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  • 1975-1979  (3)
  • 1970-1974  (2)
  • Rat vas deferens  (3)
  • Noradrenaline  (2)
  • Inhibition of Uptake
  • 1
    Electronic Resource
    Electronic Resource
    The prejunctional effect of cocaine on the isolated nictitating membrane of the cat (1972)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 275 (1972), S. 69-82 
    Details
    ISSN: 1432-1912
    Keywords: Cocaine ; Nictitating Membrane ; Uptake Theory ; Inhibition of Uptake ; Supersensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Pairs of smooth muscles isolated from the nictitating membrane of reserpine-pretreated cats were incubated four times with 1.2 ml of Krebs' solution containing 10 ng/ml of 3H-(±)-noradrenaline for 7.5 min each (in the presence of ascorbic acid and EDTA to prevent autoxidation and of U-0521 to block COMT). The appearance of deaminated 3H-catechols in the bath was measured and regarded as a measure of neuronal uptake. 2. Cocaine caused a concentration-dependent inhibition of the rate of deamination; the ID50 was 5.62 μM. 3. Cocaine caused a concentration-dependent increase in responses of the isolated muscles to 0.059 μM (−)-noradrenaline with a maximum increase of about 115 times normal. 4. The results were applied to the model proposed by Maxwell et al. (1966). The agreement between the expected and observed relationship between rate of uptake and degree of supersensitivity was satisfactory. Apparently, the effect of cocaine on the nictitating membrane is predominatly or entirely prejunctional. 5. The results indicate that the true K m for noradrenaline and the true K i for cocaine are considerably smaller than the apparent Km and Ki values obtained with conventional methods.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505068
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  • 2
    Electronic Resource
    Electronic Resource
    On the stereoselectivity of the neuronal uptake in the cat's nictitating membrane (1972)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 275 (1972), S. 45-68 
    Details
    ISSN: 1432-1912
    Keywords: Stereoselectivity of Uptake ; Noradrenaline ; Neuronal Uptake ; Neuronal Deamination ; Nictitating Membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Pairs of smooth muscles isolated from the nictitating membrane of the cat were incubated with 1.2 ml of Krebs' solution containing 10 ng/ml of 3H-(±)-noradrenaline for 7.5 min (in the presence of U-0521 to inhibit COMT). Removal of the amine from the bath as well as the appearance of deaminated 3H-catechols in the bath were measured. 2. Pretreatment with reserpine did not affect the rate of removal, while increasing the rate of deamination. The ability of the muscles to retain exogenous amine for one hour was reduced to 12% of normal. 3. A certain fraction of the total production of deaminated 3H-catechols escaped into the medium. For any given duration of incubation this fraction was independent of the concentration of noradrenaline in the medium. On repeated incubation the fraction remained constant. Therefore, reliable estimates of the rate of deamination were obtained with repeated incubations of the same muscle. 4. Sympathetic denervation and/or cocaine revealed that 60% of removal (of which 10% are due to dilution) and 25% of deamination are extraneuronal. 5. For incubations of 7.5 min measured rates of deamination represent initial rates, measured rates of removal do not. 6. Unlabelled (−)- and (+)-noradrenaline were equipotent (ID50=about 1 μM) in inhibiting the deamination of 10 ng/ml of 3H-(±)-noradrenaline. This inhibitory effect must be exerted on neuronal deamination, since extraneuronal deamination (in denervated muscles) was not affected by the addition of unlabelled isomers. 7. It is proposed that, under these experimental conditions, neuronal unptake is the rate limiting step for neuronal deamination, and that neuronal uptake in the cat's nictitating membrane lacks stereoselectivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505067
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  • 3
    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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  • 4
    Electronic Resource
    Electronic Resource
