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  • 1
    Electronic Resource
    Electronic Resource
    Inhibition by K+ of uptake2 of3H-(±)-isoprenaline in the perfused rat heart (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 393-396 
    Details
    ISSN: 1432-1912
    Keywords: Isoprenaline ; Uptake2 ; Extracellular potassium ; Rat heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The kinetics of the inhibitory effect of extracellular K+ on uptake2 of3H-(±)-isoprenaline were determined in isolated hearts obtained from reserpine-pretreated rats; catechol-O-methyl transferase was inhibited. 1. Initial rates of uptake2 of a very low concentration of3H-(±)-isoprenaline (10 nmol/l) were determined in the presence of various extracellular concentrations of K+ (2.7 to 60 mmol/l). The inhibitory effect of K+ was concentration-dependent with an IC50 of about 20 mmol/l. — In these experiments KCl was added to the perfusion solution, and some hypertonicity resulted. In some experiments NaCl was added to a solution containing 5 mmol/l K+ to result in the same degree of hypertonicity as that obtained for 60 mmol/l K+; hypertonicity increased the initial rate of uptake2 of3H-(±)-isoprenaline. Thus, the inhibitory effect of K+ had been slightly underestimated. 2. In subsequent experiments the increase of the concentration of K+ in the perfusion fluid to 30 mmol/l was compensated for by a corresponding reduction of Na+. Initial rates of uptake2 of 10 nmol/l3H-(±)-isoprenaline were determined in the absence and presence of various concentrations of unlabelled (±)-isoprenaline. At 30 mmol/l K+ the IC50 (=K m for uptake2) did not significantly differ from that determined in an earlier study of 2.7 mmol/l K+ (Grohmann and Trendelenburg 1984). Finally, theV max for uptake2 of3H-(±)-isoprenaline was determined at either 2.7 or 30 mmol/l K+. At 30 mmol/l K+ theV max was only about 1/4 of that observed at 2.7 mmol/l K+. 3. Extracellular K+ inhibits uptake2 of3H-(±)-isoprenaline primarily by a reduction ofV max.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569376
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  • 2
    Electronic Resource
    Electronic Resource
    The release of3H-noradrenaline by p- and m-tyramines and -octopamines, and the effect of deuterium substitution in α-position (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 433-440 
    Details
    ISSN: 1432-1912
    Keywords: Indirectly acting sympathomimetic amines ; Tyramine ; Octopamine ; Deuterium in α-position ; Rat vas deferens ; Noradrenaline outward transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The3H-noradrenaline-releasing effects of p- and m-tyramines and -octopamines, either deuterated or not, were studied in isolated vasa deferentia of the rat (COMT inhibited and calcium-free solution in all experiments). K m, for uptake1 was higher for octopamines than for tyramines, but not increased by the introduction of deuterium in α-position, except for (probably contaminated) deuterated p-octopamine. Other tissues were preloaded with3H-noradrenaline. After inhibition of vesicular uptake and MAO equi-releasing concentrations of the eight amines were strictly correlated withK m, they were 6 to 7 times higher for unsubstituted octopamines than for corresponding tyramines. When only MAO (but not vesicular uptake) was inhibited, this difference decreased to about 4-fold, but the releasing potency of the deuterated amines (relative to their parent amines) remained unchanged (except for p-octopamine). When vesicular uptake and MAO were intact, unsubstituted octopamines were only 1.5 to 2.2 times less potent than the corresponding tyramines. Analysis of the efflux of3H-DOPEG confirmed that this gain in the relative potencies of octopamines is due to their increased ability to mobilize vesicular 3H-noradrenaline; moreover, deuterated amines as well were then better mobilizers than were their parent amines. It is concluded that, provided vesicular uptake is intact, the introduction of a \-OH-group enhances the ability of indirectly acting sympathomimetic amines to mobilize vesicular noradrenaline; the introduction of deuterium in α-position, on the other hand, enhances this mobilizing effect exclusively when MAO is intact.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00736058
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  • 3
    Electronic Resource
    Electronic Resource
    Veratridine-induced outward transport of 3H-noradrenaline from adrenergic nerves of the rat vas deferens (1987)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 336 (1987), S. 621-630 
    Details
    ISSN: 1432-1912
    Keywords: Veratridine ; Ouabain ; Rat vas deferens ; Adrenergic nerve endings ; Neuronal outward transport
