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  • 1
    Electronic Resource
    Electronic Resource
    Sodium-dependence of the potency of inhibitors of the neuronal noradrenaline carrier in the rat vas deferens (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 397-402 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal noradrenaline carrier ; Inhibition of transport-Na+-dependence ; Desipramine ; Cocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Vasa deferentia obtained from reserpine-pretreated rats were incubated (monoamine oxidase and catechol-O-methyltransferase inhibited) in media containing various concentrations of3H-(−)noradrenaline and Na+ and initial rates of the neuronal uptake of3H-noradrenaline measured both in the absence and presence of uptake inhibitors after 1 min of incubation. 2. When rates of uptake were determined at various3H-noradrenaline (1.0–12.2 μmol/l) and two fixed Na+ concentrations (25 and 140 mmol/l), the inhibition of uptake produced by (+)amphetamine, (−)metaraminol, desipramine, nomifensine and cocaine was competitive with respect to3H-noradrenaline at both Na+ concentrations. While theK i for (+)amphetamine, (−)metaraminol desipramine and nomifensine increased when the Na+ concentration was lowered, that for cocaine decreased. 3. When the Na+ concentration was varied (10–140 mmol/l) and the3H-noradrenaline concentration held constant (1.2 μmol/l), (+)amphetamine, (−)metaraminol, nomifensine and desipramine acted as mixed-type inhibitors with respect to Na+, and the inhibition of uptake produced by these drugs was the more pronounced, the higher the Na+ concentration. On the other hand, cocaine was competitive with Na+ and the inhibition produced by this drug was the more pronounced, the lower the Na+ concentration. 4. It is concluded that the inhibitors of neuronal uptake tested here act in dependence on the external Na+ concentration. Desipramine and nomifensine resemble alternative amine substrates in being more potent at high than at low Na+ concentrations. On the other hand cocaine is more potent at low than at high Na+ concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569377
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  • 2
    Electronic Resource
    Electronic Resource
    Chloride-dependence of the potency of inhibitors of the neuronal noradrenaline carrier in the rat vas deferens (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 65-70 
    Details
    ISSN: 1432-1912
    Keywords: Cl−-dependence ; Neuronal uptake ; Inhibition of neuronal uptake ; Desipramine ; Cocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary (1) Vasa deferentia obtained from reserpine-pretreated rats were exposed to 0.15 μmol 1−1 3H-(−)noradrenaline (with monoamine oxidase and catechol-O-methyltransferase being inhibited) and initial rates of the neuronal 3H-noradrenaline uptake as well as IC50 values for inhibition of uptake by desipramine, cocaine or (−)metaraminol determined at various external Cl− concentrations (0–145 mmol 1−1) and a fixed high Na+ concentration (145 mmoll−1). (2) When the Cl− concentration in the medium was decreased neuronal uptake fell. As far as Cl− concentrations ranging from 10 to 145 mmol 1−1 are concerned, the dependence of uptake on Cl− obeyed Michaelis-Menten kinetics with an apparent K m and V max of 6.2 mmol 1−1 and 116 pmol g−1 min−1, respectively. At Cl− concentrations below 10 mmol l−1, uptake was higher than expected from the values of K m and V max, and even in the nominal absence of Cl− from the medium a remainder of neuronal uptake was still detectable. Evidence is presented to show that, on incubation at Cl− concentrations below 10 mmol l−1, intracelluar Cl− leaks out, so that the actual Cl− concentrations in the extracellular fluid are probably higher than in the medium. (3) The potencies of desipramine and cocaine for inhibition of neuronal uptake were markedly dependent on the Cl− concentration in the medium, but the type of Cl− dependence differed. While the IC50 for desipramine decreased, that for cocaine increased with increasing Cl− concentration (2–145 mmol l−1). The value of IC50 for cocaine and that of 1/IC50 for desipramine approached saturation (with an apparent Hill coefficient of about unity) when plotted against the Cl− concentration; half-maximum values were observed at Cl− concentrations of 9 and 24 mmol l−1, respectively. (4) (−)Metaraminol (an alternative substrate of the noradrenaline carrier) remained equally potent in inhibiting neuronal uptake when the Cl− concentration was decreased from 145 to 2 mmol