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  • 1
    Electronic Resource
    Electronic Resource
    Sodium-dependence of the saturability of carrier-mediated noradrenaline efflux from noradrenergic neurones in the rat vas deferens (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 332 (1986), S. 131-134 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal efflux ; Noradrenaline carrier ; Veratridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The carrier-mediated transport of 3H-noradrenaline out of noradrenergic neurones was studied in vasa deferentia obtained from rats after pretreatment with reserpine and pargyline (to inhibit vesicular storage and monoamine oxidase, respectively). The tissue was first preincubated with various concentrations of 3H-noradrenaline (0.3–100 μmol/l; 30 min) and then washed out for 110 min with amine-free medium. During the last 10 min of washout, carrier-mediated neuronal efflux of 3H-noradrenaline was elicited by exposure to either Na+-free medium or 100 μmol/l veratridine; it was measured at 1-min intervals. 2. While the peak rates of carrier-mediated 3H-noradrenaline efflux elicited by Na+-free medium were linearly related to the 3H-noradrenaline content of the tissue (which cannot be raised beyond a certain maximal value, since uptake is saturable), those evoked in response to veratridine approached saturation as the 3H-noradrenaline level in the tissue was raised. Hence, saturation of 3H-noradrenaline outward transport was demonstrated at high (exposure to veratridine), but not at low (exposure to Na+-free medium) intraneuronal Na+ concentrations. 3. The results indicate that the K m for the mediated outward transport of noradrenaline across the plasma membrane of noradrenergic neurones is inversely related to the internal Na+ concentration, just as the K m for the mediated inward transport of noradrenaline (i.e., the neuronal noradrenaline uptake) is inversely related to the external Na+ concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00511402
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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
    Tetrodotoxin-sensitive and-resistant effects of veratridine on the noradrenergic neurone of the rat vas deferens (1983)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 324 (1983), S. 264-270 
    Details
    ISSN: 1432-1912
    Keywords: Veratridine ; Exocytotic release ; Neuronal efflux ; “Reserpine-like” effects ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1) The veratridine-induced release of 3H-noradrenaline from noradrenergic neurones was examined in the isolated vas deferens of either untreated or reserpine plus pargyline-pretreated rats. The rat vas deferens, whose catechol O-methyltransferase was inhibited, was first incubated with 0.4 μmol/l 3H-(−)noradrenaline (30 min) and then washed repeatedly with amine-free solution. After 120 min (i.e., well after the efflux of tritium from the tissue had reached a steady level and was predominantly of neuronal origin), washout was continued in the presence of veratridine for further 10–15 min. 2) In vasa deferentia of untreated rats, variatridine (1–100 μmol/l) caused a concentration-dependent increase in the efflux of tritium. At high concentrations of the drug (30 or 100 μmol/l), this increase in efflux was peak-like during the first 3 min (“peak response”) and then fell to a plateau (“plateau response”). In the presence of veratridine, unchanged 3H-noradrenaline accounted for about 75% of the tritium efflux (the rest being represented by deaminated 3H-catechol metabolites). 3) The “peak response” to veratridine (100 μmol/l) was abolished by tetrodotoxin (TTX; 1 μmol/l) or the absence of external Ca2+. Cocaine (10 μmol/l) affected neither the “peak response” as such nor the contribution by 3H-noradrenaline to the efflux of tritium during that response. Hence, the “peak response” was due to exocytotic release of 3H-noradrenaline from the neurone. 4) The “plateau response” to veratridine (100 μmol/l) was unaffected by the absence of external Ca2+, largely resistant to TTX (1 μmol/l) and moderately reduced by cocaine. However, both TTX and cocaine drastically changed the composition of the radioactivity during the “plateau response”: they greatly reduced or even abolished the efflux of unchanged 3H-noradrenaline and markedly increased the efflux of deaminated 3H-metabolites. Hence, the “plateau response” represented a “reserpine-like” vesicular effect of varatridine; the ensuing 3H-noradrenaline efflux out of the neurone was mediated by the neuronal amine carrier. 