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  • 1
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 344 (1991), S. 720-727 
    ISSN: 1432-1912
    Schlagwort(e): Nitric oxide (EDRF) ; l-NG-Monomethyl-arginine ; Noradrenaline release ; Adrenaline release ; Anaesthetized rabbit
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 2
    ISSN: 1432-1912
    Schlagwort(e): Key wordsα1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 3
    ISSN: 1432-1912
    Schlagwort(e): α1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 4
    ISSN: 1432-1912
    Schlagwort(e): Noradrenaline clearance ; Fractional noradrenaline extraction ; Differently 3H-labelled noradrenaline ; Plasma DOPEG ; Anaesthetized rabbit
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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  • 5
    Digitale Medien
    Digitale Medien
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 726-732 
    ISSN: 1432-1912
    Schlagwort(e): 3,4-Dihydroxyphenylglycol ; Presynaptic noradrenaline metabolism ; Noradrenaline infusion ; Desipramine ; Anaesthetized rabbit
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
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