l−1. However, when Cl− was omitted from the medium, the IC50 for (−)metaraminol increased. Hence, the C−-dependence of the potency of (−)metaraminol appears to be restricted to very low extracellular Cl− concentrations. (5) It is concluded that not only the neuronal uptake process itself, but also its inhibition by desipramine and cocaine are highly Cl−-dependent. Since desipramine and cocaine differ with respect to the type of Cl−-dependence of their inhibitory potency, they are likely to act by combining with distinctly different states of the noradrenaline carrier. It is suggested that desipramine interacts with the carrier loaded with Cl− while cocaine is capable of interacting with its Cl−-free state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00165128
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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    The determination of the rate constant for the efflux of an amine from efflux curves for amine and metabolite (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 304 (1978), S. 147-155 
    Details
    ISSN: 1432-1912
    Keywords: Rate constant for efflux of amine ; Isoprenaline ; Simulated efflux curves ; Extraneuronal mechanism ; Mathematical model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Rat hearts were perfused with 0.1 μM 3H-isoprenaline for 10 min in the presence of 10 μM U-0521 to inhibit catechol-O-methyl transferase (COMT) and then washed out with amine-free solution. Analysis of efflux curves revealed a preferential filling of one (compartment III) of the two extraneuronal compartments described by Bönisch et al. (1974). U-0521 inhibited the efflux of isoprenaline from compartment III. Omission of U-0521 from the wash out solution quickly restored COMT activity. It was then possible to determine the rate constant for the efflux (k s) of isoprenaline from rate of efflux and amine content of tissue. 2. A procedure is developed which permits the calculation of k s from efflux curves for amine and metabolite without any need for determining the amine content of the tissue. With this procedure, k s can be determined even when there is a “bound fraction” (i.e., a second compartment, the amine content of which does not contribute to the experimentally determined efflux). The procedure is based on the fact that, for a single compartment in which the amine is metabolized and from which there is efflux of amine and metabolite, parallel efflux curves (i.e., plots of log rate of efflux against time) are obtained, if the rate constant for the efflux of the metabolite (k p) is higher than the rate constant for the loss of amine from the compartment (k system). The activity of the metabolizing enzyme determines k system and the ratio “initial rate of efflux of metabolite/initial rate of efflux of amine” (F 0). 3. A mathematical model (simulating metabolism in, and efflux of amine and metabolite from a single compartment) was used to determine the distortion of F 0 by “k system/k P” (when k P limits the efflux of the metabolite). An estimate of k s obtained from F 0 and from k system agrees well with the estimate of k s obtained directly (see 1, above).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00495551
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  • 7
    Electronic Resource
    Electronic Resource
    Kinetics of the uptake and metabolism of 3H-(±) isoprenaline in the rat submaxillary gland (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 305 (1978), S. 51-63 
    Details
    ISSN: 1432-1912
    Keywords: Isoprenaline ; Submaxillary gland ; Extraneuronal catecholamine uptake ; “O-methylating systems” ; Corticosteroids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The uptake and O-methylation of 3H-(±)isoprenaline was studied in slices of the rat submaxillary gland. 2. The initial uptake of 3H-isoprenaline after inhibition of catechol-O-methyl transferase (COMT) was described by a single saturable process with relatively high K m (311 μM) and V max (101 nmoles·g−1·min−1). Both corticosterone and normetanephrine were competitive inhibitors of uptake. 