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  • 1
    Electronic Resource
    Electronic Resource
    The effect of newα-glucosidase inhibitors (BAY m 1099 and BAY o 1248) on meal-stimulated increases in glucose and insulin levels in man (1986)
    Springer
    Journal of molecular medicine 64 (1986), S. 393-396 
    Details
    ISSN: 1432-1440
    Keywords: α-Glucosidase inhibitor ; Healthy volunteers ; Blood glucose ; Serum insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To confirm findings obtained from animal experiments demonstrating the metabolic effect of two new glucosidase inhibitors, 7 single blind cross-over studies with 42 healthy male volunteers were performed. In each group 6 subjects received 25, 50, 100 and 200 mg BAY m 1099 and 10, 20, and 40 mg BAY o 1248 or placebo with a standardized breakfast. Blood glucose and serum insulin were measured in venous blood before and 30, 60, 90, 120 and 180 min after each of 3 meals. ECG, blood pressure, body weight, monitor ECG and haematological and clinico-chemical parameters were also examined. The postprandial increase in blood glucose and serum insulin after breakfast were significantly and dose-dependently reduced by BAY m 1099. 10 and 20 mg BAY o 1248 not only reduced the increases in blood glucose and serum insulin after breakfast, but also after lunch (10 mg). 40 mg BAY o 1248 prevented the postprandial increase in both metabolic parameters after breakfast (p〈0.05), an effect which was sustained after lunch. Intestinal problems occurred (flatulence, meteorism, diarrhoea) in 25 of 42 volunteers. Objective tolerability was good. The results of these first clinical pharmacological studies with two new glucosidase inhibitors justify studies on patients with diabetes mellitus.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01728191
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  • 2
    Electronic Resource
    Electronic Resource
    Plasma concentrations of noradrenaline and 3,4-dihydroxyphenylethyleneglycol under conditions of enhanced sympathetic activity (1988)
    Springer
    European journal of clinical pharmacology 35 (1988), S. 261-267 
    Details
    ISSN: 1432-1041
    Keywords: noradrenaline ; desipramine ; plasma DOPEG ; sympathetic tone ; orthostatic stress ; bicycle exercise
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Antecubital venous blood was sampled at rest and during orthostasis or supine bicycle exercise. The plasma was analyzed for noradrenaline and 3,4-dihydroxyphenylethyleneglycol (DOPEG) by HPLC. Orthostasis resulted in increases in plasma concentrations of both noradrenaline and DOPEG. The magnitude of changes in both was dependent on the degree of orthostasis. In conditions of supine rest, sitting, and standing the plot of the geometric mean values of plasma DOPEG (ordinate) against those of plasma noradrenaline was linear, had a slope of about unity, and intersected the ordinate at a finite value of plasma DOPEG. After administration of desipramine (to block uptake1), plasma concentrations of DOPEG fell both at rest and during orthostasis. Moreover, desipramine abolished the plasma DOPEG response to orthostasis without affecting the plasma noradrenaline response. Hence, changes in plasma DOPEG brought about by changes in sympathetic tone are presynaptic in origin. The plasma concentration of DOPEG observed in the presence of desipramine was virtually identical with the ordinate intercept of the regression line relating plasma DOPEG to plasma noradrenaline in the absence of desipramine. This pool of plasma DOPEG (which amounted to about 75% of that observed at supine rest in the absence of desipramine) probably stems from intraneuronal noradrenaline leaking out of the storage vesicles of peripheral sympathetic neurones and may in part also be derived from the central nervous system. Supine bicycle exercise failed to increase plasma DOPEG. This may be due to the separation of the sampling site from the site of noradrenaline release (i.e. the exercising limbs) by organs involved in DOPEG extraction. The failure of plasma DOPEG to rise under these conditions may also be a consequence of increased blood flow in the exercising limbs, resulting in a marked decrease in the proportion of the released noradrenaline being recaptured by the sympathetic nerve endings.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558263
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  • 3
    Electronic Resource
    Electronic Resource
    Haemodynamics as a determinant of the pharmacokinetics of and the plasma catecholamine responses to isoprenaline (1989)
    Springer
    European journal of clinical pharmacology 37 (1989), S. 493-500 
    Details
