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Biomedical subjects

U Trendelenburg

Publications and source records attributed to U Trendelenburg.

At least 73 records · Page 4Linked to original sources
PubMed1978

The neuronal and extraneuronal uptake and metabolism of 3H-(-)-noradrenaline in the perfused rat heart.

1. Hearts were obtained from reserpine-pretreated rats and perfused with 0.95 micron 3H(-)-noradrenaline. The rate of removal of 3H-noradrenaline from the perfusion fluid was measured (from the arterio-venous difference) as well as the rate at which the 3H-metabolites appeared in the venous effluent. 2. When either 30micron corticosterone was added under steady-state conditions during perfusion with 3H-noradrenaline (to inhibit neuronal and extraneuronal uptake, respectively), each inhibitor reduced the removal of noradrenaline by about 50%; in the presence of both inhibitors removal was abolished. 3. Dihydroxymandelic acid (DOMA) was of neuronal, normetanephrine (NMN) of extraneuronal origin; dihydroxyphenylglycol (DOPEG) and the OMDA fraction (containing methoxyhydroxyphenylglycol-MOPEG-and methoxyhydroxymandelic acid-VMA) were formed both neuronally and extra-neuronally. 4. The extraneuronal metabolism of 3H-noradrenaline was in quick equilibrium with the 3H-noradrenaline in the perfusion fluid; most of the total formation of DOPEG, MOPEG and NMN was recovered from the venous effluent. 5. Extraneuronally formed DOPEG, MOPEG and NMN distributed in the tissue with half times corresponding to their half time for efflux. 6. Inhibition of monoamine oxidase (MAO) by pargyline increased the extraneuronal formation of NMN; MAO and catechol-O-methyl transferase (COMT) appear to be contained in the same extraneuronal compartment. 7. The extraneuronal accumulation of 3H-noradrenaline required 30 min or more to reach a steady state; inhibition of one or both enzymes slowed this process. Inhibition of MAO increased the extra-neuronal accumulation of 3H-noradrenaline; inhibition of COMT failed to do so, since the enzyme inhibitor (U-0521) was a weak inhibitor of extra-neuronal uptake. 8. The rate constants for the efflux of the metabolites of noradrenaline decreased in the order of MOPEG greater than DOPEG greater than NMN greater than DOMA greater than VMA.

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PubMed1977

Alpha-and- beta-activity of O-methylated derivatives of norepinephrine and epinephrine.

Metanephrine, iso-metanephrine, normetanephrine and isonormetaephrine were tested for alpha- and beta-activity on various tissues obtained from rats, guinea-pigs and cats. It was found that methylation of the hydroxyl groups of norepinephrine or epinephrine in either the 3- or 4-position markedly reduces or abolishes alpha- and beta-activity with the exception of the nictitating membrane of the cat. This receptor seems to show a tissue difference.

Animals↗
PubMed1976

The effect of inhibitors of extraneuronal uptake on the distribution of 3H-(+/-)noradrenaline in nerve-free rabbit aortic strips.

1. Nerve-free rabbit aortic strips were exposed to 1.18muM 3H-(+/-)noradrenaline for 30 min. When either MAO or COMT was inhibited, far more O-methylated (MAO inhibited) than deaminated metabolites (COMT inhibited) were formed during the incubation. The accumulation of unchanged amine in the extraneuronal stores was inversely related to the rate of metabolism. 2. After inhibition of both metabolizing enzymes, nerve-free strips were first incubated with the amine and then washed out with amine free solution. Compartmental analysis of the efflux curves showed that two extraneuronal compartments were involved in accumulation (with half times of efflux of 3 and 11 min, respectively). 3. 86muM corticosterone or 30muM phenoxybenzamine greatly decreased the accumulation of noradrenaline in these two compartments. 4. When corticosterone or phenoxybenzamine was added to the wash out solution only, the half time of the efflux from both compartments was greatly increased. However, this effect was seen only after inhibition of COMT and not after inhibition of MAO only (the filling of the extraneuronal stores with unchanged noradrenaline being better after inhibition of COMT than when this enzyme was intact). The effect of corticosterone appeared to be reversible, that of phenoxybenzamine irreversible. 5. Analysis of the efflux of metabolites (in experiments in which only one enzyme was inhibited) indicated that corticosterone affected the efflux of noradrenaline but not that of the metabolites. 6. When either COMT or MAO was inhibited throughout the experiment, very little or no metabolism of noradrenaline occured during prolonged wash out. On the other hand, dis-inhibition of COMT during wash out (by the omission of U-0521 from the wash out solution after it had been present during the initial incubation) revealed that noradrenaline, stored extraneuronally during the initial incubation, is quickly O-methylated during wash out, especially when the efflux of the parent amine is inhibited by corticosterone. 7. The results show that COMT is the major extraneuronal noradrenaline-metabolizing enzyme of rabbit aorta, that inhibition of COMT is a pre-requisite for any corticosterone-sensitive accumulation of noradrenaline, that there are two important extraneuronal compartments (compartments III and IV; Henseling et al., 1976a), and that inhibitors of extraneuronal uptake inhibit both, influx and efflux of noradrenaline.

