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  • 1
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 268-274 
    Details
    ISSN: 1432-1912
    Keywords: Key wordsα1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diethyl-2,2′-cyanine (decynium22) and 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 μmol kg–1) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fall in diastolic blood pressure was 59% after decynium22 and 43% after disprocynium24 administration. The pharmacokinetics of decynium22 and disprocynium24 were similar; they were characterized by short half-lives for elimination (8.2 and 4.5 min, respectively) and very high plasma clearances (173 and 180 ml kg–1 min–1, respectively). The mechanism underlying the blood pressure-lowering effect of decynium22 was explored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA2 for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. In a membrane preparation from rat myocardium, decynium22 as well as disprocynium24 inhibited the specific binding of [125I]-2-[β-(4-hydroxy-3-iodophenyl)-ethylaminomethyl]-tetralone (125I-HEAT), a selective ligand to α1-adrenoceptors. The Ki‘s were 5.3 and 240 nmol l–1 for decynium22 and disprocynium24, respectively. The type of binding inhibition by decynium22 was competitive. It is concluded that the two inhibitors of extraneuronal monoamine transport decynium22 and disprocynium24 lower blood pressure by blocking α1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and α1-adrenoceptors clearly indicates that disprocynium24 is more suitable for studies designed to determine the role of extraneuronal monoamine transport in vivo. Considering its very fast elimination kinetics, disprocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171057
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  • 2
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 268-274 
    Details
    ISSN: 1432-1912
    Keywords: α1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diethyl-2,2′-cyanine (decynium22) and 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 μmol kg−1) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fall in diastolic blood pressure was 59% after decynium22 and 43% after disprocynium24 administration. The pharmacokinetics of decynium22 and disprocynium24 were similar; they were characterized by short half-lives for elimination (8.2 and 4.5 min, respectively) and very high plasma clearances (173 and 180 ml kg−1 min−1, respectively). The mechanism underlying the blood pressure-lowering effect of decynium22 was explored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA2 for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. In a membrane preparation from rat myocardium, decynium22 as well as disprocynium24 inhibited the specific binding of [125I]-2-[β-(4-hydroxy-3-iodophenyl)-ethy-laminomethyl]-tetralone (125I-HEAT), a selective ligand to α1-adrenoceptors. The Ki's were 5.3 and 240 nmol l−1 for decynium22 and disprocynium24, respectively. The type of binding inhibition by decynium22 was competitive. It is concluded that the two inhibitors of extraneuronal monoamine transport decynium22 and disprocynium24 lower blood pressure by blocking α1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and α1-adrenoceptors clearly indicates that disprocynium24 is more suitable for studies designed to determine the role of extraneuronal monoamine transport in vivo. Considering its very fast elimination kinetics, disprocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171057
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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
    Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline (1991)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 344 (1991), S. 720-727 
    Details
    ISSN: 1432-1912
    Keywords: Nitric oxide (EDRF) ; l-NG-Monomethyl-arginine ; Noradrenaline release ; Adrenaline release ; Anaesthetized rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary This study in the anaesthetized rabbit aimed at determining the role of nitric oxide (NO), the putative endothelium-derived relaxing factor, in the regulation of haemodynamics and the release into plasma of noradrenaline and adrenaline. Specific inhibition of NO formation was achieved by i.v. bolus injection of l-NG-monomethyl-arginine (l-NMMA; 3–100 mg kg−1). Phenylephrine was infused i.v. at constant rates (2.5–20 μg kg−1 min−1) in order to assess baroreflex-mediated changes in release due to direct peripheral vasoconstriction. Rates of noradrenaline and adrenaline release into plasma were determined by the radio-tracer technique. l-NMMA, but not d-NMMA, dose-dependently increased mean arterial pressure and total peripheral vasular resistance, whereas both heart rate and cardiac output decreased concomitantly. The corresponding ED50 values for l-NMMA ranged from 11.2 to 18.5 mg kg−1. Inhibition of NO formation by l-NMMA as well as phenylephrine infusion caused decreases in the plasma clearance of noradrenaline and adrenaline which were correlated with the drug-induced decreases in cardiac output. Both l-NMMA and phenylephrine reduced the rate of noradrenaline release into plasma as they increased total peripheral resistance. Moreover, the curvilinear relationship between these two parameters obtained for l-NMMA was virtually identical to that produced by phenylephrine, indicating that the reduction in noradrenaline release by l-NMMA is mediated solely by the baroreflex. From the l-NMMA-induced maximum inhibition of noradrenaline release, it is concluded that the counter-regulation against peripheral vasodilation by NO accounts for 69% of basal noradrenaline release. The baroreflex-sensitive component of noradrenaline release, as determined by the maximum inhibition of release induced by phenylephrine, amounted to 83% of basal release. l-NMMA also reduced the release into plasma of adrenaline; the maximum inhibition of release was 52%. However, when related to total peripheral resistance, this inhibition of adrenaline release was more pronounced than that induced by phenylephrine, suggesting that the formation of endogenous NO facilitates the release of adrenaline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00174757