    ISSN: 1432-1041
    Keywords: isoprenaline ; desipramine ; total body fractional extraction ; cardiac output ; plasma catecholamines ; neuronal uptake ; sympathetic tone
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The total body clearance and fractional extraction of isoprenaline (ISO) have been determined, and the relation between these parameters and cardiac output established. Whether desipramine, an inhibitor of neuronal uptake, altered the plasma catecholamine response to ISO was also investigated. Seven healthy subjects were given i.v., infusions of ISO in two, consecutive 25-min periods, at constant dose rates of 31–43 and 80–124 pmol·kg−1·min−1, respectively. The total-body (ER), pulmonary (ERp) and forearm (ERf) fractional extractions and the total body clearance (CL) of ISO were obtained from measurements of cardiac output and the steady-state ISO concentration in mixed central venous, arterial and forearm venous plasma. ISO-induced increases in cardiac output resulted in increases in CL, decreases in ER and no consistent change in ERf. ERp did not differ from zero. ISO also produced a dose-dependent increase in the mixed venous plasma concentrations of noradrenaline and 3,4-dihydroxyphenylglycol (DOPEG), and a decrease in that of adrenaline. Pretreatment with desipramine did not alter any of the pharmacokinetic parameters of ISO. Desipramine, however, reduced the mixed venous baseline plasma levels of noradrenaline (47%) and DOPEG (40%), and tended to reduce that of adrenaline (34%). It enhanced the plasma noradrenaline response 2.4-fold, abolished the plasma DOPEG response and did not alter the plasma adrenaline response to ISO. Hence, owing to its haemodynamic effects, ISO modifies its own pharmacokinetics which involve non-neuronal removal processes only. The increased DOPEG in plasma resulting from the ISO-induced increase in noradrenaline release was presynaptic in origin. Desipramine appears to reduce sympathetic activity. The enhancement by desipramine of the ISO-induced increase in plasma noradrenaline points towards recapture by neuronal uptake of at least 58% of the noradrenaline released in response to ISO.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00558130
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  • 4
    Electronic Resource
    Electronic Resource
    Cardiovascular Effects of Dihydropyridine Calcium Channel Antagonists and Their Relation to Drug Levels in Plasma (1988)
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 522 (1988), S. 0 
    Details
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1749-6632.1988.tb33406.x
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  • 5
    Electronic Resource
    Electronic Resource
    Sodium-dependence of the saturability of carrier-mediated noradrenaline efflux from noradrenergic neurones in the rat vas deferens (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 332 (1986), S. 131-134 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal efflux ; Noradrenaline carrier ; Veratridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The carrier-mediated transport of 3H-noradrenaline out of noradrenergic neurones was studied in vasa deferentia obtained from rats after pretreatment with reserpine and pargyline (to inhibit vesicular storage and monoamine oxidase, respectively). The tissue was first preincubated with various concentrations of 3H-noradrenaline (0.3–100 μmol/l; 30 min) and then washed out for 110 min with amine-free medium. During the last 10 min of washout, carrier-mediated neuronal efflux of 3H-noradrenaline was elicited by exposure to either Na+-free medium or 100 μmol/l veratridine; it was measured at 1-min intervals. 2. While the peak rates of carrier-mediated 3H-noradrenaline efflux elicited by Na+-free medium were linearly related to the 3H-noradrenaline content of the tissue (which cannot be raised beyond a certain maximal value, since uptake is saturable), those evoked in response to veratridine approached saturation as the 3H-noradrenaline level in the tissue was raised. Hence, saturation of 3H-noradrenaline outward transport was demonstrated at high (exposure to veratridine), but not at low (exposure to Na+-free medium) intraneuronal Na+ concentrations. 3. The results indicate that the K m for the mediated outward transport of noradrenaline across the plasma membrane of noradrenergic neurones is inversely related to the internal Na+ concentration, just as the K m for the mediated inward transport of noradrenaline (i.e., the neuronal noradrenaline uptake) is inversely related to the external Na+ concentration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00511402