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PubMed1976

Factors determining the rate of relaxation of rabbit aortic strips after an exposure to noradrenaline.

1. When noradrenaline distributes exclusively into the: extraneuronal o-methylation of about one third of the extracellular space (i.e., when both, neuronal and extraneuronal uptake mechanisms are blocked by the presence of cocaine and corticosterone), the response of rabbit aortic strips to noradrenaline is concentration-dependent and relaxation curves (obtained during wash out and starting from different heights) are parallel. Under these conditions the "time required for relaxation to 50 or 20% of the initial contraction" (t50 and t20, respectively) is positively correlated with the initial height of contraction. 2. Measurements of the rate of relaxation that are independent of the height of the initial contraction are obtained either by appropriate correction of the t50 (or t20) or by determination of the "average rate of relaxation down to the 25% level of maximum contraction". 3. Relaxation experiments should a) be carried out with initial contractions of less than 75% of maximum and b) use a measure of the rate of relaxation that is independent of the initial height of contraction. 4. When the experimental conditions favour the extraneuronal accumulation of noradrenaline, corticosterone affects the relaxation of the strips in a way which is consistent with the view that efflux of unchanged amine from extraneuronal stores influences the rate of relaxation. 5. When extraneuonal uptake is operative and accumulation of noradrenaline is poor (i.e., when extraneuronal catechol-O-methyl transferase is intact), corticosterone affects relaxation in a way which is consistent with the view that normally the extraneuronal system serves as a site of loss. Under these conditions corticosterone prevented, during the first 5 min of wash out, the extracellularly distributed amine. 6. It is concluded that the experimental conditions of relaxation experiments determine whether the noradrenaline stores serve as a source of efflux of unchanged amine or as a site of loss.

Animals↗
PubMed1976

Relaxation of splenic strips during wash out with amine-free solution after an exposure to noradrenaline.

1. Strips were prepared from the spleens of normal or of reserpine-pretreated cats or rabbits. The strips were first exposed to (-)noradrenaline and then washed out with amine-free solution. 2. After inhibition of monoamine oxidase by pargyline "secondary sensitization" was prominent during the incubation with noradrenaline, and the early phase of quick relaxation was followed by a late phase of slow relaxation. The latter was cocaine-sensitive and has to be attributed to a slowly declining efflux of noradrenaline from adrenergic nerve endings. 3. Inhibition of catechol-O-methyl transferase by U-0521 or inhibition of extraneuronal uptake by hydrocortisone (cat) or corticosterone (rabbit) failed to alter relaxation. Apparently, an efflux of noradrenaline from extraneuronal stores plays little or no role in the relaxation of splenic strips. 4. During prolonged exposure to noradrenaline strips become desensitized to noradrenaline; on wash out of the amine, sensitivity is restored. As a consequence of this temporary desensitization the response to noradrenaline is not well maintained during prolonged exposure to this amine (when MAO is intact), and the relaxation curve is distorted (whenever a late phase of slow relaxation is prominent). 5. Indometacin enhances the sensitivity of rabbit (but not of cat) splenic strips to noradrenaline but fails to substantially alter relaxation curves. 6. When the distribution of noradrenaline is restricted to the extracellular space and when the concentration of the amine is varied over a wide range, essentially parallel relaxation curves are obtained on wash out, provided the initial contraction does not exceed 80% of maximum. For higher initial contractions relaxation is slowed during the first minute of wash out, probably because of the sigmoid shape of the dose-response curve.

Animals↗
PubMed1976

The effect of corticosterone on the fluxes of 3H-normetanephrine into and out of the extraneuronal compartments of the perfused rat heart.

