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PubMed1981

The extraneuronal O-methylation of 3H-(+)isoprenaline by guinea-pig tracheal rings in vitro.

Tracheal rings isolated from male guinea-pigs and incubated in Krebs' solution at 37 degrees C O-methylated 3H-(+/-)-isoprenaline by a saturable, high affinity mechanism. 1. With 3H-isoprenaline at 1 mumol . 1-1, O-methyl 3H-(+/-)isoprenaline (3H-OMI) appeared in the tissue with a half-time for approach to steady state of approximately 10 min and was measured in the incubation medium after about 5 min, its concentration increasing linearly thereafter. With 3H-isoprenaline concentrations ranging from 1 to 200 mumol . 1-1, the total formation of 3H-OMI (estimated from that contained in the tissue and the medium) was maintained at steady state rates for up to 60 min, after initial lag times of between 1 and 3 min. O-methylation obeyed Michaelis-Menten saturation kinetics; Km = 6.14 +/- 0.13 mumol . 1-1, Vmax = 0.31 +/- 0.01 nmol . g-1 . min-1. 2. The catechol-O-methyl transferase (COMT) inhibitor U-O521 and the extraneuronal uptake inhibitor corticosterone both reduced O-methylation of 3H-isoprenaline (0.1 mumol . 1-1) by tracheal rings. However, U-O521 was fully inhibitory (IC50 = 2.6 mumol . 1-1), but corticosterone inhibited by only 46% at concentrations up to 1 mmol . 1-1. 3. The O-methylating activity of the "smooth muscle-rich" component of the trachea was approximately three-times greater than for complete tracheal rings. However, considerable activity was also associated with "cartilage-rich", "smooth muscle-poor" sections. This activity did not seem to be associated with endothelial cells. 4. Histamine strongly inhibited O-methylation (IC50 = 30 mumol . 1-1), but two other contractile agonists, 5-hydroxytryptamine and bethanechol, were weakly active and inactive, respectively.

Animals↗
PubMed1984

Vasoconstrictor and norepinephrine potentiating action of 5-hydroxykynuramine in the isolated perfused rat kidney: involvement of serotonin receptors and alpha 1-adrenoceptors.

Kynuramines are endogenously occurring diamines derived from tryptophan. In the present study, we have compared the pharmacological actions of 5-hydroxykynuramine (5-OH-K) with kynuramine and 5-hydroxytryptamine (5-HT) on vascular resistance changes and responsiveness to adrenergic stimuli in the isolated perfused rat kidney. 5-OH-K was found to mimic the actions of 5-HT in that it produced vasoconstriction, potentiation of alpha 1-adrenoceptor-mediated responses to norepinephrine (NE) and periarterial nerve stimulation, and displaced specific [3H]spiroperidol binding from rat cortical membranes. With regard to all parameters measured, 5-OH-K was about 15-times less active than 5-HT. Vascular responses to 5-OH-K and 5-HT were inhibited noncompetitively by ketanserin and cyproheptadine. Unlike 5-OH-K, kynuramine, failed to evoke vasoconstriction and inhibited vascular responses to NE via alpha 1-adrenoceptors. Thus, kynuramine lacks serotonin receptor agonist activity but possesses alpha 1-adrenoceptor blocking properties. In contrast, 5-OH-K potentiates NE and acts as a serotonin agonist. The present results raise the possibility that kynuramine and 5-OH-K might act as endogenous modulators of serotonergic and adrenergic mechanisms in the renal vascular bed.

Animals↗
PubMed1984

Effect of ovarian steroids on the metabolism of noradrenaline in rabbit uterus.

