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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    Electronic Resource
    Electronic Resource
    Early intraneuronal mobilization and deamination of noradrenaline during global ischemia in the isolated perfused rat heart (1987)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 336 (1987), S. 508-518 
    Details
    ISSN: 1432-1912
    Keywords: Myocardial ischemia ; Noradrenaline ; Amine carrier ; Noradrenaline metabolism
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Isolated rat hearts were perfused according to the Langendorff technique and both extraneuronal uptake of noradrenaline and COMT were inhibited. The noradrenergic neurones were first prelabelled with 3H-(−)-noradrenaline (13 nmol/1). Thereafter the hearts were submitted to global ischemia (perfusion rate reduced from 5 up to 0.5 ml/min) for 60 min and subsequently reperfused for 5 min. The coronary effluent was continuously collected and analyzed for the appearance of 3H-noradrenaline and its metabolites. 1. Global ischemia was associated with an early release of 3H-noradrenaline. At reperfusion a brisk increase in the FRL of 3H-noradrenaline was observed which may indicate that, on severe restriction in coronary flow, perfusion of the tissue became heterogenous and thus partially masked the amount of 3H-noradrenaline released from the noradrenergic nerve terminals. Gradual reduction in coronary flow also progressively reduced (but did not abolish) the total formation of 3H-DOPEG. 2. The maximal efflux of 3H-noradrenaline was observed during the 1st min of reperfusion whereafter the efflux declined rapidly, indicating a wash-out of transmitter trapped in the extracellular space. The efflux of the lipophilic metabolite 3H-DOPEG, on the other hand, continuously increased during the reperfusion. This was due to both new formation and “wash-out” of 3H-DOPEG retained and/or distributed into the tissue during the period of restricted flow. 3. Neither a reduction of the extracellular calcium concentration (from 2.6 mmol/l to 0.1 mmol/1) nor the presence of the calcium entry blocker verapamil (250 nmol/l) reduced the efflux of 3H-noradrenaline seen during ischemia and reperfusion. 4. Desipramine (100 nmol/l) markedly reduced the ischemia-induced release of 3H-noradrenaline and simultaneously attenuated the formation of 3H-DOPEG. 5. A moderate reduction in the ischemia-induced mobilization of 3H-noradrenaline was seen in hearts perfused with 1μol/l reserpine, whereas the formation of 3H-DOPEG from such hearts was markedly higher than in corresponding controls. Only minor deviations from this pattern was observed when desipramine was present in addition to reserpine. It is concluded that a severe restriction in myocardial perfusion rate is associated with an enhanced net leakage of vesicular noradrenaline. This results in a rise of the free axoplasmic noradrenaline concentration which, in combination with an altered transmembrane sodium gradient, induces an increased local release of noradrenaline partly mediated by a calcium-independent, carrier-mediated outward transport. Desipramine, which inhibits this transport mechanism, may have, in addition to its effect on the membrane carrier, an additional effect in reducing the net leakage of transmitter from storage vesicles. Furthermore, despite severe restriction in coronary flow, and thus oxygen delivery, DOPEG is still formed, possibly as a consequence of the elevated axoplasmic noradrenaline concentration which may in part compensate for a reduced monoamineoxidase activity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00169307
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  • 7
    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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  • 8
    Electronic Resource
    Electronic Resource
    The heterogeneity of the neuronal distribution of exogenous noradrenaline in the rat vas deferens (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 160-170 
    Details
    ISSN: 1432-1912
    Keywords: Rat vas deferens ; Heterogeneous labelling ; 3H-noradrenaline ; Desipramine ; Inhibition of vesicular uptake
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary After loading of the incubated rat vas deferens with 0.2 μmol/l 3H-noradrenaline (followed by 100 min of wash-out with amine-free solution), the efflux of endogenous and exogenous compounds was determined by HPLC with electrochemical detection and by column chromatography with scintillation counting. Two different types of heterogeneity of labelling were found. The first one is due to the preferential labelling of varicosities close to the surface of the tissue, the second one to the preferential labelling of vesicles close to the surface of loaded varicosities. As diffusion distances within the tissue and within varicosities are then longer for endogenous than for exogenous amine and metabolites, the composition of spontaneous efflux of exogenous compounds differed from that for endogenous compounds. Because of preferential neuronal and vesicular re-uptake of endogenous noradrenaline, the percentage contribution by noradrenaline to overall efflux was: endogenous 〈 exogenous. While 3H-DOPEG was the predominant exogenous metabolite, DOPEG and MOPEG equally contributed to the “endogenous” efflux. Desipramine abolished the consequences of the first heterogeneity of labelling, i.e., it increased the efflux more for endogenous than for exogenous noradrenaline; moreover it decreased the efflux of 3H-DOPEG, but increased that of 3H-MOPEG. The reserpine-like compound Ro 41284, on the other hand, abolished the consequences of the second type of heterogeneity; it reduced the specific activity of “total efflux” (i.e., of the sum of noradrenaline + DOPEG + MOPEG) to the specific activity of the tissue noradrenaline. The degree of heterogeneity of labelling was reduced after inhibition of monoamine oxidase and also when the tissues were loaded with 2 or 20 μmol/l 3H-noradrenaline. It is proposed that the various “compartments” and “pools” of noradrenaline described in the literature reflect the two heterogeneities described here.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00166959
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  • 9
    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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  • 10
    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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