    Kinetic analysis of the interaction between noradrenaline and Na+ in neuronal uptake: Kinetic evidence for CO-transport (1979)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 309 (1979), S. 99-107 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal uptake ; Noradrenaline ; Effects of Na+ ; Na+-coupled membrane transport ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Vasa deferentia obtained from reserpine-pretreated rats were incubated (under conditions of inhibition of both monoamine oxidase and catechol O-methyltransferase) in medium containing various concentrations of 3H-(−)noradrenaline (1.25–30.25 μmol·l−1) and Na+ (0–143 mmol·l−1; isosmolality maintained by Tris+). Initial rates of neuronal uptake (v i ) were determined in each single vas from the difference between the uptake of noradrenaline occurring in the absence and that occurring in the presence of 100 μmol·l−1 cocaine. 2. The uptake of noradrenaline observed after exposure to cocaine was virtually identical with that observed after incubation in Na+-free medium (containing or not containing cocaine). Under these experimental conditions, 70% of the uptake was due to extracellular distribution of the amine, and not only this part of uptake, but also the remaineder was linearly related to the noradrenaline concentration in the medium. 3. The neuronal uptake of noradrenaline showed saturation with increasing concentrations of noradrenaline or Na+. When determined at several fixed concentrations of Na+ (or noradrenaline), the plots of 1/v i vs. 1/[noradrenaline] (or 1/[Na+]) were all linear and intersected at a common point to the left of the ordinate and above the abscissa. Increases in the fixed concentration of Na+ (or noradrenaline) progressively increased the apparent V max and progressively decreased the apparent K m of the system for noradrenaline (or Na+). Moreover, the vertical intercept (1/apparent V max) and the slope (apparent ratio of K m /V max) of the Lineweaver-Burk plots were linearly related to the reciprocal of the concentration of the “fixed” substrate. 4. Thus, the neuronal uptake mechanism exhibits the kinetic properties of a two-substrate sequential reaction in which both noradrenaline and Na+ (1:1) must bind to the carrier for transport of noradrenaline to occur and in which noradrenaline and Na+ act as mutually cooperative co-substrates.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00501216
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  • 5
    Electronic Resource
    Electronic Resource
    The inhibitory effect of some monovalent cations on the stimulation by Na+ of the neuronal uptake of noradrenaline (1979)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 309 (1979), S. 89-97 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal noradrenaline uptake ; Na+-dependent noradrenaline transport ; Effect of monovalent cations ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Vasa deferentia obtained from reserpine-pretreated rats were incubated (after inhibition of both monoamine oxidase and catechol O-methyltransferase) in media containing 1.1 μmol·l−1 3H-(−)noradrenaline and various concentrations of Na+ (0–140 mmol·l−1; isosmolality maintained by sucrose or by several monovalent cations). Initial rates of neuronal uptake were determined in each single vas from the difference between “total” and “cocaine-resistant” uptake of 3H-noradrenaline. 2. The “cocaine-resistant” uptake (i.e., the distribution of 3H-noradrenaline observed in the presence of 100 μmol·l−1 cocaine) was considered to be nonneuronal. It was entirely independent of both the external Na+ concentration and the substance used to replace Na+ (or NaCl) in the medium. 3. The neuronal uptake of 3H-noradrenaline was virtually absent in Na+-free medium and was progressively stimulated by increasing Na+ concentrations. The stimulation of uptake by low Na+ concentrations was most pronounced when Tris+ was used to replace Na+; i.e., all other substitutes tested here (including sucrose, Li+, choline+ and K+) inhibited neuronal uptake when compared with Tris+. 4. While the Na+-dependent stimulation of neuronal uptake followed Michaelis-Menten kinetics in Tris+- or Li+-containing media, the kinetics of uptake stimulation by Na+ were rather complex in media containing choline+ or K+ as the substitute cation. 5. Li+ and K+ acted as competitive inhibitors with respect to Na+, whereas the inhibition of neuronal uptake by choline+ was the more pronounced, the higher the concentration of external Na+. 6. At concentrations higher than 25 mmol·l−1, the impairment of neuronal uptake by K+ exceeded that predictable from competitive inhibition of the action of Na+. This was due to the fact that high external K+ concentrations decelerated net uptake very early in the time course of amine accumulation, so that initial rates of uptake are likely to be underestimated under these conditions. 7. Thus, apart from maintaining isosmolality, several substances used to replace Na+ in the medium have inhibitory effects which must be considered in experiments designed to examine the role of Na+ in membrane transport of noradrenaline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00501215
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