The metabolism of (-)-3H-noradrenaline was examined in uterine slices from ovariectomized rabbits which were either untreated or treated with 17 beta-oestradiol, alone or in combination with progesterone. 17 beta-oestradiol caused uterine enlargement which was not accompanied by a change in the formation per g of O-methylated metabolites (3H-NMN, 3H-VMA, 3H-MOPEG). Accumulation of unchanged 3H-noradrenaline and the formation of deaminated catechols (3H-DOMA and 3H-DOPEG) were decreased per g tissue, but increased per uterine horn. Progesterone produced further enlargement of the oestrogen-dominated uteri which was accompanied by (a) a decrease in deaminated catechol formation and (b) an increase in 3H-NMN formation per unit mass of tissue. In all uteri (control and hormone-treated), cocaine inhibited the formation of deaminated catechols, but not that of the O-methylated metabolites. It is suggested, therefore, that, per unit of uterine mass, the neuronal deamination of (-)-3H-noradrenaline is decreased by 17 beta-oestradiol and further decreased by progesterone, and that these changes reflect failure of the intraneuronal deaminating system in the whole uterus to increase in proportion to the increase in uterine mass. Since other agents which decreased the deamination of (-)-3H-noradrenaline (cocaine and nialamide) did not affect 3H-NMN formation in oestrogen-dominated uteri, it is suggested that stimulation of 3H-NMN formation represents a direct effect of progesterone on the extraneuronal O-methylation of noradrenaline.

Animals↗
PubMed1976

The distribution of 3H-(+/-)noradrenaline in rabbit aortic strips after inhibition of the noradrenaline-metabolizing enzymes.

Rabbit aortic strips (nerve-free, reserpine-pretreated or normal) whose noradrenaline-metabolizing enzymes were inhibited (by in vitro treatment with 0.5 mM pargyline for 30 min and by the presence of 0.1 mM U-0521) were exposed to 1.18 muM 3H-(+/-)noradrenaline for 30 min (in most experiments). At the end of the incubation some strips were used for analysis of radioactivity (i.e., of noradrenaline and its metabolites), while for others the efflux of radioactivity was determined during 240 min of wash out with amine-free solution. An estimate of the original distribution of the amine into the various extraneuronal and neuronal compartments of the tissue was obtained by compartmental analysis of the efflux curves. 1. Extracellular amine distributes into "compartment I + II" (characterized by a half time for efflux of less than 1 min); compartment size and half time for efflux were similar to those obtained for 14C-sorbitol. 2. The extraneuronal accumulation of noradrenaline is a quickly equilibrating process which involves compartments III and IV (with half times for efflux of 3 and 11 min, respectively). Compartment IV represents not only extraneuronally but also neuronally distributed noradrenaline (see below, 4). 3. The neuronal accumulation of noradrenaline is a slowly equilibrating process which can be subdivided into axoplasmic and vesicular accumulation. 4. The axoplasmic accumulation of noradrenaline is associated with compartments IV and V (the latter characterized by a half time for efflux of 95 min). The half time of the efflux from compartment V was independent of the original filling of this compartment (the degree of filling having been varied by changes in the duration and the amine concentration of the incubation). 5. The vesicular accumulation of noradrenaline resulted in the appearance of a "bound fraction" (i.e., of amine not participating in the efflux determined during 240 min of wash out) and in an increase in the half time of the efflux from compartment V. 6. The results support the view that the rate of relaxation (of strips initially exposed to noradrenaline and then washed out) is affected by the efflux of unchanged amine from extraneuronal and neuronal stores.

Animals↗
PubMed1976

Stereoselectivity of the distribution of labelled noradrenaline in rabbit aortic strips after inhibition of the noradrenaline-metabolizing enzymes.

Rabbit aortic strips (nerve-free, reserpine-pretreated or normal) whose noradrenaline-metabolizing enzymes were inhibited (by in vitro treatment with 0.5 mM pargyline for 30 min and by the presence of 0.1mM U-0521) were exposed to 1.18 muM labelled (-)- or (+)noradrenaline for 30 min. At the end of the incubation period some strips were used for analysis of radioactive (i.e., of noradrenaline and its metabolites), while for others the efflux of radioactivity was determined during 250 min of wash out with amine-free solution. An estimate of the original distribution of the amine into the various extraneuronal and neuronal compartments of the tissue was obtained by compartmental analysis of the efflux curves. 1. The mechanisms responsible for the accumulation of radioactivity in extraneuronal and axoplasmic compartments lack stereoselectivity; the rate constants for the efflux of radioactivity from these compartments are the same for (-)- and (+)noradrenaline. 2. The accumulation of radioactivity in storage vesicles is stereospecific with preference for the (-)isomer. 3. Despite the use of enzyme inhibitors, the "late neuronal efflux" of radioactivity (i.e., the efflux collected between the 200th and 250th min of wash out) contained a considerable proportion of metabolites of noradrenaline. The metabolism of noradrenaline was stereoselective: while dihydroxyphenylglycol (DOPEG) was the predominant metabolite in the efflux from strips incubated with (-)noradrenaline, a considerable part of the efflux from strips incubated with the (+) isomer consisted of dihydroxymandelic acid and "O-methylated and deaminated" metabolites (in addition to DOPEG).

