Indomethacin potentiation of the response of the rabbit portal vein to electrical stimulation: effect of stimulus frequency and train length.

The response of the rabbit isolated portal vein to electrical stimulation was potentiated by indomethacin (10 mug/ml). This potentiation was dependent upon frequency but independent of the number of pulses in a train. It is concluded that these results add further support for the idea that indomethacin increases the release of newly synthesized noradrenaline as a result of inhibition of prostaglanding synthesis.     

The variation of acetylcholine release from myenteric neurones with stimulation frequency and train length

The effects of scopolamine on the release of 3H-acetylcholine (ACh) from the guinea-pig myenteric plexus were studied at different stimulation frequencies (0.03-10 Hz) and train lengths (1-180 pulses). Release of 3H-ACh was measured in the absence of cholinesterase inhibitors as the outflow of tritium from myenteric plexus-longitudinal muscle preparations preloaded with 3H-choline. In control experiments the volley output of 3H-ACh declined with increasing train length and increasing stimulation frequency. Stimulation by one pulse produced the highest volley output. Scopolamine facilitated the evoked output of 3H-ACh via blockade of presynaptic muscarine receptors. A significant increase was already observed when the preparation was stimulated with 3 pulses at 10 Hz which indicates that the inhibitory muscarinic mechanism becomes operational within 200 ms. The facilitatory effects of scopolamine depended on both train length and frequency of stimulation. Maximal increases in 3H-ACh output were seen with brief trains (3 and 6 pulses) at a high frequency (10 Hz), or with longer trains (20 and 180 pulses) at lower frequencies (0.3 and 1 Hz). Scopolamine compensated for the frequency-dependent decline of 3H-ACh volley output only during brief periods of stimulation (3 and 6 pulses). It is therefore concluded that the decline in volley output during the first few pulses of a train is due to the negative feedback mechanism which is activated by the transmitter released by the preceding impulses. With longer trains of stimulation the negative feedback mechanism plays only a minor role in regulating the output per pulse.     

Role of noradrenaline and 5-hydroxytryptamine in tetrahydroanaphthylamine-induced temperature changes in the rat

1. Intraperitoneal administration of graded doses of tetrahydronaphthylamine (THN) to rats caused a dose dependent decrease in body temperature.2. Intracisternal injection of graded doses of THN induced hypothermia, and implantation of crystalline THN rostral to the medial preoptic area and caudal to the striatum, caused hyperthermia.3. Pretreatment of the rats with a MAO inhibitor changed the hypothermia into hyperthermia.4. Intraperitoneal injection of 5-hydroxytryptophan caused a hypothermia which could be reversed into hyperthermia when the rats were pretreated with a MAO inhibitor.5. Pretreatment with parachlorophenylalanine enhanced the THN-induced hypothermia.6. Depletion of brain monoamines by Ro-4-1284 in combination with an inhibition of the biosynthesis of noradrenaline (diethyldithiocarbamate) changed the THN-induced hypothermia into hyperthermia.7. It is concluded that THN affects body temperature in rats by two central mechanisms, viz. a decrease mediated by noradrenaline, probably in the hypothalamus, and an increase which might be mediated by 5-hydroxytryptamine rostral to the medial preoptic area.     

Quantitative changes in pharmacodynamic parameters of noradrenaline in different rat aorta preparation: influence of endogenous EDRF

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Effect of frequency of stimulation on the inhibition by noradrenaline of the acetylcholine output from parasympathetic nerve terminals

1. The relationship between the number of shocks delivered, the frequency of stimulation and the acetylcholine output per volley from nerve terminals of the longitudinal muscle strip of the guinea-pig ileum was studies.2. There was an inverse correlation between acetylcholine output per volley and the frequency of stimulation when the same number of shocks was applied in each train.3. With sustained stimulation, the volley output declined more rapidly the higher the frequency of stimulation. There was no decrease in volley output (11.7 (ng/g)/volley) when the frequency applied was 0.1 Hz or less.4. Noradrenaline (10(-6) g/ml) reduced the acetylcholine output per volley to the level produced by sustained stimulation at 10 Hz (1.4-1.9 (ng/g)/volley). The acetylcholine output following application of the first shocks of a train at high frequency stimulation was much reduced by noradrenaline as the output was higher than 1.4-1.9 (ng/g)/volley. This action of noradrenaline was antagonized by phentolamine (2 mug/ml for 20 min).5. Amphetamine and methylamphetamine, which release NA from sympathetic nerve terminals, were active in reducing the acetylcholine output to low frequency parasympathetic nerve stimulation. Reserpine and alpha-methyl-p-tyrosine pretreatment prevented the effect of amphetamine and reduced that of methylamphetamine.6. The fact that addition or release of noradrenaline, reduced acetylcholine output when the firing rate was high but short in duration, suggests that noradrenaline plays a general modulator role in controlling the output of acetylcholine from the parasympathetic nerve terminals.     

