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  • 1
    Electronic Resource
    Electronic Resource
    Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 344 (1991), S. 720-727 
    Details
    ISSN: 1432-1912
    Keywords: Nitric oxide (EDRF) ; l-NG-Monomethyl-arginine ; Noradrenaline release ; Adrenaline release ; Anaesthetized rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study in the anaesthetized rabbit aimed at determining the role of nitric oxide (NO), the putative endothelium-derived relaxing factor, in the regulation of haemodynamics and the release into plasma of noradrenaline and adrenaline. Specific inhibition of NO formation was achieved by i.v. bolus injection of l-NG-monomethyl-arginine (l-NMMA; 3–100 mg kg−1). Phenylephrine was infused i.v. at constant rates (2.5–20 μg kg−1 min−1) in order to assess baroreflex-mediated changes in release due to direct peripheral vasoconstriction. Rates of noradrenaline and adrenaline release into plasma were determined by the radio-tracer technique. l-NMMA, but not d-NMMA, dose-dependently increased mean arterial pressure and total peripheral vasular resistance, whereas both heart rate and cardiac output decreased concomitantly. The corresponding ED50 values for l-NMMA ranged from 11.2 to 18.5 mg kg−1. Inhibition of NO formation by l-NMMA as well as phenylephrine infusion caused decreases in the plasma clearance of noradrenaline and adrenaline which were correlated with the drug-induced decreases in cardiac output. Both l-NMMA and phenylephrine reduced the rate of noradrenaline release into plasma as they increased total peripheral resistance. Moreover, the curvilinear relationship between these two parameters obtained for l-NMMA was virtually identical to that produced by phenylephrine, indicating that the reduction in noradrenaline release by l-NMMA is mediated solely by the baroreflex. From the l-NMMA-induced maximum inhibition of noradrenaline release, it is concluded that the counter-regulation against peripheral vasodilation by NO accounts for 69% of basal noradrenaline release. The baroreflex-sensitive component of noradrenaline release, as determined by the maximum inhibition of release induced by phenylephrine, amounted to 83% of basal release. l-NMMA also reduced the release into plasma of adrenaline; the maximum inhibition of release was 52%. However, when related to total peripheral resistance, this inhibition of adrenaline release was more pronounced than that induced by phenylephrine, suggesting that the formation of endogenous NO facilitates the release of adrenaline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00174757
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  • 2
    Electronic Resource
    Electronic Resource
    1,1′-Diisopropyl-2,4′-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 115-125 
    Details
    ISSN: 1432-1912
    Keywords: Key words Disprocynium24 ; Noradrenaline ; Adrenaline ; Dopamine ; Renal excretion ; Organic cation transport ; Inulin clearance ; Uptake2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: 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 (Clu) 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, Clu 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 Clu were obtained for infused 3H-adrenaline and 3H-noradrenaline, but not for infused 3H-dopamine; Clu 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 Clu 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 Clu 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005018
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  • 3
    Electronic Resource
    Electronic Resource
    The heterogeneity of the neuronal distribution of exogenous noradrenaline in the rat vas deferens (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 160-170 
    Details
    ISSN: 1432-1912
    Keywords: Rat vas deferens ; Heterogeneous labelling ; 3H-noradrenaline ; Desipramine ; Inhibition of vesicular uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary After loading of the incubated rat vas deferens with 0.2 μmol/l 3H-noradrenaline (followed by 100 min of wash-out with amine-free solution), the efflux of endogenous and exogenous compounds was determined by HPLC with electrochemical detection and by column chromatography with scintillation counting. Two different types of heterogeneity of labelling were found. The first one is due to the preferential labelling of varicosities close to the surface of the tissue, the second one to the preferential labelling of vesicles close to the surface of loaded varicosities. As diffusion distances within the tissue and within varicosities are then longer for endogenous than for exogenous amine and metabolites, the composition of spontaneous efflux of exogenous compounds differed from that for endogenous compounds. Because of preferential neuronal and vesicular re-uptake of endogenous noradrenaline, the percentage contribution by noradrenaline to overall efflux was: endogenous 〈 exogenous. While 3H-DOPEG was the predominant exogenous metabolite, DOPEG and MOPEG equally contributed to the “endogenous” efflux. Desipramine abolished the consequences of the first heterogeneity of labelling, i.e., it increased the efflux more for endogenous than for exogenous noradrenaline; moreover it decreased the efflux of 3H-DOPEG, but increased that of 3H-MOPEG. The reserpine-like compound Ro 41284, on the other hand, abolished the consequences of the second type of heterogeneity; it reduced the specific activity of “total efflux” (i.e., of the sum of noradrenaline + DOPEG + MOPEG) to the specific activity of the tissue noradrenaline. The degree of heterogeneity of labelling was reduced after inhibition of monoamine oxidase and also when the tissues were loaded with 2 or 20 μmol/l 3H-noradrenaline. It is proposed that the various “compartments” and “pools” of noradrenaline described in the literature reflect the two heterogeneities described here.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00166959
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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    Electronic Resource
    Electronic Resource
    The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1996), S. 193-199 
    Details
    ISSN: 1432-1912
    Keywords: Key words Noradrenaline ; Adrenaline ; Dopamine ; Total-body plasma clearance ; Pulmonary plasma clearance ; MAO inhibition ; COMT inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERp) of the infused amines and the cardiac output of plasma (COp) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results. At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of COp) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P〈0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp=ERp×COp) of noradrenaline and dopamine was 13 and 25 ml kg-1 min-1, respectively, in group I and 12 and 28 ml kg-1 min-1, respectively, in group II. Clp of adrenaline did not differ from zero in either group. Clp of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168757
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