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The neuronal release by 100 μmol/l veratridine of preloaded 3H-noradrenaline was studied in the rat vas deferens, the MAO, COMT and vesicular uptake of which were inhibited. To prevent any exocytotic release of the 3-Hamine, all solutions were calcium-free. Veratridine induced an early and a late peak of tritium efflux. The early peak was abolished by the presence of 1 μmol/l desipramine, the late peak was abolished by 1 μmol/l tetrodotoxin (administered subsequently to the first peak). The administration of veratridine plus 1 mmol/l ouabain resulted in only the early peak of efflux. 2. The peak response to veratridine plus ouabain was increased by a very early administration of veratridine plus ouabain (after 40 min of wash-out instead of the usual 130 min) (i. e., when the relative size of the axoplasmic distribution compartment was increased). However, very high axoplasmic 3H-noradrenaline levels (after loading with 37 instead of the usual 0.2 μmol/l) reduced the height of the peak (when expressed as a FRL). 3. Substantially similar responses to vcratridine plus ouabain were obtained after loading with 3H-noradrenaline, 3H-adrenaline or 3H-dopamine. 4. As the second peak of veratridine-induced release is ouabain-sensitive, it appears to be caused by exhaustion of neuronal ATP stores; this, in turn, raises the intravesicular pH and induces efflux of 3H-noradrenaline from the vesicles into the axoplasm. The first peak, on the other hand, represents outward transport of 3H-noradrenaline from the axoplasmic compartment. Evidently, a pronounced vesicular distribution of 3H-noradrenaline takes place even after inhibition by reserpine of the vesicular uptake. 5. In preparations with intact vesicular uptake (MAO and COMT inhibited) a plateauresponse was obtained; in the presence of 10 μmol/l Ro 4-2184 (a reserpine-like compound) a peak response was restored after loading with 0.2 μmol/l3H-noradrenaline, less so after loading with 37 μmol/l. 6. It is confirmed that veratridine (plus ouabain) exerts a reserpine-like effect when applied to tissues with intact vesicular uptake and intact MAO.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00165752
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  • 4
    Electronic Resource
    Electronic Resource
    The effect of partial inhibition of monoamine oxidase on the steady-state rate of deamination of 3H-catecholamines in two metabolizing systems (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 333 (1986), S. 253-261 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal deamination ; Extraneuronal deamination ; Rat vas deferens ; Rat heart ; Monoamine oxidase ; Pargyline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Two different “deaminating systems” were compared (i.e., intact tissues in which an uptake process translocates the 3H-catecholamine from the extracellular space to the intracellular MAO): 1) the adrenergic nerve endings of the rat vas deferens exposed to 10 nmol/l 3H-(−)-noradrenaline, and 2) the extraneuronal deaminating system of the rat heart perfused with 50 nmol/l 3H-(−)-adrenaline. Vesicular uptake and COMT were inhibited. In both systems MAO was partially inhibited by pargyline, and the steady-state tissue content of the 3H-catecholamine was determined as well as the steady-state rate of deamination. 1. Rat vas deferens (preincubated with 10–40 nmol/l pargyline for 30 min). Inhibition of neuronal MAO caused not more than a moderate decrease of the steady-state rate of deamination of 3H-(−)-noradrenaline, but the steady-state tissue content was greatly increased. Determinations of the activity of MAO in homogenates of vasa deferentia showed that preincubation with 10 and 20 nmol/l pargyline inhibited the enzyme by 80 to 95%. 2. Rat heart (of animals pretreated with 1 to 30 mg/kg pargyline). Inhibition of extraneuronal MAO caused a steep decline of the steady-state rate of deamination of 3H-(−)-noradrenaline but only a small rise in the steady-state tissue content. 3. The decisive difference between the two deaminating systems lies in the fact that the ratio “k mao/k out” (where the two k-values characterize the activity of the unsaturated intracellular MAO and the ability of the 3H-catecholamine to leave the relevant cells, respectively) is much higher for the neuronal deaminating system exposed to 3H-(−)-noradrenaline than for the extraneuronal deaminating system exposed to 3H-(−)-adrenaline. Whenever this ratio is high, pronounced (but incomplete) inhibition of MAO results in a very pronounced increase in the intracellular steady-state 3H-amine concentration (during exposure of the tissue to a 3H-catecholamine); as far as the steady-state rate of deamination is concerned, the pronounced rise in substrate concentration largely masks the pronounced degree of inhibition of MAO. When, however, the ratio is close to unity, inhibition of MAO fails to result in any pronounced increase in the intracellular steady-state 3H-amine concentration; as a consequence, any pronoumced inhibition of MAO is then reflected by a pronounced decrease of the steady-state rate of deamination. 4. From the present results it is concluded that, in experiments with intact tissues, the degree of inhibition of MAO cannot be derived from measurements of rates of deamination of 3H-catecholamines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00512938
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  • 5
    Electronic Resource
    Electronic Resource