Animals↗
PubMed1976

The effect of cocaine on the distribution of labelled noradrenaline in rabbit aortic strips and on efflux of radioactivity from the strips.

Reserpine-pretreated or normal rabbit aortic strips (whose noradrenaline-metabolizing enzymes were inhibited by treatment with 0.5 mM pargyline and by the presence of 0.1 mM U-0521) were incubated with 1.18 muM labelled noradrenaline for 30 min. Subsequently, strips were either analysed or washed out with amine-free solution for 240 to 250 min. From the efflux curves the original distribution of radioactivity was estimated by compartmental analysis. 1. The accumulation of radioactivity in the strips was reduced by 30 muM cocaine to that observed for nerve-free strips. In reserpine-pretreated strips this was due to a partial reduction of the filling of comartment IV (characterized by a half time of efflux of 10 to 20 min; earlier evidence had already shown that part of this compartment is of neuronal origin; Hensling et al., 1976) and a pronounced decrease of the filling of compartment V (characterized by the longest half time). In normal strips the same changes were observed as well as pronounced reduction of the "bound fraction". Thus, cocaine reduced the filing of those compartments which had been identified as neuronal ones (Henseling et al., 1976). 2. When 30 muM cocaine was added to the wash out solution only, the neuronal efflux of radioactivity from reserpine-pretreated strips was accelerated, while the efflux from extraneuronal or extracellular compartments remained unaffected. This effect of cocaine was the same for (-)- and (+)noradrenaline, and its was not significaltly decreased when paired strips exposed to an inhibitor of extraneuronal uptake (86 muM corticosterone) throughout the experiment. In normal strips, cocaine had very little or no effect on the efflux of radioactivity. 3. The results are consistent with the view that cocaine impairs the influx of amine into the neurone, while block of re-uptake of unchanged amine is one of the determinants of its effect on the rate of efflux from the axoplasm. Comparison of efflux curves with corresponding relaxation curves (determined in the absence and presence of cocaine) indicates that, when both noradrenaline-metabolizing enzymes are inhibited, relaxation of the strips is accounted for by a) the efflux of unchanged amine from neuronal (and extraneuronal) stores and b) the sensitivity of the preparation to noradrenaline.

Animals↗
PubMed1983

Beta-blocking and electrophysiological effects of propafenone in volunteers.

The chemical structure of propafenone (P) and certain experimental findings suggest that this antiarrhythmic compound could possess beta-blocking properties. To evaluate the clinical relevance of the latter cardiovascular effects of P during exercise were studied. After oral administration of P 150 and 300 mg in solution, six healthy volunteers were subjected to graded exercise. These doses of P, which are usually effective against arrhythmias, decreased exercise-induced tachycardia, whereas the systolic blood pressure was lowered but only at rest, and the diastolic pressure was slightly raised. However, taking into account dose ratio, and the intensity and duration of the reduction in exercise tachycardia, this effect of P was only about 5% at its maximum compared to propranolol and similar active beta-blocking compounds. The reduction in heart rate produced by P was not correlated with the plasma level nor did it show dose dependency, in contrast to beta-blocking agents, and also in contrast to its electrophysiological effects on the PQ interval.

Adult↗
PubMed1984

Alcohol and bupropion pharmacokinetics in healthy male volunteers.

