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  • 1
    Electronic Resource
    Electronic Resource
    The disposition of 3H-(−)noradrenaline in the Perfused cat and rabbit heart (1981)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 318 (1981), S. 71-82 
    Details
    ISSN: 1432-1912
    Keywords: (−)Noradrenaline ; Neuronal metabolism ; Extraneuronal metabolism ; Perfused heart ; Efflux of noradrenaline metabolites
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Hearts of cats and rabbits were perfused at a constant rate with 3H-(−)noradrenaline for 60–120 min. During the perfusion the rate of net removal of 3H-noradrenaline from the perfusion fluid and the rate of efflux of 3H-metabolites from the hearts were followed. From these results and from the amount of 3H-metabolites recovered from the hearts (at the end of experiments), the time course of the cumulative metabolite formation was obtained. The following metabolites were determined: 3,4-dihydroxyphenylethyleneglycol (DOPEG), 3,4-dihydroxymandelic acid (DOMA), normetanephrine (NMN) and a fraction consisting of 3-methoxy-4-hydroxyphenylethyleneglycol and 3-methoxy-4-hydroxymandelic acid (OMDA). 2. In normal hearts, the rate of formation of DOPEG, DOMA and OMDA became constant only after a considerable delay, and the rate of efflux of these metabolites did not reach a constant value within 120 min. By contrast, the formation of NMN proceeded at a constant rate throughout the perfusion with 3H-noradrenaline, and the rate of efflux of NMN approached a steady level within about 30 min. 3. In hearts of reserpine-pretreated animals not only NMN, but also DOPEG, DOMA and OMDA quickly approached a constant rate of formation. In addition, the efflux of all metabolites attained a steady level, and after about 70 min, the hearts of both species reached a steady state in which the net removal of 3H-noradrenaline was fully accounted for by the formation of metabolites. 4. The metabolite pattern during the steady state showed striking species differences. The rate of metabolite formation (expressed in % of the steady-state rate of 3H-noradrenaline removal) decreased in the order DOPEG (40.0%)〉NMN (30.8%)〉DOMA (18.1%)〉OMDA (9.0%) in the cat heart and DOPEG (66.8%)〉DOMA (20.0%)〉OMDA (6.6%)〉NMN (1.5%) in the rabbit. 5. In both species, 30 μmol · l−1 cocaine (to inhibit neuronal uptake) decreased the rate of formation of DOPEG, DOMA and OMDA to very low values, but increased the formation of 3H-NMN. 6. In the cat heart, 30 μmol · l−1 hydrocortisone (to inhibit extraneuronal uptake) decreased the formation of NMN, while having no effect on the formation of DOPEG, DOMA and OMDA. Moreover, in the cat and rabbit heart perfused in the presence of cocaine, inhibition of extraneuronal uptake markedly affected the formation of NMN. 7. A linear relationship was found for all metabolites between the rate of efflux and the tissue content (both parameters being determined during steady state), indicating first-order kinetics of efflux. The ranking order of the overall rate constants for efflux was DOPEG≫NMN〉DOMA.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00508829
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  • 2
    Electronic Resource
    Electronic Resource
    The rate constants for the efflux of the metabolites of noradrenaline from rabbit aortic strips (1978)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 302 (1978), S. 207-215 
    Details
    ISSN: 1432-1912
    Keywords: Rate constants for efflux ; Efflux of noradrenaline metabolites ; Rabbit aorta ; Metabolism of noradrenaline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Rabbit aortic strips were incubated with 1.18 μM labelled noradrenaline for 30 min and then washed with amine-free solution for at least 110 min. From the last efflux sample and from the metabolite content of the strip analysed at the end of the experiment, rate constants for the efflux of the metabolites were calculated in two ways: a) as k = rate of efflux/metabolite content of strip, or b) as the slope of the regression line relating rate of efflux to metabolite content of the strip. Both determinations yielded essentially the same ranking order, and the results of b) indicated that there was no tight binding of metabolites in the tissue. 2. The rate constants for the efflux of glycols (DOPEG and MOPEG) and normetanephrine were much higher than those of the acid metabolites (DOMA and VMA). Although this ranking order agrees with results obtained with perfused hearts, k-values obtained from experiments with incubated strips tended to be lower (by a factor of 1.6 to 14.1) than k-values derived from experiments with perfused hearts. Since this difference was smallest for the acid metabolites and highest for the glycols, it is likely that considerable redistribution of the metabolites with high rate constants takes place in incubated, but less so in perfused tissues. 3. The rate constants for the efflux of metabolites also influence the rate of the approach of the metabolite content of the strip to steady state (during the incubation with noradrenaline): the rate of approach to steady state increases with increasing rate constant for efflux. 4. The apparent half time for the efflux of a metabolite (obtained from the slope of the efflux curve) equals the half time calculated from the rate constant for efflux $$\left( {t/2 = \frac{{1{\text{n 2}}}}{k}} \right)$$ , provided there is no formation of the metabolite during the relevant period of wash out. However, a discrepancy between the two parameters becomes the more noticeable, the higher the rate of formation of the metabolite during the period of observation. 5. In conjunction with earlier observations, the present results show that the efflux of metabolites observed during wash out of tissues previously loaded with noradrenaline is determined by a) the rate constant for efflux (k) and b) the formation (or lack of formation) of the metabolites during the period of observation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00517987
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  • 3
    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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  • 4
    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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