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  • 1
    Electronic Resource
    Electronic Resource
    Saturation kinetics of the adrenergic neurone uptake system in the perfused rabbit heart. A new method for determination of initial rates of amine uptake (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 263-273 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal uptake ; Initial rates of amine uptake ; Lag period for amine uptake ; Cocaine ; Rabbit heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Hearts were obtained from normal or reserpine-pretreated rabbits and perfused at a constant rate (3.6 ml·g−1·min−1) with Tyrode's solution containing 14C- or 3H-sorbitol and various concentrations of 3H-(−)noradrenaline (NA), 14C-(+)NA or 3H-(±)metaraminol; when NA was used, monoamine oxidase and catechol-O-methyl transferase were inhibited. During perfusion for 2 min the arterio-venous difference for 3H and 14C activity (and in this way the removal of amine and sorbitol from the perfusion fluid) was determined at intervals of 5 s. The uptake of amine into intracellular spaces of the heart was obtained by subtraction of the removal of sorbitol from that of amine; it was cumulatively added and plotted against time (uptake curve). Uptake was overwhelmingly neuronal. 2. The uptake curves were sigmoidal: after a brief initial lag period, uptake curves became linear; there-after, the slope of the curves decreased. The last phase of divergence from linearity occurred the earlier and was the more pronounced, the higher the amine concentration. It was interpreted to indicate that neuronal efflux of amine then began to reduce net uptake. 3. From the slope of the linear phase of the uptake curves initial rates of amine transport were obtained. They were saturable with increasing amine concentrations and obeyed Michaelis-Menten kinetics. The apparent K m values of the three amines were similar in magnitude and ranged from 2.9 to 5.9 μM. Uptake was stereoselective in that the V max of (+)NA was significantly lower than that of (−)NA. Pretreatment with reserpine affected neither the K m nor the V max for uptake. Cocaine was a potent competitive inhibitor of amine transport (K i=0.5–1.0 μM). 4. The intercept of the linear phase of the uptake curves on the time axis (t lag) (corrected for the time necessary for transit through the dead space) was taken as a measure of the lag period. It declined when uptake was progressively saturated (or inhibited) by increasing substrate (or cocaine) concentrations. Moreover, t lag was always linearly correlated with the fraction of amine removed from the perfusion fluid. These findings indicate that the equilibration of the uptake sites with the substrate concentration in the perfusion fluid is delayed by the uptake process itself, especially under low saturation conditions (i.e., when S〈K m).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00508295
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    The influence of the rate of perfusion on the kinetics of neuronal uptake in the rabbit isolated heart (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 275-283 
    Details
    ISSN: 1432-1912
    Keywords: Rate of perfusion ; Neuronal uptake ; Accessibility of neuronal uptake sites ; Perfusion pressure ; Rabbit heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Rabbit hearts (with monoamine oxidase and catechol-O-methyl transferase inhibited) were obtained from reserpine-pretreated animals. They were perfused at rates ranging from 1.3–11.3 ml·g−1·min−1 with 0.1 mM 14C-sorbitol and various concentrations of 3H-(−)noradrenaline (NA). From measurements of the arterio-venous concentration difference of 3H and 14C activity the removal of NA and sorbitol from the perfusion fluid was followed for 2–3 min at intervals of 5 s. The uptake of NA into intracellular spaces of the heart (known to be over-whelmingly into sympathetic nerve terminals) was obtained by subtracting the removal of sorbitol from that of NA. If was cumulated and plotted against time. 2. The progress curves of NA uptake were sigmoid in shape: following a lag period, uptake proceeded at first at a constant initial rate and from then on at gradually decreasing rates. Irrespective of the NA concentration used, the lag period became shorter and the initial rate of uptake increased whenever the rate of perfusion was increased. Furthermore, at high rates of perfusion the initial rate was maintained for a shorter time than at low ones. 3. At any given perfusion rate, the initial rates of NA uptake obeyed Michaelis-Menten kinetics. While changes of the rate of flow did not alter the apparent K m (range: 2.2–2.4 μM), a rectangular hyperbolic relationship was found between V max and the perfusion rate. The V max was half-maximal at a rate of flow of 2.7 ml·g−1·min−1 and approached a maximum value of 9.0 nmoles·g−1·min−1. 