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PubMed1975

Prejunctional effects of a purified toxin from the scorpion Tityus serrulatus: release of 3H-noradrenaline and enhancement of transmitter overflow elicited by nerve stimulation.

The effects of a purified fraction of the venom of the Brazilian scorpion, Tityus serrulatus, were studied in isolated guinea-pig atria previously labelled with 3H-noradrenaline. Exposure to 0.3 and 1.0 mug/ml of the scorpion toxin resulted in a long lasting positive chronotropic effect which was concentration-dependent. The increase in atrial rate coincided with an enhancement in spontaneous outflow of radioactivity. The increase in outflow of radioactive products elicited by exposure to 1.0 mug/ml of the scorpion toxin was approximately 3-fold. 3H-noradrenaline accounted for 60% of the total increase in outflow of radioactivity elicited by the scorpion toxin and the 3H-deaminated glycol (3,4-dihydroxyphenyl-glycol) represented the main metabolite formed, accounting for approximately 35% of the total release. 20 min after exposure to 1.0 mug/ml of the scorpion toxin the overflow of the labelled transmitter elicited by accelerans nerve stimulation (4 Hz, during 60 sec. supramaximal voltage) was increased 8-fold. This effect of the scorpion toxin appears to be unrelated to inhibition of neuronal uptake, block of alpha-adrenoceptors or stimulation of beta-adrenoceptors. Consequently, in addition to releasing noradrenaline, the scorpion toxin enhances transmitter overflow elicited by nerve stimulation through a prejunctional effect which appears to reflect a nove mechanism of action.

Animals↗
PubMed1975

Selective inhibition by hydrocortisone of 3H-normetanephrine formation during 3H-transmitter release elicited by nerve stimulation in the isolated nerve-muscle preparation of the cat nictitating membrane.

The metabolism of 3H-noradrenaline released by nerve stimulation in the isolated nerve-muscle preparation of the cat nictitating membrane was determined under control conditions and in the presence of hydrocortisone, 28 muM, a concentration which inhibits the high affinity extraneuronal uptake of noradrenaline in this tissue. In the controls the main fraction in the overflow elicited by stimulation at 10 Hz during 2 min was the deaminated glycol, 3H-DOPEG (3,4-dihydroxyphenylglycol), which accounted for 45.2 +/- 2.96% of the total radioactivity. Under these conditions, 3H-noradrenaline represented 30.8 +/- 1.92%, while 3H-normetanephrine accounted for 14.5 +/- 0.94% of the total overflow of radioactivity. During exposure to hydrocortisone there was a selective inhibition in 3H-normetanephrine formation from 3H-noradrenaline released by stimulation while the other fractions were not affected significantly. In contrast to these results, there were no changes in the spontaneous outflow of 3H-normetanephrine during exposure to hydrocortisone. The results obtained support the view that 3H-normetanephrine in spontaneous release originates from the activity of prejunctional catechol-O-methyltransferase. On the other hand, 3H-normetanephrine formed during transmitter release elicited by nerve stimulation is due to the activity of extraneuronal catechol-O-methyltransferase. Access of 3H-noradrenaline released by nerve stimulation to extraneuronal catechol-O-methyltransferase is mediated through the high-affinity, hydrocortisone-sensitive extraneuronal uptake mechanism.

Animals↗
PubMed1978

Metabolic fate of 3H-noradrenaline released from the mouse hypothalamus.

In slices of mouse hypothalamus labelled in vitro with 3H-noradrenaline (3-H-NA), the deaminated metabolite 3H-3,4-dihydroxyphenylglycol (3H-DOPEG), represented 40.2 +/- 2.6% of the total outflow of radioactivity and was the main fraction in the spontaneous efflux. Inhibition of neuronal monoamine oxidase by exposure to 60 micron bretylium, reduced the outflow of 3H-DOPEG to 9.7 +/0 0.3%. At the same time, the proportion of 3H-normetanephrine (3H-NMN) was significantly increased. On the other hand, an increased outflow of 3H-DOPEG and a lower proportion of 3H-NMN was obtained in the presence of 2.9 micron of the reserpine like agent Ro 4-1284. It is suggested that in the mouse hypothalamus, the deaminated metabolite, DOPEG, is formed inside the nerve terminals, while the O-methylated metabolite, NMN, might result from the activity of extraneuronal catechol O-methyltransferase.

Animals↗
PubMed1984

Saturation of monoamine oxidase by intraneuronal noradrenaline accumulation.

After pretreatment of the rats with reserpine and pargyline (to inhibit vesicular uptake and MAO), after an additional in vitro treatment with pargyline, and in the presence of U-0521 (to inhibit COMT), the adrenergic nerve endings of vasa deferentia were loaded with 3H-(-)-noradrenaline by exposure to various concentrations of this amine. Subsequently, tissues were washed out with amine-free solution, and the neuronal efflux of tritium was analysed. During 180 min of wash-out the apparent rate constant for the efflux of tritium decreased with increasing tritium content of the tissue. Prolongation of the wash-out period to 305 min revealed that efflux curves for tritium from heavily loaded tissues became steeper after the 180th min of wash-out. This phenomenon is indicative of saturation (followed by desaturation) of a process that limits the efflux of tritium from heavily loaded tissues. Analysis of the radioactivity of the efflux revealed a characteristic efflux curve for DOPEG: the formation of DOPEG appears to be saturated when the 3H-(-)-noradrenaline content of the tissue is high, in order to become desaturated during prolonged wash-out. These results cannot distinguish between MAO and alcohol dehydrogenase as the saturable enzyme. The formation of the mainly deaminated metabolites (during 60 min of wash-out) was determined in lightly and in heavily loaded tissues. The ratio "formation of metabolites/3H-(-)-noradrenaline content" was lower in heavily than in lightly loaded tissues; the relative decline in DOPEG formation was not accompanied by a compensatory increase in the formation of DOMA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The effect of pregnancy on the metabolism of noradrenaline in reproductive organs of the rabbit.