3. When examined at substrate concentrations lower than the K m for uptake (and after block of COMT), 3H-isoprenaline distributed into two compartments in the tissue which approached equilibrium with half times of 2.4 and 15.8 min. The filling of both compartments was inhibited by corticosterone or phenoxybenzamine and also by high-K+ medium (in which 118 mM NaCl of the incubation medium had been replaced by KCl), but remained unaffected on substituting 118 mM NaCl with Tris-HCl. 4. In tissues in which COMT was not inhibited, the metabolism of 3H-isoprenaline to 3H-O-methylisoprenaline proceeded at a constant rate from the beginning of the incubation with the amine. When the substrate concentration was very low, little unchanged 3H-isoprenaline was found in the tissue. On the other hand, at high substrate concentrations the parent amine accumulated in the tissue, and at a time when 0-methylation had reached a steady state, the accumulation of 3H-isoprenaline was continuing. 5. The formation of 3H-O-methylisoprenaline was impaired by the presence of corticosterone, normetanephrine, phenoxybenzamine or 17-β-oestradiol with no indication of inhibition of COMT. While lowering the external Na+ concentration (on replacing 118 mM NaCl by 236 mM sucrose) did not affect the formation of 3H-O-methylisoprenaline, replacement of 118 mM NaCl by KCl reduced it. 6. The dependence of the steady-state rate of formation of 3H-O-methylisoprenaline on the substrate concentration in the incubation medium showed that two saturable components participated in the O-methylation of 3H-isoprenaline (low K m system: K m =7.2 μM and V max=1.2 nmoles·g−1·min−1; high-K m system: K m =339 μM and V max=4.6 nmoles·g−1·min−1). Corticosterone and normetanephrine competitively inhibited both the low-K m and the high-K m O-methylation. 7. The results indicate that the submaxillary gland of the rat resembles other tissues in having a low-K m (high-affinity) “O-methylating system” as well as a high-K m (low-affinity) extraneuronal uptake mechanism for catecholamines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00497006
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  • 8
    Electronic Resource
    Electronic Resource
    Plasma 3,4-dihydroxyphenylglycol as a tool to assess the role of neuronal uptake in the anaesthetized rabbit (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 726-732 
    Details
    ISSN: 1432-1912
    Keywords: 3,4-Dihydroxyphenylglycol ; Presynaptic noradrenaline metabolism ; Noradrenaline infusion ; Desipramine ; Anaesthetized rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary (1.) The purpose of this study was to investigate the role of neuronal uptake in the appearance in plasma of the primary noradrenaline metabolite 3,4-dihydroxyphenylglycol (DOPEG). To this end, steady-state changes in mixed central-venous plasma concentrations of noradrenaline and DOPEG produced by noradrenaline infusions or by changes in sympathetic tone were determined in anaesthetized rabbits either under control conditions or after treatment with desipramine (2 mg kg−1). The steady-state kinetics of infused DOPEG were also evaluated. (2.) Infused DOPEG (2.9 nmol kg−1 min−1 i.v. for 75 min) reached steady-state concentrations in plasma within less than 30 min, disappeared from plasma with a half-life of 2.3 min and showed a total-body plasma clearance of 84.0 ml kg−1 min−1 (3.) Constant-rate infusions of noradrenaline (1.2–5.9 nmol kg−1). (min−1 i.v. for 75 min) produced increases in plasma noradrenaline and DOPEG concentrations which were linearly related to the rate of noradrenaline infusion. Thus, the plasma clearance of infused noradrenaline (75.8 ml kg−1). min−1 as well as the increase in plasma DOPEG expressed in % of that in plasma noradrenaline (9.4%) was virtually independent of the noradrenaline infusion rate. (4.) Desipramine reduced the plasma clearance of infused noradrenaline by 35.4% and the increment in plasma DOPEG relative to that in plasma noradrenaline by 75.3%. From these results and the plasma clearance of noradrenaline and DOPEG it was calculated that the rate at which presynaptically formed DOPEG appeared in plasma amounted to 7.9% of the rate of total noradrenaline removal and to 22.3% of the rate of neuronal uptake. (5.) The rate of appearance in plasma of DOPEG originating from the neuronal re-uptake of endogenous noradrenaline was 192.3 pmol (kg−1). min−1 suggesting that the rate of neuronal re-uptake amounted to 862.3 pmol (kg−1) min−1 (6.) The slope of the regression line relating plasma DOPEG to plasma noradrenaline concentrations under conditions of noradrenaline release exceeded that of the corresponding regression line observed during noradrenaline infusion by a factor of about 10. This difference in slope suggests that, in the absence of infused noradrenaline, the average noradrenaline concentration at all noradrenergic neuroeffector junctions of the rabbit is 3.2 times as high as that in plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169681
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