Effect of ethanol and of noise on reaction time in the monkey: Variation with stimulus level

To determine whether the latency-increasing effects of ethanol were differential with respect to the intensity of the stimulus that initiated the response, three rhesus monkeys were trained on a behavioral task in which the latency of a simple motor response was measured following the onset of a pure tone stimulus. Following training, the animals were tested at a number of different tone intensities and functions relating latency to tone intensity were constructed. When these were stable, the animals were given ethanol in doses of 1.0–2.5 g/kg and the effects on response latencies to different tone intensities were determined. It was found that, for all except the lowest stimulus levels, the effect of ethanol was dose-related, while for a given dose the effect was equal across intensity. These results indicate that the effects of ethanol in this situation are on response execution rather than stimulus detection. The effects of ethanol were compared to those of exposure to high intensity noise. This treatment, which affects primarily the inner ear, resulted in substantial increases in latency to low intensity tones, but little, if any, shift at high intensities.     

Age-related changes in neuronal uptake of noradrenaline

Summary Age-related changes in the neuronal uptake of noradrenaline were studied in the vas deferens of 4-, 12-and 20-months old rats by determining the potentiating effect of cocaine on concentration-effect curves to noradrenaline and by evaluating the kinetic parameters (V _max and apparent K _m) of neuronal ³H-noradrenaline uptake. Since the neurotransmitters released by nerve terminals and the density of noradrenergic innervation are different in the epididymal and prostatic portion of the vas, the experiments were carried out in these two portions of the organ.In the epididymal portion, the ratio beween EC₅₀ for noradrenaline in the presence and in the absence of cocaine was reduced in tissues of middle-aged (12-months) and old (20-months) animals when compared with young (4-months) animals. The pD₂ values for noradrenaline in the absence of cocaine and the kinetic parameters for neuronal ³H-noradrenaline uptake were not modified by ageing. Thus, in the epididymal portion there was no age-related change in neuronal uptake. The age-related decrease in the cocaine-induced supersensitivity to noradrenaline was due to an age-related decrease in the pD₂ value for noradrenaline observed in the presence of cocaine, suggesting postsynaptic changes.In the prostatic portion, the ratio between EC₅₀ for noradrenaline in the presence and in the absence of cocaine was also reduced in tissues of old animals (20-months) when compared with middle-aged and young animals. The pD₂ value for noradrenaline in the absence of cocaine obtained in the prostatic portion of 20-months old rats was higher than that in the younger groups (4- and 12-months). Since in the presence of cocaine no age-related changes in the pD₂ value for noradrenaline were obtained, postsynaptic changes might not occur in this portion. Thus, the reduction in the EC₅₀ ratio for noradrenaline in the prostatic portion of 20-months old rats suggested a loss of function of the neuronal uptake system. Further support for this hypothesis was that the V _max value of neuronal ³H-noradrenaline uptake tended to decline with age only in the prostatic portion.Therefore, the age-related decrease in the cocaine-induced supersensitivity was probably due to an age-related loss of function of the neuronal uptake system in the prostatic portion and to a decrease in the sensitivity to noradrenaline in the epididymal portion. The loss of function of neuronal uptake and the change in sensitivity to noradrenaline occurred at different ages.Part of the present results have been reported in the III Annual Meeting of the Federação de Sociedades de Biologia Experimental, Caxambu, MG, June 29 — July 3, 1988 Send offprint requests to R. P. Markus, Departamento de Farmacologia, Instituto de Ciencias Bimédicas, Universidade de São Paulo, Av. Prof. Linen Prestes, 1524, 05508, Sao Paulo, Brasil     

Role of brain noradrenaline in morphine-induced stereotyped behaviour

The injections of morphine into rats which had been made tolerant to morphine produced stereotyped sniffing, licking and biting reminiscent of amphetamine-stereotypy. Pretreatment with drugs acting on the brain catecholamines such as reserpine, H 44/68, FLA-63 and receptor blockers could inhibit this behaviour. Comparison between morphine and amphetamine stereotypy indicated that brain noradrenaline plays a more important role than dopamine in morphine induced stereotyped behaviour, in contrast to amphetamine stereotypy where dopamine is the most important brain amine. The result of experiments with intraventricular injections of noradrenaline supported this conclusion, because the noradrenaline suppressed the blocking action of FLA-63 on morphine-induced stereotypy.     