5) After pretreatment with reserpine (to inhibit vesicular uptake) and pargyline (to inhibit monoamine oxidase), veratridine (100 μmol/l) elicited a phasic, peak-like increase in the efflux of tritium (about 90% of which was unchanged 3H-noradrenaline). This response to veratridine was abolished by TTX (1 μmol/l) and unaffected by the absence of external Ca2+; moreover, it was greatly reduced by either cocaine (10 μmol/l) or desipramine (1 μmol/l) and, hence brought about by carrier-mediated outward transport across the axonal membrane. 6) It is concluded that, in addition to its well-known action on the fast sodium channel, veratridine somehow increases the leakage of noradrenaline from storage vesicles; this “reserpine-like” effect of veratridine is resistant to TTX and therefore not a consequence of the drug-induced changes in the sodium permeability of the axolemma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00502621
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  • 4
    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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  • 5
    Electronic Resource
    Electronic Resource
    Stereoselectivity in the metabolism of 3H-noradrenaline during uptake into and efflux from the isolated rat vas deferens (1977)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 299 (1977), S. 225-238 
    Details
    ISSN: 1432-1912
    Keywords: Stereoselective metabolism of noradrenaline ; Neuronal efflux ; Cocaine ; Phenoxybenzamine ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The metabolism of 3H-(-)- and 3H-(±)-noradrenaline (NA) was studied in the isolated rat vas deferens either under conditions of uptake or of efflux of the amine. Any differences obtained between 3H-(-)-and 3H-(±)NA as substrate were interpreted as being a reflection of differences between the two isomers of the amine. 2. Uptake experiments (0.13 μM; 7.5 min) showed that neuronal mechanisms of amine disposition prevail over extraneuronal ones. Thus, most of the metabolites of 3H-NA formed during incubation with the amine (including the O-methylated products) were of neuronal origin. The acid deaminated metabolite 3,4-dihydroxymandelic acid (DOMA), tended to be much better retained by the tissue than the neutral deaminated metabolite, 3,4-dihydroxyphenylethyleneglycol (DOPEG). While neuronal uptake exhibited no stereoselectivity, a pronounced stereoselectivity was found for monoamine oxidase (MAO) [(-)NA〉 (+)NA] as well as for the enzymes which are in series with MAO, namely, aldehyde reductase and aldehyde dehydrogenase [(-)DOPEG〉 (+)DOPEG; (-)DOMA 〈(+)DOMA]. 3. After about 2 h of washout, the efflux of radioactivity from the tissue [which was previously incubated for 30 min with 1.2 μM of either 3H-(-)- or 3H-(±)NA] originated from one neuronal compartment with no stereoselectivity of the rate constant for the efflux of total tritium. The rate-limiting step for the neuronal efflux of tritium resided either in the net efflux of amine from the storage vesicles (normal tissues) or in the net efflux across the axonal membrane (tissues with the amine metabolizing enzymes inhibited). The effects of cocaine and phenoxybenzamine on the neuronal efflux of tritiated compounds strongly depended on the intraneuronal distribution of the 3H-amine. The results indicate that cocaine has only one site of action (neuronal uptake), while phenoxybenzamine exerts reserpine-like as well as cocaine-like effects. 4. The neuronal efflux of tritium from normal tissues preloaded with 3H-(-)- or 3H-(±)NA consisted mainly of amine metabolites (90% of the total; most of this was DOPEG). Since after 2 h of washout the tissue contained hardly any metabolites, these metabolites did not represent pre-formed metabolites (formed during the period of preloading) but newly formed metabolites resulting from the catabolism of the neuronally stored amine. This catabolism was brought about through the activity of presynaptic enzymes and was stereoselective in that more DOPEG, less DOMA and less O-methylated metabolites were formed from (-)-than from (+)NA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00500315
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