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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
    Choline+: A substrate of the neuronal noradrenaline carrier in the rat vas deferens (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 223-227 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal noradrenaline carrier ; Choline+ ; Accelerative exchange diffusion ; Substitution for Na+ ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. The effects of choline+ (10–40 mmol/l) on 3H-noradrenaline uptake by, and 3H-noradrenaline efflux from, noradrenergic neurones were studied in vasa deferentia of reserpine-pretreated rats at an external Na+ concentration of 100 mmol/l. Monoamine oxidase and catechol-O-methyltransferase were inhibited. 2. Choline+ (20 and 40 mmol/l) competitively inhibited the neuronal uptake of 3H-noradrenaline. From the choline+-induced changes in the apparent Km for 3H-noradrenaline transport, a Ki of 35 mmol/l was obtained. 3. Choline+ (10, 20 and 40 mmol/l) accelerated the neuronal efflux of 3H-noradrenaline in a concentration-dependent manner. This acceleration of efflux was greatly reduced in the presence of 1 μmol/l desipramine, indicating that choline+ is capable of eliciting “accelerative exchange diffusion”. 4. Choline+ (40 mmol/l) and (−)noradrenaline (4.5 μmol/l) (i.e., concentrations about equivalent to the Ki and Km for choline+ and (−)noradrenaline, respectively) produced virtually identical increases in the neuronal efflux of 3H-noradrenaline. 5. Choline+ (3–300 mmol/l) inhibited the specific binding of 3H-desipramine to plasma membranes derived from cultured rat phaeochromocytoma (PC-12) cells. The Ki for this interaction was 48 mmol/l. 6. This results suggest that choline+ acts as alternative substrate of the neuronal noradrenaline transport system and should, therefore, not be used in transport studies with noradrenaline as substitute for Na+ in Na+-deficient media.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00508775
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  • 8
    Electronic Resource
    Electronic Resource
    Failure of K+ to affect the potency of inhibitors of the neuronal noradrenaline carrier in the rat vas deferens (1987)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 335 (1987), S. 250-254 
    Details
    ISSN: 1432-1912
    Keywords: High K+ ; Neuronal uptake ; Inhibition of neuronal uptake ; Potencies of uptake inhibitors ; Rat vas deferens
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. To examine whether K+ affects the potency of inhibitors of neuronal uptake, experiments were carried out in the rat vas deferens after pretreatment of the animals with reserpine and after inhibition of monoamine oxidase and catechol-O-methyltransferase. Initial rates of the neuronal uptake of 3H-noradrenaline and IC50 values for uptake inhibition by desipramine, cocaine and (−)metaraminol were determined in the presence of various concentrations of external K+ (5–45 mmol/l), both at 100 mmol/l Na+ and 50 mmol/l Na+. 2. When measured at the 3H-noradrenaline concentration used to determine IC50 values (0.024 μmol/l), neuronal uptake was progressively impaired by increasing K+ concentrations at 50, but not at 100 mmol/l Na+. 3. Neither at 100 mmol/l Na+ nor at 50 mmol/l Na+ was there any consistent, concentration-dependent effect of K+ on the IC50 values of desipramine, cocaine and (−)metaraminol. 4. The analysis of the saturation kinetics of 3H-noradrenaline uptake (determined in the presence of 50 mmol/l Na+ at 5 mmol/l K+ or 45 mmol/l K+) showed that high K+ concentrations inhibit neuronal uptake by decreasing V max without any change in K max. 5. The results indicate that K+ does not competitively interact with Na+ at sites on the noradrenaline carrier which mediate the tansport-stimulating properties of Na+ Hence, the inhibition of neuronal uptake produced by high K+ concentrations is probably due to membrane depolarization which simply reduces V max.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00172792
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  • 9
    Electronic Resource
    Electronic Resource
    Sodium-dependence of the potency of inhibitors of the neuronal noradrenaline carrier in the rat vas deferens (1986)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 334 (1986), S. 397-402 
    Details
    ISSN: 1432-1912
