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  • Disprocynium24  (3)
  • Decynium22  (2)
  • Efflux of noradrenaline metabolites  (2)
  • Pharmacokinetics  (2)
  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 268-274 
    Details
    ISSN: 1432-1912
    Keywords: Key wordsα1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diethyl-2,2′-cyanine (decynium22) and 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 μmol 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-[β-(4-hydroxy-3-iodophenyl)-ethylaminomethyl]-tetralone (125I-HEAT), a selective ligand to α1-adrenoceptors. The Ki‘s were 5.3 and 240 nmol 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 α1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and α1-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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171057
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 268-274 
    Details
    ISSN: 1432-1912
    Keywords: α1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diethyl-2,2′-cyanine (decynium22) and 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 μmol 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-[β-(4-hydroxy-3-iodophenyl)-ethy-laminomethyl]-tetralone (125I-HEAT), a selective ligand to α1-adrenoceptors. The Ki's were 5.3 and 240 nmol 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 α1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and α1-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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171057
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    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 275-286 
    Details
    ISSN: 1432-1912
    Keywords: Key words Plasma clearance of catecholamines ; MAO-inhibition ; COMT-inhibition ; Disprocynium24 ; Uptake2 ; Organic cation transporters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract As selective inhibitors of the extraneuronal monoamine uptake system (uptake2) suitable for in-vivo studies were not available, the question of whether uptake2 plays a definite role in vivo is largely unresolved. We attempted to resolve the question by using 1,1′-diisopropyl-2,4′-cyanine iodide (disprocynium24), a novel agent that blocks uptake2 in vitro with high potency. Anaesthetized rabbits were infused with 3H-labelled noradrenaline, adrenaline and dopamine, and catecholamine plasma clearances as well as rates of spillover of endogenous catecholamines into plasma were measured before and during treatment with either disprocynium24 or vehicle. Four groups of animals were studied: group I, no further treatment; group II, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited; group III, neuronal uptake (uptake1) inhibited; group IV, uptake1 as well as MAO and COMT inhibited. Disprocynium24 (270 nmol kg–1 i.v. followed by an i.v. infusion of 80 nmol kg–1 min–1) did not alter heart rate and mean arterial blood pressure, but increased cardiac output by 22% and decreased the total peripheral vascular resistance by 16% with no difference between groups. When compared with vehicle controls, catecholamine clearances (normalized for the cardiac output of plasma) were decreased and spillover rates increased in response to disprocynium24. Although there were statistically significant between-group differences in baseline clearances (which decreased in the order: group I 〉 group II 〉 group III 〉 group IV), the drug-induced clearance reductions relative to vehicle controls were similar in groups I to IV and amounted to 29–38% for noradrenaline, 22–31% for adrenaline and 16–22% for dopamine. Hence, there was still a significant % reduction in catecholamine clearances even after the combined inhibition of MAO and COMT, and there was no increase in the % reduction of clearances after inhibition of uptake1. Noradrenaline spillover increased in response to disprocynium24 in all four groups by 1.6- to 1.9-fold, whereas a 1.5- to 2.0-fold increase in adrenaline and dopamine spillover was observed in groups II and IV only. The results indicate that disprocynium24 interferes with the removal of circulating catecholamines not only by inhibiting uptake2, but also by inhibiting related organic cation transporters. As disprocynium24 increased the spillover of endogenous catecholamines into plasma even after inhibition of MAO and COMT, organic cation transporters may also be involved in the removal of endogenous catecholamines before they enter the circulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171058
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  • 4
    Electronic Resource
    Electronic Resource
    The disposition of 3H-(−)noradrenaline in the Perfused cat and rabbit heart (1981)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 318 (1981), S. 71-82 
    Details
    ISSN: 1432-1912
