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  • 1
    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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  • 2
    Electronic Resource
    Electronic Resource
    Tetrodotoxin-sensitive and-resistant effects of veratridine on the noradrenergic neurone of the rat vas deferens (1983)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 324 (1983), S. 264-270 
    Details
    ISSN: 1432-1912
    Keywords: Veratridine ; Exocytotic release ; Neuronal efflux ; “Reserpine-like” effects ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1) The veratridine-induced release of 3H-noradrenaline from noradrenergic neurones was examined in the isolated vas deferens of either untreated or reserpine plus pargyline-pretreated rats. The rat vas deferens, whose catechol O-methyltransferase was inhibited, was first incubated with 0.4 μmol/l 3H-(−)noradrenaline (30 min) and then washed repeatedly with amine-free solution. After 120 min (i.e., well after the efflux of tritium from the tissue had reached a steady level and was predominantly of neuronal origin), washout was continued in the presence of veratridine for further 10–15 min. 2) In vasa deferentia of untreated rats, variatridine (1–100 μmol/l) caused a concentration-dependent increase in the efflux of tritium. At high concentrations of the drug (30 or 100 μmol/l), this increase in efflux was peak-like during the first 3 min (“peak response”) and then fell to a plateau (“plateau response”). In the presence of veratridine, unchanged 3H-noradrenaline accounted for about 75% of the tritium efflux (the rest being represented by deaminated 3H-catechol metabolites). 3) The “peak response” to veratridine (100 μmol/l) was abolished by tetrodotoxin (TTX; 1 μmol/l) or the absence of external Ca2+. Cocaine (10 μmol/l) affected neither the “peak response” as such nor the contribution by 3H-noradrenaline to the efflux of tritium during that response. Hence, the “peak response” was due to exocytotic release of 3H-noradrenaline from the neurone. 4) The “plateau response” to veratridine (100 μmol/l) was unaffected by the absence of external Ca2+, largely resistant to TTX (1 μmol/l) and moderately reduced by cocaine. However, both TTX and cocaine drastically changed the composition of the radioactivity during the “plateau response”: they greatly reduced or even abolished the efflux of unchanged 3H-noradrenaline and markedly increased the efflux of deaminated 3H-metabolites. Hence, the “plateau response” represented a “reserpine-like” vesicular effect of varatridine; the ensuing 3H-noradrenaline efflux out of the neurone was mediated by the neuronal amine carrier. 5) After pretreatment with reserpine (to inhibit vesicular uptake) and pargyline (to inhibit monoamine oxidase), veratridine (100 μmol/l) elicited a phasic, peak-like increase in the efflux of tritium (about 90% of which was unchanged 3H-noradrenaline). This response to veratridine was abolished by TTX (1 μmol/l) and unaffected by the absence of external Ca2+; moreover, it was greatly reduced by either cocaine (10 μmol/l) or desipramine (1 μmol/l) and, hence brought about by carrier-mediated outward transport across the axonal membrane. 6) It is concluded that, in addition to its well-known action on the fast sodium channel, veratridine somehow increases the leakage of noradrenaline from storage vesicles; this “reserpine-like” effect of veratridine is resistant to TTX and therefore not a consequence of the drug-induced changes in the sodium permeability of the axolemma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00502621
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  • 3
    Electronic Resource
    Electronic Resource
    The effect of cocaine on uptake of and sensitivity to noradrenaline in isolated nictitating membranes before and after storage in the cold (1970)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 267 (1970), S. 383-398 
    Details
    ISSN: 1432-1912
    Keywords: Cocaine ; Cold-Stored Tissues ; Neuronal Uptake of Nor-adrenaline ; Nictitating Membrane of Cat ; Supersensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were carried out on fresh isolated cat nictitating membranes as well as on muscles stored in the cold for 7 days. Storage reduced the cocaine-induced supersensitivity to (−)-noradrenaline but did not abolish it it also reduced responses to tyramine, and about halved the noradrenaline content of the tissue. Cocaine failed to potentiate responses of fresh or of stored muscles to the methoxamine (which is not taken up by adrenergic nerves). The incubation with 2.5 ml of 100 ng/ml of (−)-noradrenaline (in the presence of the inhibitor of catechol-O-methyl transferase), fresh muscles removed noradrenaline from the incubation medium at a rate of about 70 ng per gram of tissue per min; 10 Μg/ml of cocaine reduced rate of removal by 81%. Muscles stored in the cold removed less noradrenaline from the medium (about 45 ng/g×min−1) than fresh ones, and cocaine reduced the rate of removal by 56%. The neuronal uptake mechanism of the nictitating membrane does not seem to be stereoselective, since the rate of removal of (+)-noradrenaline from the incubation medium was similar to that of the (−)-isomer. It is concluded that cold storage of the muscle abolishes neither the neuronal uptake of noradrenaline nor the ability of cocaine to impair this uptake; however, both parameters were reduced. Since the sensitizing action of cocaine is similarly reduced, there is no reason to doubt the causal relation between impairment by cocaine of neuronal uptake and ensuing supersensitivity to (−)-noradrenaline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00997276