4. From the lack of change in the K m it can be concluded that the uptake sites of the perfused heart are functionally arranged in parallel. The change in V max, on the other hand, indicate that the accessibility of the sites is limited by the rate of perfusion.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00508296
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    Uptake of 14C-tyramine and release of extravesicular 3H-noradrenaline in isolated perfused rabbit hearts (1983)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 323 (1983), S. 233-244 
    Details
    ISSN: 1432-1912
    Keywords: Uptake of tyramine ; Indirectly acting amines ; Extravesicular binding ; Neuronal efflux of noradrenaline ; Compartment analysis ; Rabbit heart
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1) In isolated perfused hearts of reserpine (R)-and pargyline (P)-pretreated rabbits (i.e. RP-hearts) initial rates of intracellular uptake of 14C-tyramine and of 3H-amphetamine were measured as described by Graefe et al. (1978). The uptake of 14C-tyramine, but not that of 3H-amphetamine was inhibited by cocaine. 2) Saturation kinetics of the intracellular uptake of 14C-tyramine revealed a non-saturable (diffusional) and a saturable (carrier-mediated) component of uptake. 3) After 30 min of perfusion with 14C-tyramine the accumulated 14C-radioactivity in RP-hearts consisted of unchanged tyramine (about 60%), octopamine (about 30%) and deaminated metabolites (about 10%). In contrast, 14C-octopamine was the main radioactive substance when the perfusion with 14C-tyramine was followed by 100 min of wash-out. 4) IC50-Values of tyramine, amphetamine, amantadine and nomifensine for inhibition of neuronal uptake of 3H-noradrenaline were determined in RPU-hearts (i.e. in RP-hearts whose COMT was inhibited by U-0521). 5) About equieffective concentrations (with respect to inhibition of 3H-noradrenaline uptake) of tyramine, amphetamine, amantadine and noradrenaline (i.e. of substrates of the neuronal amine carrier) caused a pronounced (and comparable) release of 3H-noradrenaline from RPU-hearts, whereas cocaine and nomifensine (i.e. uptake inhibitors) caused only a very small release. Low sodium caused a release comparable to that induced by substrates of the amine carrier. 6) Increasing concentrations of tyramine (0.2–24 μmol/l) caused mobilization of 3H-noradrenaline from a small “bound fraction” and partial mobilization from a large compartment which was characterized by a rate constant for efflux of about 0.014 min−1 (compartment I). The peak-value of the tyramine-induced efflux of 3H-noradrenaline exhibited saturability with increasing concentrations of tyramine. Half-maximal release was observed at a tyramine concentration which corresponded to a) the IC50-value for inhibition of uptake of 3H-noradrenaline and b) the K m of the saturable component of uptake of 14C-tyramine. 7) That part of neuronally accumulated 3H-noradrenaline (mainly in compartment I) which was not further mobilized by high concentrations of tyramine was also hardly mobilized by veratridine (in the absence of Ca2+). However, in the presence of Ca2+, veratridine as well as nicotine induced a release of this “tyramine-resistant” 3H-noradrenaline. 8) It is concluded that in RPU-hearts the distribution of 3H-noradrenaline within the partially “tyramine-resistant” compartment I and within the “bound fraction” might represent 3H-noradrenaline “trapped” within the acid interior of “reserpinized” vesicles and within a small population of intact storage vesicles, respectively. The fast release of 3H-noradrenaline (from RPU-hearts) by tyramine, noradrenaline, amphetamine and amantadine might be caused by facilitation of the outward transport of axoplasmic noradrenaline; the extend of facilitation may be directly connected to the velocity of uptake of these substrates by the amine carrier.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00497669
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