1. Hearts were obtained from pargyline-pretreated rats and perfused with 40 nM 3H-normethanephrine for 21 min. 87 muM corticosterone reduced the accumulation of 3H-normethanephrine in the heart. 2. When the initial perfusion with 3H-normetanephrine was followed by perfusion of the hearts with amine-free solution for 90 min, efflux of radioactivity was determined. Analysis of efflux curves showed that, apart from its distribution into extracellular space and fluid content of cardiac cavities, radioactivity distributed mainly into one corticosterone-sensitive, extra-neuronal compartment (compartment III, half time for efflux about 6 min). 3. When corticosterone was added to the wash out solution only, it failed to affect the efflux of radioactivity. 4. Although monoamine oxidase was inhibited, some deaminated metabolites of normetanephrine were detected in the efflux. Efflux of 3H-metabolites was monophasic in about half the hearts (short half time corresponding to that of compartment III) and biphasic in the other half. The early phase of efflux (short half time) seemed to represent efflux of newly formed metabolite(s), while the late phase (if present) appeared to be due to efflux of metabolites formed early in the experiment. 5. While corticosterone is known to inhibit the extraneuronal influx and efflux of catecholamines, it appears to impair the influx of normetanephrine without affecting the efflux.

Animals↗
PubMed1976

The distribution of 3H-(+/-)noradrenaline in rabbit aortic strips after inhibition of the noradrenaline-metabolizing enzymes.

Rabbit aortic strips (nerve-free, reserpine-pretreated or normal) whose noradrenaline-metabolizing enzymes were inhibited (by in vitro treatment with 0.5 mM pargyline for 30 min and by the presence of 0.1 mM U-0521) were exposed to 1.18 muM 3H-(+/-)noradrenaline for 30 min (in most experiments). At the end of the incubation some strips were used for analysis of radioactivity (i.e., of noradrenaline and its metabolites), while for others the efflux of radioactivity was determined during 240 min of wash out with amine-free solution. An estimate of the original distribution of the amine into the various extraneuronal and neuronal compartments of the tissue was obtained by compartmental analysis of the efflux curves. 1. Extracellular amine distributes into "compartment I + II" (characterized by a half time for efflux of less than 1 min); compartment size and half time for efflux were similar to those obtained for 14C-sorbitol. 2. The extraneuronal accumulation of noradrenaline is a quickly equilibrating process which involves compartments III and IV (with half times for efflux of 3 and 11 min, respectively). Compartment IV represents not only extraneuronally but also neuronally distributed noradrenaline (see below, 4). 3. The neuronal accumulation of noradrenaline is a slowly equilibrating process which can be subdivided into axoplasmic and vesicular accumulation. 4. The axoplasmic accumulation of noradrenaline is associated with compartments IV and V (the latter characterized by a half time for efflux of 95 min). The half time of the efflux from compartment V was independent of the original filling of this compartment (the degree of filling having been varied by changes in the duration and the amine concentration of the incubation). 5. The vesicular accumulation of noradrenaline resulted in the appearance of a "bound fraction" (i.e., of amine not participating in the efflux determined during 240 min of wash out) and in an increase in the half time of the efflux from compartment V. 6. The results support the view that the rate of relaxation (of strips initially exposed to noradrenaline and then washed out) is affected by the efflux of unchanged amine from extraneuronal and neuronal stores.

Animals↗
PubMed1976

Stereoselectivity of the distribution of labelled noradrenaline in rabbit aortic strips after inhibition of the noradrenaline-metabolizing enzymes.