Role of angiotensin and sodium intake in cardiac noradrenaline release

Summary The effects of exogenous and of endogenous angiotensin on noradrenaline overflow were investigated in saline perfused rat hearts with intact sympathetic nerves. The overflow of endogenous noradrenaline induced by electrical stimulation of the left stellate ganglion was determined in the coronary venous effluent by HPLC. The activity of the renin-angiotensin system was modulated by varying of the nutritional sodium load prior to the experiments. Endogenous angiotensin formation was blocked by angiotensin-converting enzyme inhibitors.Following high sodium intake, both angiotensin II (100 nmol/l) and angiotensin I (1 µmol/l) caused a marked increase of the electrically evoked noradrenaline overflow. After inhibition of the angiotensin-converting enzyme using captopril (350 nmol/l) or ramiprilat (50 nmol/l), angiotensin I (1 µmol/l) did not enhance noradrenaline overflow. This indicates an active cardiac angiotensin conversion, since the sole administration of captopril and ramiprilat did not affect noradrenaline overflow in rats with high sodium intake. Following low sodium intake, neither angiotensin II (100 nmol/l) nor angiotensin I (1 µmol/l) significantly affected noradrenaline overflow. Both captopril and ramiprilat, however, significantly reduced noradrenaline overflow induced by electrical stimulation, suggesting a facilitory action of endogenous angiotensin under these conditions.This concept was substantiated when evaluating the noradrenaline overflow during control stimulations. Following low sodium intake, stimulation evoked noradrenaline overflow was higher as compared to that after nutritional sodium load. The results are in keeping with a sodium-dependent intracardiac formation of angiotensin II which facilitates noradrenaline release from sympathetic nerve terminals. Following low sodium intake, cardiac angiotensin II formation is active, as indicated by the suppression of noradrenaline release by angiotensin-converting enzyme inhibitors and the ineffectiveness of exogenous application of angiotensin II. In contrast, suppression of endogenous angiotensin 11 formation in sodium loaded animals sensitizes the sympathetic nerves to exogenous angiotensin.This work was supported by a grant from the Deutsche Forschungsgemeinschaft (SFB 320 — Herzfunktion and ihre Regulation)Presented in part at the 63nd Scientific Sessions of the American Heart Association, Dallas/USA, November 1990 Send offprint requests to G. Richardt at the above address     

Effect of propranolol and controlled cardiac output on acute tolerance to noradrenaline

The effects of propranolol and controlled blood flow on the acute tolerance which develops to the pressor response to noradrenaline infusions was studied in the anaesthetized open-chest dog, both intact and during left heart bypass, and in the perfused forelimb. The acute tolerance which develops to noradrenaline infusion is characterized by an early and a late phase. The early phase of tolerance observed during infusion of low noradrenaline concentrations was due to a decrease in vascular resistance in the anaesthetized dog and in the perfused forelimb. Since the early phase of tolerance was not observed after treatment with propranolol, it is suggested that vascular β-adrenoreceptors are involved in the phenomena of tolerance. The early phase of tolerance is abolished and the late phase diminished during infusion of high concentrations of noradrenaline when blood flow is maintained constant with a pump although venous return decreased. It is concluded that changes in the cardiac output are important in the development of acute tolerance to the pressor effect of noradrenaline in the dog.     

Interactions of angiotensin and cocaine on the output of noradrenaline from isolated rabbit hearts

Summary The output of noradrenaline from isolated rabbit hearts during sympathetic nerve stimulation is increased by angiotensin (1.3 ng/ml) to 176% of the preceding control stimulation period. During inhibition of noradrenaline re-uptake by cocaine (5 or 15 g/ml), the augmentation caused by the peptide is unchanged (181 and 171%, respectively). The result favours the assumption that angiotensin enhances the output of noradrenaline by an increase of the amount of transmitter liberated from the nerve terminals rather than by interfering with transmitter inactivation.     

Time-dependent changes in neuronal net uptake of noradrenaline after pretreatment with pargyline and/or reserpine

Summary Isolated rabbit hearts were perfused with 20 to 200 ng/ml of (–)-noradrenaline and arterio-venous differences were determined at various times to measure the rate of net removal of the amine from the perfusion fluid. Animals were untreated or pretreated with reserpine and/or pargyline to block vesicular retention and/or intraneuronal monoamine oxidase (MAO).The arterio-venous difference (in percent of the arterial concentration) remained rather constant during prolonged perfusions of untreated hearts with (–)-noradrenaline, the magnitude of the difference being inversely related to the arterial concentration. After block of MAO the rate of net removal declined exponentially with time; the rate of decline increased with increasing arterial concentration of the amine and also after the additional pretreatment with reserpine. The time-dependent decline in the rate of net removal was shown to be due to an increased efflux of the amine from the nerve endings. The net removal of noradrenaline-H³ at the 5th min of perfusion of pargyline-pretreated hearts was mainly due to neuronal net uptake, since a) O-methylation accounted for only 5% of the removal, and b) cocaine (10–30 (g/ml) virtually abolished net removal.Initial rates of removal were not affected by the various pretreatments.In untreated hearts retention of exogenous (–)-noradrenaline increased linearly with the duration of the perfusion but the increase was exponential after block of MAO. Apparently, the storage capacity becomes exhausted during prolonged perfusions of pargyline-pretreated hearts.The ratio noradrenaline retained by the heart/noradrenaline removed by the heart was quite small in untreated (0.16), very small in reserpine-pretreated (0.03) and nearly unity in pargyline-pretreated hearts.It is concluded that any impairment of the intraneuronal mechanisms of inactivation (vesicular storage and MAO) leads to an increase in the axoplasmic concentration of free noradrenaline which causes an increased efflux of the amine, while the influx remains unchanged. The axoplasmic concentration of free noradrenaline seems to rise more after block of MAO than after pretreatment with reserpine and is most pronounced after both. Changes in the sensitivity of the pacemaker to (–)-noradrenaline were found to be correlated with changes in the rate of removal of the amine from the perfusion fluid.Part of this study was supported by the Deutsche Forschungsgemeinschaft.