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  • 4
    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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  • 5
    Electronic Resource
    Electronic Resource
    The influence of block of catechol-O-methyl transferase on the sensitivity of isolated organs to catecholamines (1971)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 271 (1971), S. 59-92 
    Details
    ISSN: 1432-1912
    Keywords: Supersensitivity to Catecholamines ; Block of COMT-U-0521 ; V-0521 ; Isolated Nictitating Membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The sensitivity of various isolated organs to catecholamines was tested before and after block of catechol-O-methyl transferase (COMT) by U-0521 (3′,4′-dihydroxy-2-methyl propiophenone; 18 μg/ml for 20 min). Isolated Nictitating Membrane of the Cat. The sensitivity to catecholamines was increased by inhibition of COMT whenever the experimental conditions resulted in a high potency of the amine, i.e., when the ED50 of the amine (in the absence of U-0521) was below about 10−6 M. Thus, block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline after denervation (or in the presence of cocaine) but not on muscles with an intact adrenergic innervation; it also increased the sensitivity to theβ-effects but not to theα-effects of isoprenaline. No potentiation was observed for dopamine which has a low potency even after denervation. The relation between potency of the catecholamine and the degree of the sensitizing effect of U-0521 was not due to saturation of COMT or of access to the enzyme. Measurements in denervated muscles of the production of O-methylated metabolites from (±)-noradrenaline-H3 (added to the bath for 20 min in concentrations of about 10−7 to 10−4 M), and of the extraneuronal accumulation of noradrenaline-H3 did not reveal any saturation of either the enzyme or the extraneuronal accumulation of the amine. When block of COMT resulted in supersensitivity to a catecholamine, the time required to reach steady-state responses was usually increased. This is consistent with the view that block of the enzyme impaired a site of loss. Block of COMT failed to produce any substantial potentiation of the effects of the indirectly acting amines, tyramine and mephentermine. O-methylation of the released transmitter seems to occur after the amine has reached the receptors of the effector cells. Isolated Strips of Cat and Bat Spleen. Results were quantitatively similar, since block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline in the presence but not (or only very little) in the absence of cocaine. However, the degree of supersensitivity after block of COMT (in the presence of cocaine) was smaller than in the nictitating membrane. In the cat spleen, cocaine causes a small but significant degree of supersensitivity to isoprenaline but not to methoxamine. Isolated Sat Aorta, Block of COMT did not increase the effect of cocaine. It is suggested that differences in the morphology of the adrenergic innervation contribute to the observed organ differences.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01002173
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  • 6
    Electronic Resource
    Electronic Resource
    The effect of hydrocortisone on the sensitivity of the isolated nictitating membrane to catecholamines (1974)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 286 (1974), S. 1-48 
    Details
    ISSN: 1432-1912
    Keywords: Hydrocortisone ; Catecholamines ; Postjunctional Supersensitivity ; Extraneuronal COMT ; Nictitating Membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary On the isolated nictitating membrane of the cat the supersensitivity to catecholamines induced by hydrocortisone was compared with the ability of hydrocortisone to block the extraneuronal uptake and metabolism of catecholamines. 1. Supersensitivity to catecholamines was induced by hydrocortisone whenever the ED50 for the catecholamine (in the absence of hydrocortisone) was 10 μM or less. 2. The degree of hydrocortisone-induced supersensitivity was (-)-noradrenaline 〉 (-)-adrenaline 〉 (±)-isoprenaline; while 28 μM hydrocortisone sufficed to induce supersensitivity to noradrenaline and adrenaline, 280 μM were required for inducement of supersensitivity to isoprenaline. 3. Hydrocortisone had no potentiating effects after block of COMT (by 0.1 mM U-0521). 4. Hydrocortisone failed to affect the sensitivity to amines which are not substrates of COMT and also to indirectly acting sympathomimetic amines (tyramine, mephentermine). 5. The sensitivity experiments are consistent with the existence of a quickly equilibrating, extraneuronal O-methylating compartment with high affinity for catecholamines; it has a saturable, hydrocortisone-sensitive uptake mechanism and little or no capacity for storage of unchanged catecholamine. This postulated compartment influences the concentration of catecholamines in the biophase whenever the concentration of the catecholamine is below the K m of the compartment. 6. When COMT was blocked, hydrocortisone inhibited the distribution of 3H-(-)-noradrenaline into a quickly equilibrating extraneuronal compartment of small size. 7. In intact smooth muscles the extraneuronal O-methylation of 3H-(-)-noradrenaline and 3H-(±)-isoprenaline was carried out by two metabolizing compartments. One of these compartments had a high, the other a low affinity for catecholamines (apparent K m 7.5–12.8 and 131–201 μM, respectively). 8. Hydrocortisone inhibited the O-methylation of catecholamines by the high affinity compartment; an apparent non-competitive type of inhibition was obtained against (-)-normadrenaline and (±)-isoprenaline as substrates. 9. The biochemical experiments demonstrate the existence of an extraneuronal, saturable, hydrocortisone-sensitive O-methylating compartment with high affinity for catecholamines; this compartment equilibrates quickly with the concentration of the catecholamine in the medium and has little or no ability to accumulate unchanged catecholamines. 10. The biochemical results are in full agreement with the results from sensitivity studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00499103