A study was performed to determine whether there is a pharmacokinetic interaction between alcohol and the novel antidepressant bupropion. In the first part 8 healthy male volunteers received single doses of 100 mg bupropion hydrochloride orally on 2 occasions accompanied by either ethanol in orange or plain orange drink according to a balanced cross over design. Plasma bupropion concentrations were determined by radioimmunoassay and kinetics analysed with the aid of NONLIN. Blood alcohol levels were assessed by breathalyser. The disposition of bupropion was adequately described by a 2 compartment model and kinetic parameters were not significantly altered by the presence of alcohol. In the second part of the study the same subjects received 40 ml ethanol in orange drink 3.5 h after ingestion of 100 mg bupropion or dummy tablet in a double blind cross over fashion. Bupropion did not affect alcohol kinetics. In contrast to many other psychotropic drugs there is no evidence for a kinetic interaction between bupropion and alcohol.

Adult↗
PubMed1985

The disposition of bupropion and its metabolites in healthy male volunteers after single and multiple doses.

The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.

Adult↗
PubMed1989

Acute haemodynamic effects of different doses of alifedrine in congestive heart failure.

The haemodynamic effects of single oral doses of alifedrine 40 mg, 50 mg, 60 mg and placebo were compared in 30 patients with mild to moderate heart failure. Individual patients received either alifedrine 60 mg and placebo (15 patients) or alifedrine 40 mg and 50 mg (15 patients). All doses of alifedrine produced qualitatively similar haemodynamic responses, with maximum changes between 90 and 180 min after drug administration. The cardiac index was increased by +39%, +57%, and +50% by 40 mg, 50 mg and 60 mg, respectively. The increases were due to rises in stroke volume index (SVI) and in heart rate of +15%, +20% and +23%. Mean arterial blood pressure fell in a dose-related fashion, with a maximum fall of 11% by 120 min after 60 mg. The systemic vascular resistance index (SVRI) fell by 28%, 39% and 41%, and pulmonary vascular resistance index (PVRI) by 32%, 44% and 32% after 40 mg, 50 mg and 60 mg, respectively. The optimum dose appears to be 40 mg, which caused very little fall in blood pressure or increase in heart rate, yet significantly improved cardiac output. Alifedrine may have a place in the treatment of heart failure as an oral by active, positive inotropic agent.

Aged↗
PubMed1975

Excretion of norephedrine by man after oral administration of oxyfedrine.

After oral administration of oxyfedrine to healthy volunteers, norephedrine was identified in the urine by thin layer chromatography and gas liquid chromatography and mass spectrography. 30 hours after single oral doses of 8, 16 or 24 mg of oxyfedrine, about 4, 8 and 9 mg, respectively, of norephedrine were found in the urine, i.e. on a molar base 75-100% of the dose was excreted as norephedrine. The peak of excretion occurred within 2-4 hours after administration of the drug. No accumulation of oxyfedrine and/or its metabolite was observed after administration of 16 mg of oxyfedrine t.i.d. for three days. It could not be decided whether oxyfedrine was metabolized to norephedrine by liver enzymes, as in rats, or was spontaneously degraded to norephedrine, e.g. in duodenal fluid before absorption. 30-150 min after oral oxyfedrine (24 mg) norephedrine was demonstrable in duodenal fluid. Thus, in addition to the direct beta-sympathomimetic effects of oxyfedrine, it may also have indirect sympathomimetic effects because of the noradrenaline-releasing properties of its metabolite norephedrine.

Administration, Oral↗
PubMed1986

Neuronal efflux of noradrenaline induced by tris or lithium as substitutes for extracellular sodium.