    Keywords: (−)Noradrenaline ; Neuronal metabolism ; Extraneuronal metabolism ; Perfused heart ; Efflux of noradrenaline metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Hearts of cats and rabbits were perfused at a constant rate with 3H-(−)noradrenaline for 60–120 min. During the perfusion the rate of net removal of 3H-noradrenaline from the perfusion fluid and the rate of efflux of 3H-metabolites from the hearts were followed. From these results and from the amount of 3H-metabolites recovered from the hearts (at the end of experiments), the time course of the cumulative metabolite formation was obtained. The following metabolites were determined: 3,4-dihydroxyphenylethyleneglycol (DOPEG), 3,4-dihydroxymandelic acid (DOMA), normetanephrine (NMN) and a fraction consisting of 3-methoxy-4-hydroxyphenylethyleneglycol and 3-methoxy-4-hydroxymandelic acid (OMDA). 2. In normal hearts, the rate of formation of DOPEG, DOMA and OMDA became constant only after a considerable delay, and the rate of efflux of these metabolites did not reach a constant value within 120 min. By contrast, the formation of NMN proceeded at a constant rate throughout the perfusion with 3H-noradrenaline, and the rate of efflux of NMN approached a steady level within about 30 min. 3. In hearts of reserpine-pretreated animals not only NMN, but also DOPEG, DOMA and OMDA quickly approached a constant rate of formation. In addition, the efflux of all metabolites attained a steady level, and after about 70 min, the hearts of both species reached a steady state in which the net removal of 3H-noradrenaline was fully accounted for by the formation of metabolites. 4. The metabolite pattern during the steady state showed striking species differences. The rate of metabolite formation (expressed in % of the steady-state rate of 3H-noradrenaline removal) decreased in the order DOPEG (40.0%)〉NMN (30.8%)〉DOMA (18.1%)〉OMDA (9.0%) in the cat heart and DOPEG (66.8%)〉DOMA (20.0%)〉OMDA (6.6%)〉NMN (1.5%) in the rabbit. 5. In both species, 30 μmol · l−1 cocaine (to inhibit neuronal uptake) decreased the rate of formation of DOPEG, DOMA and OMDA to very low values, but increased the formation of 3H-NMN. 6. In the cat heart, 30 μmol · l−1 hydrocortisone (to inhibit extraneuronal uptake) decreased the formation of NMN, while having no effect on the formation of DOPEG, DOMA and OMDA. Moreover, in the cat and rabbit heart perfused in the presence of cocaine, inhibition of extraneuronal uptake markedly affected the formation of NMN. 7. A linear relationship was found for all metabolites between the rate of efflux and the tissue content (both parameters being determined during steady state), indicating first-order kinetics of efflux. The ranking order of the overall rate constants for efflux was DOPEG≫NMN〉DOMA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00508829
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  • 5
    Electronic Resource
    Electronic Resource
    The rate constants for the efflux of the metabolites of noradrenaline from rabbit aortic strips (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 207-215 
    Details
    ISSN: 1432-1912
    Keywords: Rate constants for efflux ; Efflux of noradrenaline metabolites ; Rabbit aorta ; Metabolism of noradrenaline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Rabbit aortic strips were incubated with 1.18 μM labelled noradrenaline for 30 min and then washed with amine-free solution for at least 110 min. From the last efflux sample and from the metabolite content of the strip analysed at the end of the experiment, rate constants for the efflux of the metabolites were calculated in two ways: a) as k = rate of efflux/metabolite content of strip, or b) as the slope of the regression line relating rate of efflux to metabolite content of the strip. Both determinations yielded essentially the same ranking order, and the results of b) indicated that there was no tight binding of metabolites in the tissue. 2. The rate constants for the efflux of glycols (DOPEG and MOPEG) and normetanephrine were much higher than those of the acid metabolites (DOMA and VMA). Although this ranking order agrees with results obtained with perfused hearts, k-values obtained from experiments with incubated strips tended to be lower (by a factor of 1.6 to 14.1) than k-values derived from experiments with perfused hearts. Since this difference was smallest for the acid metabolites and highest for the glycols, it is likely that considerable redistribution of the metabolites with high rate constants takes place in incubated, but less so in perfused tissues. 3. The rate constants for the efflux of metabolites also influence the rate of the approach of the metabolite content of the strip to steady state (during the incubation with noradrenaline): the rate of approach to steady state increases with increasing rate constant for efflux. 4. The apparent half time for the efflux of a metabolite (obtained from the slope of the efflux curve) equals the half time calculated from the rate constant for efflux $$\left( {t/2 = \frac{{1{\text{n 2}}}}{k}} \right)$$ , provided there is no formation of the metabolite during the relevant period of wash out. However, a discrepancy between the two parameters becomes the more noticeable, the higher the rate of formation of the metabolite during the period of observation. 5. In conjunction with earlier observations, the present results show that the efflux of metabolites observed during wash out of tissues previously loaded with noradrenaline is determined by a) the rate constant for efflux (k) and b) the formation (or lack of formation) of the metabolites during the period of observation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00517987
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    Paper (German National Licenses)
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