uptake 2 , a low-affinity, corticosteroid-sensitive catecholamine removal system, which was characterized initially in sympathetically innervated tissues. Although the presence of both Uptake 2 -like transport and most OCT subtypes has also been demonstrated in the brain, the physiological role of this family of transporters in CNS remained totally unknown. In the present work, we show that the OCT3 transporter is found throughout the brain and highly expressed in regions regulating fluid exchange, including circumventricular organs such as area postrema and subfornical organ (SFO), and in other structures implicated in the sensing of changes in blood osmolarity and regulation of salt and water ingestion. OCT3/Slc22a3-deficient mice show an increase in the level of ingestion of hypertonic saline under thirst and salt appetite conditions, as well as alterations of the neural response in the SFO after sodium deprivation, as monitored by Fos immunoreactivity. This work demonstrates that the presence of OCT3 is critical for the balanced neural and behavioral responses to environmentally induced variations in osmolarity and provides for the first time physiological evidence of the importance of OCTs for CNS function.

show abstract

“…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).…”

mentioning

confidence: 99%

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

Zwart

Verhaagh

Buitelaar

et al. 2001

Molecular and Cellular Biology

186

147

View full text Add to dashboard Cite

Two uptake systems that control the extracellular concentrations of released monoamine neurotransmitters such as noradrenaline and adrenaline have been described. Uptake-1 is present at presynaptic nerve endings, whereas uptake-2 is extraneuronal and has been identified in myocardium and vascular and nonvascular smooth muscle cells. The gene encoding the uptake-2 transporter has recently been identified in humans (EMT), rats (OCT3), and mice (Orct3/Slc22a3). To generate an in vivo model for uptake-2, we have inactivated the mouse Orct3 gene. Homozygous mutant mice are viable and fertile with no obvious physiological defect and also show no significant imbalance of noradrenaline or dopamine. However, Orct3-null mice show an impaired uptake-2 activity as measured by accumulation of intravenously administered [ H]MPP ؉ (1-methyl-4-phenylpyridinium). A 72% reduction in MPP؉ levels was measured in hearts of both male and female Orct3 mutant mice. No significant differences between wild-type and mutant mice were found in any other adult organ or in plasma. When [ 3 H]MPP ؉ was injected into pregnant females, a threefold-reduced MPP ؉ accumulation was observed in homozygous mutant embryos but not in their placentas or amniotic fluid. These data show that Orct3 is the principal component for uptake-2 function in the adult heart and identify the placenta as a novel site of action of uptake-2 that acts at the fetoplacental interface.

show abstract

The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit

Cited by 28 publications

References 42 publications

Pharmacokinetic and ?1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport

Pharmacokinetic and ?1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport

Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

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

Contact Info

Product

Resources

About