    Temperature sensitivity of the extraneuronal uptake and metabolism of isoprenaline in the perfused rat heart (1979)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 306 (1979), S. 229-239 
    Details
    ISSN: 1432-1912
    Keywords: Extraneuronal uptake ; Temperature ; Rat heart ; Catecholamines ; Rate constants for efflux ; Extraneuronal COMT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The influence of lowering the temperature (from 37° to either 27° or 20°C) on extraneuronal mechanisms was studied in the rat heart perfused with 3H-isoprenaline. 1. During perfusion at a constant rate, lowering of the temperature increased the resistance to flow. The consequent impairment of the effectiveness of the perfusion of the tissue accounts for most (or all) of the temperature-sensitivity of the non-saturable (probably diffusional) extraneuronal uptake of isoprenaline. 2. For various other extraneuronal mechanisms the effect of lowering the temperature clearly exceeded that attributable to changes in perfusion. This applied to the V max (but not to the K max) of saturable extraneuronal uptake and extraneuronal O-methylation, as well as to the rate constants for the efflux of isoprenaline and its O-methylated metabolite, OMI. 3. Lowering of the temperature impaired the efflux of isoprenaline from compartment III (characterized by Bönisch et al., 1974, as having a half time of about 10 min) much more than that from compartment IV (characterized by Bönisch et al., 1974, as having a half time of about 25 min). Since these effects are similar to those of an inhibitor of extraneuronal uptake, corticosterone, it is possible that amine efflux from compartment III (but not from compartment IV) is carrier-mediated. 4. It is concluded that the temperature-sensitivity of the extraneuronal accumulation of catecholamines reported in the literature is not solely due to extraneuronal uptake being temperature-sensitive; the intracellular enzyme and the rate constants for the efflux of amine and metabolite are also greatly influenced by temperature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00507108
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  • 6
    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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  • 7
    Electronic Resource
    Electronic Resource
    Autoradiographic study of the rat vas deferens incubated with 3H-noradrenaline (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 245-248 
    Details
    ISSN: 1432-1912
    Keywords: Rat vas deferens ; Heterogeneous labelling ; 3H-noradrenaline ; Neuronal uptake ; Autoradiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Rat vasa deferentia were incubated with 0.2 μmol/l 3H-noradrenaline for 60 min and then washed out with amine-free solution for 100 min. Autoradiography then revealed a preferential labelling of the varicosities in the immediate vicinity of the surface of the tissue. However, when tissues were obtained from reserpine-and pargyline-pretreated rats (to block vesicular uptake and monoamine oxidase), 3H-noradrenaline was able to penetrate more deeply into the tissue. These differences are in accordance with the view that the autoradiographs reflect the 3H-noradrenaline concentration gradient (within the extracellular space) generated by the neuronal uptake of the 3H-amine; the concentration gradient is steeper (and the heterogeneity of labelling is more pronounced) in tissues with intact vesicular uptake and monoamine oxidase than in tissues in which these mechanisms had been inhibited.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00166972
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  • 8
    Electronic Resource
    Electronic Resource
    Carrier-mediated outward transport of dopamine from adrenergic varicosities of the vas deferens of reserpine-pretreated rats (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 344 (1991), S. 619-622 
    Details
    ISSN: 1432-1912
    Keywords: Rat vas deferens ; Endogenous dopamine ; Pretreatment with reserpine ; Carrier-mediated outward transport ; Inhibition of COMT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In vasa deferentia of reserpine-pretreated rats a carrier-mediated (i. e., desipramine-sensitive) outward trAnsport of endogenous dopamine was induced by either tyramine or ouabain. The dopamine taking part in the efflux induced by tyramine (and the concomitant efflux of DOPAC) was derived from ongoing synthesis of dopamine. Inhibition of MAO trebled the rate of spontaneous efflux of dopamine and reduced the spontaneous efflux of DOPAC by 90%. After inhibition of MAO, desipramine caused a further five-fold increase in the basal efflux of dopamine with no change in the basal efflux of DOPAC. Inhibition of COMT failed to affect the spontaneous efflux of dopamine but increased that of DOPAC. It is concluded that, after depletion of the noradrenaline stores by pretreatment with reserpine, an outward transport of axoplasmic dopamine is induced by the same mechanisms that (without any pretreatment with reserpine) are known to initiate an outward transport of noradrenaline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00174744