    Keywords: Neuronal noradrenaline carrier ; Inhibition of transport-Na+-dependence ; Desipramine ; Cocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Vasa deferentia obtained from reserpine-pretreated rats were incubated (monoamine oxidase and catechol-O-methyltransferase inhibited) in media containing various concentrations of3H-(−)noradrenaline and Na+ and initial rates of the neuronal uptake of3H-noradrenaline measured both in the absence and presence of uptake inhibitors after 1 min of incubation. 2. When rates of uptake were determined at various3H-noradrenaline (1.0–12.2 μmol/l) and two fixed Na+ concentrations (25 and 140 mmol/l), the inhibition of uptake produced by (+)amphetamine, (−)metaraminol, desipramine, nomifensine and cocaine was competitive with respect to3H-noradrenaline at both Na+ concentrations. While theK i for (+)amphetamine, (−)metaraminol desipramine and nomifensine increased when the Na+ concentration was lowered, that for cocaine decreased. 3. When the Na+ concentration was varied (10–140 mmol/l) and the3H-noradrenaline concentration held constant (1.2 μmol/l), (+)amphetamine, (−)metaraminol, nomifensine and desipramine acted as mixed-type inhibitors with respect to Na+, and the inhibition of uptake produced by these drugs was the more pronounced, the higher the Na+ concentration. On the other hand, cocaine was competitive with Na+ and the inhibition produced by this drug was the more pronounced, the lower the Na+ concentration. 4. It is concluded that the inhibitors of neuronal uptake tested here act in dependence on the external Na+ concentration. Desipramine and nomifensine resemble alternative amine substrates in being more potent at high than at low Na+ concentrations. On the other hand cocaine is more potent at low than at high Na+ concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00569377
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  • 10
    Electronic Resource
    Electronic Resource
    Chloride-dependence of the potency of inhibitors of the neuronal noradrenaline carrier in the rat vas deferens (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 65-70 
    Details
    ISSN: 1432-1912
    Keywords: Cl−-dependence ; Neuronal uptake ; Inhibition of neuronal uptake ; Desipramine ; Cocaine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary (1) Vasa deferentia obtained from reserpine-pretreated rats were exposed to 0.15 μmol 1−1 3H-(−)noradrenaline (with monoamine oxidase and catechol-O-methyltransferase being inhibited) and initial rates of the neuronal 3H-noradrenaline uptake as well as IC50 values for inhibition of uptake by desipramine, cocaine or (−)metaraminol determined at various external Cl− concentrations (0–145 mmol 1−1) and a fixed high Na+ concentration (145 mmoll−1). (2) When the Cl− concentration in the medium was decreased neuronal uptake fell. As far as Cl− concentrations ranging from 10 to 145 mmol 1−1 are concerned, the dependence of uptake on Cl− obeyed Michaelis-Menten kinetics with an apparent K m and V max of 6.2 mmol 1−1 and 116 pmol g−1 min−1, respectively. At Cl− concentrations below 10 mmol l−1, uptake was higher than expected from the values of K m and V max, and even in the nominal absence of Cl− from the medium a remainder of neuronal uptake was still detectable. Evidence is presented to show that, on incubation at Cl− concentrations below 10 mmol l−1, intracelluar Cl− leaks out, so that the actual Cl− concentrations in the extracellular fluid are probably higher than in the medium. (3) The potencies of desipramine and cocaine for inhibition of neuronal uptake were markedly dependent on the Cl− concentration in the medium, but the type of Cl− dependence differed. While the IC50 for desipramine decreased, that for cocaine increased with increasing Cl− concentration (2–145 mmol l−1). The value of IC50 for cocaine and that of 1/IC50 for desipramine approached saturation (with an apparent Hill coefficient of about unity) when plotted against the Cl− concentration; half-maximum values were observed at Cl− concentrations of 9 and 24 mmol l−1, respectively. (4) (−)Metaraminol (an alternative substrate of the noradrenaline carrier) remained equally potent in inhibiting neuronal uptake when the Cl− concentration was decreased from 145 to 2 mmol l−1. However, when Cl− was omitted from the medium, the IC50 for (−)metaraminol increased. Hence, the C−-dependence of the potency of (−)metaraminol appears to be restricted to very low extracellular Cl− concentrations. (5) It is concluded that not only the neuronal uptake process itself, but also its inhibition by desipramine and cocaine are highly Cl−-dependent. Since desipramine and cocaine differ with respect to the type of Cl−-dependence of their inhibitory potency, they are likely to act by combining with distinctly different states of the noradrenaline carrier. It is suggested that desipramine interacts with the carrier loaded with Cl− while cocaine is capable of interacting with its Cl−-free state.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00165128
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