The metabolites of (-)-3H-noradrenaline (1.2 mumol l-1) formed by uteri from non-pregnant mature rabbits were, in descending order of importance, 3H-DOPEG greater than 3H-MOPEG greater than 3H-NMN greater than 3H-VMA (3H-DOMA not measured). The pattern of metabolite formation per unit mass of tissue was markedly different in uteri from 28 day pregnant rabbits due to a fourfold increase in 3H-NMN formation and a fourfold decrease in 3H-DOPEG formation. The effects of cocaine indicated that 3H-NMN was largely extraneuronal in origin and 3H-DOPEG was both neuronal and extraneuronal in origin. The pattern of metabolite formation in pregnant rabbit uteri closely resembled the reported pattern in uteri from ovariectomized rabbits treated with 17 beta-oestradiol and progesterone. In the rabbit oviduct and ovary, the patterns of metabolite formation, and their modification by cocaine, indicated that (-)-3H-noradrenaline was metabolised mainly by intraneuronal deamination in the oviduct and mainly by extraneuronal O-methylation in the ovary. Pregnancy did not affect (-)-3H-noradrenaline metabolism in the oviduct, but decreased the metabolism in the ovary.

Animals↗
PubMed1994

Long-term changes in urodynamic studies of voiding in the elderly.

Urodynamic studies were conducted in 80 incontinent elderly patients (27 men and 53 women; mean age, 77 years) and repeated 2-4 weeks later after patients had been subject to interventions. Interpretable voiding studies were performed in 84% of sessions. Interpretable initial and repeat studies were performed in 74% of patients. For detrusor pressure at maximum flow the intra-individual, between-sessions variability was +/- 11.7 cm H2O (SD) and the initial-repeat correlation coefficient was 0.61. For maximum flow rate the corresponding figures were +/- 4.7 ml/s and 0.44. Mean residual urine volume was 195 ml, with a between-sessions variability of +/- 113 ml (SD). These results suggest that there is substantial long-term variability in voiding function, including urethral resistance. Of the mean, 5% showed a change in obstruction classification (unobstructed/obstructed) between sessions. This variability and the modest proportion of interpretable studies should be taken into account when assessing urethral obstruction and designing clinical trials.

Aged↗
PubMed1988

The pharmacokinetics of oxybutynin in man.

We have studied the pharmacokinetics of oxybutynin (Ditropan) after single oral (5 mg) and intravenous administration (1 and 5 mg), and after repeated oral administration in healthy volunteers. Oxybutynin was rapidly absorbed, maximum plasma concentrations (8 ng.ml-1) being reached in less than 1 h. The absolute systemic availability averaged 6% and the tablet and solution forms displayed similar relative systemic availability. Plasma concentrations of oxybutynin fell biexponentially, the elimination half-life being about 2 h. There was a large interindividual variation in oxybutynin plasma concentrations. Almost no intact drug could be recovered in the urine. During repeated oral administration steady-state was reached after eight days of treatment. The low absolute systemic availability of oxybutynin, the large interindividual variability in its plasma concentrations, and the apparent absence of intact oxybutynin in the urine suggest that its major pathway of elimination is hepatic metabolism.

Administration, Oral↗
PubMed1979

Sympathetic activity and transcendental meditation.

Ten male advanced meditators and ten male long-term meditators subjected themselves four times to slight physical exercise following a period of rest, meditation or reading. Daily urine excretions of catecholamines and VMA were determined in both groups. On the experimental days 4-hour urine specimens, one before and one after the experiments, were again collected for analysis. During the experiments blood pressure and heart rate were measured continuously and blood samples were taken for plasma catecholamine levels immediately before and after the physical exercise. Daily catecholamine and VMA excretions showed to be higher in advanced meditators. During the experiments the pattern of noradrenaline, adrenaline and VMA excretions were different in both groups, long-term meditators showing a higher adrenaline excretion after exercise. After the resting period there was in both groups a similar increase of plasma catecholamine levels during exercise. However, after meditation the advanced meditators showed a significant increase in plasma noradrenaline and no further increase in plasma noradrenaline level during the following physical exercise. Also after the reading period differences between both groups in plasma catecholamine levels during exercise could be observed. In advanced meditators heart rate reduction after meditation was about 9% and diastolic blood pressure was slightly raised. The preceding conditions of rest, meditation or reading had a significant different influence on the behaviour of heart rate and blood pressure during the following physical exercise and this pattern was different for both groups.

Adult↗
PubMed1976

[Urinary phenylalanine metabolites in hyperphenylalaninemia (author's transl)].

Urinary phenylalanine metabolites after phenylalanine load of 4 healthy controls, 15 patients with classical phenylketonuria and 8 patients with hyperphenylalaninemic variants are measured quantitatively by gas chromatography. Statistically significant differences are found for a number of metabolites, e.g. phenylpyruvate, phenyllactate, ortho-hydroxy-phenylacetate, para-hydroxy-phenylpyruvate and para-hydroxy-phenyllactate. The results are discussed with respect to discrimination of phenylketonuria patients and patients with hyperphenylalaninemic variants and in respect to pathophysiological aspects.

Humans↗