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  • 9
    Electronic Resource
    Electronic Resource
    Saturation of monoamine oxidase by intraneuronal noradrenaline accumulation (1984)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 328 (1984), S. 135-141 
    Details
    ISSN: 1432-1912
    Keywords: Adrenergic nerve endings ; Inhibition of MAO ; Saturation of MAO in intact cells ; 3H-(-)-Noradrenaline ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary After pretreatment of the rats with reserpine and pargyline (to inhibit vesicular uptake and MAO), after an additional in vitro treatment with pargyline, and in the presence of U-0521 (to inhibit COMT), the adrenergic nerve endings of vasa deferentia were loaded with 3H-(-)-noradrenaline by exposure to various concentrations of this amine. Subsequently, tissues were washed out with amine-free solution, and the neuronal efflux of tritium was analysed. 1. During 180 min of wash-out the apparent rate constant for the efflux of tritium decreased with increasing tritium content of the tissue. 2. Prolongation of the wash-out period to 305 min revealed that efflux curves for tritium from heavily loaded tissues became steeper after the 180th min of wash-out. This phenomenon is indicative of saturation (followed by desaturation) of a process that limits the efflux of tritium from heavily loaded tissues. 3. Analysis of the radioactivity of the efflux revealed a characteristic efflux curve for DOPEG: the formation of DOPEG appears to be saturated when the 3H-(-)-noradrenaline content of the tissue is high, in order to become desaturated during prolonged wash-out. These results cannot distinguish between MAO and alcohol dehydrogenase as the saturable enzyme. 4. The formation of the mainly deaminated metabolites (during 60 min of wash-out) was determined in lightly and in heavily loaded tissues. The ratio “formation of metabolites/3H-(-)-noradrenaline content” was lower in heavily than in lightly loaded tissues; the relative decline in DOPEG formation was not accompanied by a compensatory increase in the formation of DOMA. Hence, in heavily loaded tissues, MAO must have been saturated by the pronounced accumulation of axoplasmic 3H-(-)-noradrenaline. 5. From the 100th to the 115th min of wash-out, the fractional rate of loss of DOPEG was negatively correlated with the 3H-(-)-noradrenaline content of the tissue; but no such correlation was observed for the fractional rate of loss of 3H-(-)-noradrenaline. 6. The results are interpreted as indicating that any very pronounced inhibition of intraneuronal MAO (by pargyline) enables the nerve ending to achieve such very high axoplasmic noradrenaline concentrations that two phenomena occur simultaneously: a) there is very little obvious sign of any inhibition of MAO, since the great loss of enzyme activity is largely compensated for by the greatly increased intraneuronal substrate concentration; consequently, DOPEG continues to be formed at a brisk rate; b) the axoplasmic noradrenaline concentration then reaches levels that saturate the intraneuronal enzyme.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00512062
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  • 10
    Electronic Resource
    Electronic Resource
    The substrate specificity of uptake2 in the rat heart (1984)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 328 (1984), S. 164-173 
    Details
    ISSN: 1432-1912
    Keywords: Extraneuronal uptake ; Rat heart ; Catecholamines ; Stereoselectivity ; Substrate specificity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were carried out with hearts isolated from reserpine- and pargyline-pretreated rats; both noradrenaline-metabolizing enzymes and uptake1 were inhibited. Initial rates of extraneuronal uptake were measured after perfusion lasting for 2 min, either in the absence or in the presence of 100 μmol/l O-methyl-isoprenaline, a potent inhibitor of uptake2. 1. The ID50 (i.e., the concentration of unlabelled substance that halves the rate of uptake of a tracer concentration of 3H-(±)-isoprenaline) was determined for a variety of agents. Two types of stereoselective preference of (-)-isomers were observed: for isoprenaline and adrenaline (but not for noradrenaline)-and also for dobutamine. 2. The stereoselective preference for the (-)-isomers of isoprenaline and adrenaline is also evident from fluorimetric determination of initial rates of uptake of unlabelled isomers. 3. Experiments with various tritiated compounds indicate that uptake2 has a broad substrate spectrum: uptake2 is not restricted to 3H-catecholamines and 3H-phenethylamines, but extends to resorcinols (3H-orciprenaline), imidazoline derivatives (3H-clonidine), 3H-histamine and 3H-5-hydroxytryptamine (3H-5-HT). 4. Determinations of the V max of uptake2 revealed a correlation between the ID50 and the V max: the higher the ID50, the higher the V max. 5. These results indicate that uptake2 is a carrier-mediated process.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00512067
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