Vasa deferentia of either untreated or reserpine (R) and/or pargyline (P) pretreated rats were incubated with 3H-noradrenaline and then washed with amine- and Ca2+-free solution until (after 100 min) the efflux of radioactivity largely originated from adrenergic nerve endings; COMT was inhibited by U-0521 (U). After 110 min of wash out, the sodium chloride in the wash-out solution was replaced by an equimolar concentration of either Tris-HCl or LiCl. This caused a desipramine-sensitive (i.e., carrier-mediated) efflux of tritiated noradrenaline. The initial increase of the "low Na+"-induced efflux dependent on the experimental conditions: it was most pronounced when the axoplasmic concentration of noradrenaline was high (RPU) and relatively small when MAO and vesicular storage were intact (U). The effects of Li+ and Tris+ differed with regard to the time course of the efflux of tritium: under all three experimental conditions (RPU, PU, U), Tris+ caused the rate of efflux of tritium to increase gradually within the 30 min period of observation, while Li+ either had a "peak-effect" (RPU, PU) or a "plateau-effect" (U). Under "U-conditions" Tris+ caused a slowly increasing, pronounced increase with time of the efflux of both, 3H-noradrenaline and 3H-DOPEG; whereas Li+ caused only a small and sustained increase of the efflux of 3H-noradrenaline and a decrease in the efflux of 3H-DOPEG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Correlation between serum concentration and pharmacological effect on atrioventricular conduction time of the antiarrhythmic drug propafenone.

Seven patients with cardiac dysrhythmias received a single, oral, therapeutically effective dose of the antiarrhythmic drug propafenone. The serum levels correlated well with changes in atrioventricular conduction times during the postabsorptive elimination phase (r = 0.8610, p less than 0.001). The mean half-lives of the serum level and the electrocardiographic effect (PQ-time) were 3.6 +/- .2 h and 3.8 +/- 0.6 h, respectively.

Adult↗
PubMed1975

Potentation of the cardiac response to aminophylline by oxyfedrine.

The influence of oxyfedrine on the cardiostimulatory effects of aminophylline was studied in the isolated perfused guinea-pig heart. It was found that oxyfedrine potentiated the stimulatory effects of aminophylline on isometric contraction, dF/dt, coronary flow and heart rate. This potentation was abolished after pretreatment with propranolol. Histamine, though to a lesser extent, also potentiated the effects of aminophylline. When oxyfedrine and histamine were infused simultaneously in the presence of propranolol, the response of the heart to aminophylline was also potentiated; the magnitude of this potentiation was comparable to that obtained with histamine alone, indicating that propranolol abolished only the action of oxyfedrine but not that of histamine. The mechanical effects of aminophylline were accompanied by a slight (15 per cent) but significant inhibition of phosphodiesterase, which was not further augmented by oxyfedrine. The results suggest that the potentiating effects of oxyfedrine or histamine on the cardiostimulatory actions of aminophylline are elicited by their stimulatory actions on adenylate cyclase activity.

Aminophylline↗
PubMed1983

Accumulation of 3H-(-)noradrenaline in the rabbit aorta not related to uptake1 and uptake2, but sensitive to 3,4-dihydroxy-2-methylpropiophenone (U-0521) and oxytetracycline.

1. Some of the extraneuronal accumulation of 3H-(-)noradrenaline in the rabbit aorta was resistant to uptake2 inhibitors (corticosterone, normetanephrine, phenoxybenzamine). Even combined treatment of the tissue with the competitive inhibitor corticosterone (87 mumol . l-1) and the irreversible inhibitor phenoxybenzamine (90 mumol . l-1) was not more effective than was corticosterone alone. 2. The corticosterone-resistant extraneuronal accumulation of 3H-(-)noradrenaline (0.12 mumol . l-1) was reduced by about 30% by the COMT inhibitor U-0521 (1000 mumol . l-1) and by oxytetracycline (100 mumol . l-1). Combined treatment with U-0521 and oxytetracycline was not more effective than was U-0521 alone. Already 1 mumol . l-1 U-0521 had a half-maximal effect, i.e., it reduced accumulation by 15%. This effect of U-0521 was not related to its known ability to block uptake2. The catechol U-0521 probably inhibited binding of noradrenaline to a catechol-specific site. Furthermore, the accumulation was sensitive to the two iron-chelating agents deferoxamine and phenanthroline but not to ascorbic acid and N-ethylmaleimide. 3. A relatively high formation of 3,4-dihydroxymandelic acid (DOMA) took place in the corticosterone-resistant extraneuronal compartment of the mechanically denervated aorta. This formation of DOMA was probably a consequence of tissue injury brought about by removing the adventitia.

Animals↗