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  • 7
    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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  • 8
    Electronic Resource
    Electronic Resource
    Time-dependent changes in neuronal net uptake of noradrenaline after pretreatment with pargyline and/or reserpine (1971)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 271 (1971), S. 1-28 
    Details
    ISSN: 1432-1912
    Keywords: Noradrenaline Uptake ; Block of Monoamine Oxidase ; Reserpine ; Axoplasmic Noradrenaline ; Perfused Rabbit Hearts
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Isolated rabbit hearts were perfused with 20 to 200 ng/ml of (−)-noradrenaline and arterio-venous differences were determined at various times to measure the rate of net removal of the amine from the perfusion fluid. Animals were untreated or pretreated with reserpine and/or pargyline to block vesicular retention and/or intraneuronal monoamine oxidase (MAO). The arterio-venous difference (in percent of the arterial concentration) remained rather constant during prolonged perfusions of untreated hearts with (−)-noradrenaline, the magnitude of the difference being inversely related to the arterial concentration. After block of MAO the rate of net removal declined exponentially with time; the rate of decline increased with increasing arterial concentration of the amine and also after the additional pretreatment with reserpine. The time-dependent decline in the rate of net removal was shown to be due to an increased efflux of the amine from the nerve endings. The net removal of noradrenaline-H3 at the 5th min of perfusion of pargyline-pretreated hearts was mainly due to neuronal net uptake, since a) O-methylation accounted for only 5% of the removal, and b) cocaine (10–30 (μg/ml) virtually abolished net removal. Initial rates of removal were not affected by the various pretreatments. In untreated hearts retention of exogenous (−)-noradrenaline increased linearly with the duration of the perfusion but the increase was exponential after block of MAO. Apparently, the storage capacity becomes exhausted during prolonged perfusions of pargyline-pretreated hearts. The ratio “noradrenaline retained by the heart/noradrenaline removed by the heart” was quite small in untreated (0.16), very small in reserpine-pretreated (0.03) and nearly unity in pargyline-pretreated hearts. It is concluded that any impairment of the intraneuronal mechanisms of inactivation (vesicular storage and MAO) leads to an increase in the axoplasmic concentration of free noradrenaline which causes an increased efflux of the amine, while the influx remains unchanged. The axoplasmic concentration of free noradrenaline seems to rise more after block of MAO than after pretreatment with reserpine and is most pronounced after both. Changes in the sensitivity of the pacemaker to (−)-noradrenaline were found to be correlated with changes in the rate of removal of the amine from the perfusion fluid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01002171
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  • 9
    Electronic Resource
    Electronic Resource
    Pharmacokinetics of ciprofloxacin after oral and intravenous administration in healthy volunteers (1984)
    Springer
    European journal of clinical microbiology & infectious diseases 3 (1984), S. 355-359 
    Details
    ISSN: 1435-4373
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The pharmacokinetics of ciprofloxacin (Bay o 9867) was examined after a single oral dose of 250 mg and a single intravenous dose of 100 mg respectively in six healthy male volunteers in an open, randomized crossover study. Although ciprofloxacin concentrations were measured in serum, plasma and urine by HPLC with fluorimetric detection and by microbiological assay, all pharmacokinetic calculations are based on the highly sensitive HPLC method only. The mean serum concentration of ciprofloxacin peaked approximately1 h after the oral dose (0.94 mg/l). The elimination half-life was about 4 h and the renal clearance was 4.75 ml/min·kg; both were independent of the route of administration. The total clearance (9.62 ml/min·kg) was about twofold higher than the renal clearance. The volume of distribution of the central compartment was calculated to be 0.16 l/kg and the total volume at steady state was 2.0 l/kg. About 27 % of the oral dose was excreted in urine, whereas the urinary recovery of the i.v. dose was 46 %. The absolute bioavailability of ciprofloxacin was found to be approximately 60 %. Ciprofloxacin appears to follow first-order, three compartment model kinetics.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01977494
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