Rabbit aortic strips (nerve-free, reserpine-pretreated or normal) whose noradrenaline-metabolizing enzymes were inhibited (by in vitro treatment with 0.5 mM pargyline for 30 min and by the presence of 0.1mM U-0521) were exposed to 1.18 muM labelled (-)- or (+)noradrenaline for 30 min. At the end of the incubation period some strips were used for analysis of radioactive (i.e., of noradrenaline and its metabolites), while for others the efflux of radioactivity was determined during 250 min of wash out with amine-free solution. An estimate of the original distribution of the amine into the various extraneuronal and neuronal compartments of the tissue was obtained by compartmental analysis of the efflux curves. 1. The mechanisms responsible for the accumulation of radioactivity in extraneuronal and axoplasmic compartments lack stereoselectivity; the rate constants for the efflux of radioactivity from these compartments are the same for (-)- and (+)noradrenaline. 2. The accumulation of radioactivity in storage vesicles is stereospecific with preference for the (-)isomer. 3. Despite the use of enzyme inhibitors, the "late neuronal efflux" of radioactivity (i.e., the efflux collected between the 200th and 250th min of wash out) contained a considerable proportion of metabolites of noradrenaline. The metabolism of noradrenaline was stereoselective: while dihydroxyphenylglycol (DOPEG) was the predominant metabolite in the efflux from strips incubated with (-)noradrenaline, a considerable part of the efflux from strips incubated with the (+) isomer consisted of dihydroxymandelic acid and "O-methylated and deaminated" metabolites (in addition to DOPEG).

Animals↗
PubMed1976

The effect of cocaine on the distribution of labelled noradrenaline in rabbit aortic strips and on efflux of radioactivity from the strips.

Reserpine-pretreated or normal rabbit aortic strips (whose noradrenaline-metabolizing enzymes were inhibited by treatment with 0.5 mM pargyline and by the presence of 0.1 mM U-0521) were incubated with 1.18 muM labelled noradrenaline for 30 min. Subsequently, strips were either analysed or washed out with amine-free solution for 240 to 250 min. From the efflux curves the original distribution of radioactivity was estimated by compartmental analysis. 1. The accumulation of radioactivity in the strips was reduced by 30 muM cocaine to that observed for nerve-free strips. In reserpine-pretreated strips this was due to a partial reduction of the filling of comartment IV (characterized by a half time of efflux of 10 to 20 min; earlier evidence had already shown that part of this compartment is of neuronal origin; Hensling et al., 1976) and a pronounced decrease of the filling of compartment V (characterized by the longest half time). In normal strips the same changes were observed as well as pronounced reduction of the "bound fraction". Thus, cocaine reduced the filing of those compartments which had been identified as neuronal ones (Henseling et al., 1976). 2. When 30 muM cocaine was added to the wash out solution only, the neuronal efflux of radioactivity from reserpine-pretreated strips was accelerated, while the efflux from extraneuronal or extracellular compartments remained unaffected. This effect of cocaine was the same for (-)- and (+)noradrenaline, and its was not significaltly decreased when paired strips exposed to an inhibitor of extraneuronal uptake (86 muM corticosterone) throughout the experiment. In normal strips, cocaine had very little or no effect on the efflux of radioactivity. 3. The results are consistent with the view that cocaine impairs the influx of amine into the neurone, while block of re-uptake of unchanged amine is one of the determinants of its effect on the rate of efflux from the axoplasm. Comparison of efflux curves with corresponding relaxation curves (determined in the absence and presence of cocaine) indicates that, when both noradrenaline-metabolizing enzymes are inhibited, relaxation of the strips is accounted for by a) the efflux of unchanged amine from neuronal (and extraneuronal) stores and b) the sensitivity of the preparation to noradrenaline.

Animals↗
PubMed1975

Supersensitivity to catecholamines after impairment of extraneuronal uptake or catechol-O-methyl transferase.

In cat papillary muscle and nictitating membrane block of extraneuronal catechol-O-methyl transferase (COMT) by 3',4'-dihydroxy-alpha-methyl propiophenone (U-0521) or of extraneuronal uptake by hydrocortisone causes supersensitivity to catecholamines whenever the experimental conditions result in a high sensitivity of the organ to catecholamines. After block of monoamine oxidase the extraneuronal O-methylation of (-)-[3H]norepinephrine by the isolated nictiating membrane is due to two O-methylating systems (Km and Vmax: 7.5 muM and 0.73 nmoles - g-1 - min-1, and 131 muM and 8.5 nmoles - g-1 - min-1, respectively). Hydrocortisone (28 muM) blocked the activity of the high affinity system without affecting the low affinity system. Apparently, there exists an extraneuronal compartment of high affinity that has a hydrocortisone-sensitive uptake mechnism; this compartment influences the concentration of catecholamines below the Km of this compartment. Supersensitivity ensues when either uptake or enzyme is blocked. Since the sensitivity effects of U-0521 and hydrocortisone are not additive, the high affinity compartment must a) metabolize most of the catecholamine transported into the compartment, and b) have a limited storage capacity for catecholamines after block of COMT.

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