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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    Total body, systemic and pulmonary clearance and fractional extraction of unlabelled and differently 3H-labelled noradrenaline in the anaesthetized rabbit (1988)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 338 (1988), S. 361-367 
    Details
    ISSN: 1432-1912
    Keywords: Noradrenaline clearance ; Fractional noradrenaline extraction ; Differently 3H-labelled noradrenaline ; Plasma DOPEG ; Anaesthetized rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Rabbits were anaesthetized with urethane/chloralose and infused intravenously with trace amounts of 3H-2,5,6-, 3H-7,8- or 3H-7-(-)noradrenaline either without or with unlabelled (\t-)noradrenaline being simultaneously infused (0.2 gg kg\t-1 min\t-1). To obtain clearance values and extraction ratios for the pulmonary, systemic and total circulation, steady-state concentrations of infused noradrenaline were determined in mixed central venous (C v) and arterial (C v) plasma. Heart rate and blood pressure were recorded via the carotid artery, and the dye dilution method was used to determine the cardiac output of plasma. 2. The simultaneous infusion of unlabelled noradrenaline, which increased plasma levels of noradrenaline by a factor of 5, had no significant effect on either heart rate, blood pressure or cardiac output (when determined at steady state of the noradrenaline infusion). 3. The simultaneous infusion of unlabelled noradrenaline did not affect the clearance values of any of the three type of 3H-noradrenaline. Moreover, the clearances of the various types of 3H-noradrenaline were virtually identical and agreed with that of unlabelled noradrenaline. However, the clearance of labelled and unlabelled noradrenaline from arterial plasma was 1.15 times higher than that from central venous plasma. This factor corresponded to the ratio of C v/C a and pointed towards net removal of noradrenaline from the pulmonary circulation. 4. The fractional pulmonary extractions [1 - (C a/C a)] of the three types of 3H-noradrenaline did not differ from each other and were not affected by the simultaneous infusion of unlabelled noradrenaline. Moreover, the fractional pulmonary extraction of endogenous noradrenaline resembled that of infused 3H- and unlabelled noradrenaline, suggesting that there was little, if any, overflow of endogenous noradrenaline into plasma during passage through the pulmonary circulation. 5. From the clearance of noradrenaline from mixed central venous plasma, its fractional pulmonary extraction and the cardiac output of plasma estimates of the following steady-state kinetic parameters for infused noradrenaline were obtained: pulmonary, systemic as well as total body clearance (13.4, 67.9, 72.6 ml kg\t-1 min\t-1) and fractional extraction (0.128, 0.650, 0.695). The rates at which infused noradrenaline was eliminated from the pulmonary and systemic circulation amounted to 18.4 and 81.6% of the total body elimination rate, respectively. 6. The infusion of unlabelled noradrenaline increased plasma levels of 3,4-dihydroxyphenylglycol (DOPEG) by a factor of 1.2. DOPEG concentrations in arterial plasma were 4.9% higher than those in mixed central venous plasma. Hence, there was some net formation of DOPEG in the pulmonary circulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172110
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  • 7
    Electronic Resource
    Electronic Resource
    Plasma 3,4-dihydroxyphenylglycol as a tool to assess the role of neuronal uptake in the anaesthetized rabbit (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 726-732 
    Details
    ISSN: 1432-1912
    Keywords: 3,4-Dihydroxyphenylglycol ; Presynaptic noradrenaline metabolism ; Noradrenaline infusion ; Desipramine ; Anaesthetized rabbit
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary (1.) The purpose of this study was to investigate the role of neuronal uptake in the appearance in plasma of the primary noradrenaline metabolite 3,4-dihydroxyphenylglycol (DOPEG). To this end, steady-state changes in mixed central-venous plasma concentrations of noradrenaline and DOPEG produced by noradrenaline infusions or by changes in sympathetic tone were determined in anaesthetized rabbits either under control conditions or after treatment with desipramine (2 mg kg−1). The steady-state kinetics of infused DOPEG were also evaluated. (2.) Infused DOPEG (2.9 nmol kg−1 min−1 i.v. for 75 min) reached steady-state concentrations in plasma within less than 30 min, disappeared from plasma with a half-life of 2.3 min and showed a total-body plasma clearance of 84.0 ml kg−1 min−1 (3.) Constant-rate infusions of noradrenaline (1.2–5.9 nmol kg−1). (min−1 i.v. for 75 min) produced increases in plasma noradrenaline and DOPEG concentrations which were linearly related to the rate of noradrenaline infusion. Thus, the plasma clearance of infused noradrenaline (75.8 ml kg−1). min−1 as well as the increase in plasma DOPEG expressed in % of that in plasma noradrenaline (9.4%) was virtually independent of the noradrenaline infusion rate. (4.) Desipramine reduced the plasma clearance of infused noradrenaline by 35.4% and the increment in plasma DOPEG relative to that in plasma noradrenaline by 75.3%. From these results and the plasma clearance of noradrenaline and DOPEG it was calculated that the rate at which presynaptically formed DOPEG appeared in plasma amounted to 7.9% of the rate of total noradrenaline removal and to 22.3% of the rate of neuronal uptake. (5.) The rate of appearance in plasma of DOPEG originating from the neuronal re-uptake of endogenous noradrenaline was 192.3 pmol (kg−1). min−1 suggesting that the rate of neuronal re-uptake amounted to 862.3 pmol (kg−1) min−1 (6.) The slope of the regression line relating plasma DOPEG to plasma noradrenaline concentrations under conditions of noradrenaline release exceeded that of the corresponding regression line observed during noradrenaline infusion by a factor of about 10. This difference in slope suggests that, in the absence of infused noradrenaline, the average noradrenaline concentration at all noradrenergic neuroeffector junctions of the rabbit is 3.2 times as high as that in plasma.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169681
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