Vascular responses and noradrenaline overflows in the isolated blood-perfused cat spleen: some effects of cocaine, normetanephrine and -blocking agents.
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1. Vascular responses and noradrenaline overflows have been studied in the isolated blood-perfused cat spleen in response to electrical stimulation of the splenic nerve with trains of 200 supramaximal pulses at a frequency of 10 Hz given at 10 min intervals.2. In the absence of blocking agents the spleen gave well-defined responses and a mean maximum overflow of 436 +/- 96 pg noradrenaline per stimulus (n = 4) at the third train of stimuli.3. Cocaine (2 x 10(-5)M) increased the response nearly threefold and raised the overflow to 840 +/- 131 pg/stim (n = 4). At later stimulations the responses remained stable, but the overflows rose progressively to 1076 +/- 51 pg/stim after five trains of stimuli.4. Normetanephrine (10(-4)M) had no significant effect on response, but elevated the overflow to a mean maximum of 868 +/- 169 pg/stim (n = 4).5. Cocaine (2 x 10(-5)M) and normetanephrine (10(-4)M) given together increased the response by a factor of 6.5 and raised the overflow to 1258 +/- 247 pg/stim (n = 4).6. Hydergine (approx. 10(-5)M) almost completely abolished the response and raised the overflow to 859 +/- 173 pg/stim (n = 4).7. Cocaine (2 x 10(-5)M), normetanephrine (10(-4)M) and hydergine (approx. 10(-5)M) given in combination abolished the response and raised the overflow to 4089 +/- 1148 pg/stim (n = 4).8. Phenoxybenzamine (10(-4)M) abolished the response and elevated the overflow to 4215 +/- 738 pg/stim (n = 4).9. These results are interpreted in terms of selective and combined block of ;uptake I', ;uptake II' and alpha-adrenergic receptors. Facilitation of transmitter release by alpha-blocking drugs, and the possible existence of an uptake process associated with the alpha-receptors are discussed. (+info)
A new approach to the measurement and classification of forms of supersensitivity of autonomic effector responses.
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1 It is proposed that sensitizations of autonomic effectors to agonists by drugs or procedures be considered in two main categories: those involving changes in the effective concentration of agonist at receptors (type I) and those involving changes in the responding tissue beyond the initial combination of agonist and receptors (type II). Type I sensitizations are appropriately described by determining the dose-ratio (horizontal shift of the dose-response curve) and type II sensitizations by assessing the change in the magnitude of the response.2 The inadequacy of the dose-ratio in assessing sensitizations related to an altered physiology of the responding tissue is illustrated by means of hypothetical examples with particular reference to the slopes of dose-response curves and altered maximal responses.3 An evaluation of the enhancement of responses of rabbit aortic strips to agonists by reserpine indicates that it is a type II sensitization. The shifts of dose-response curves to noradrenaline, isoprenaline, normetanephrine and 5-hydroxytryptamine after reserpine-treatment, were described both by the dose-ratio and by the increment in the magnitude of the response at various contraction amplitudes. The dose-ratio varied unpredictably for each agonist depending on the response level selected for comparison and also varied between agonists. However, the mm increment in response magnitude after reserpine approximated a constant value. Responses to potassium which by horizontal procedures were assessed among the least increased, were found to be enhanced the most when considered as a type II sensitization.4 It is concluded that both type I and type II procedures should be applied when dealing with an unidentified sensitization and that the data be critically assessed. The appropriate use of these procedures can aid in identifying and clarifying sensitizations, as well as in elucidating the sequence of steps between receptor activation and response in an effector. (+info)
Morphine analgesia and the bulbospinal noradrenergic system: increase in the concentration of normetanephrine in the spinal cord of the rat caused by analgesics.
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1 Administration of an analgesic dose (10 mg/kg, s.c.) of morphine increased the concentration of a noradrenaline metabolite, normetanephrine (NM) in the spinal cord of normal rats. The time course of the change in the NM concentration corresponded approximately to that of the morphine analgesia. The concentration of noradrenaline was not affected.2 A similar effect on the NM concentration was also observed after the administration of pentazocine (30 mg/kg, s.c.) and nalorphine (20 mg/kg, s.c.).3 The NM increasing effect of morphine, pentazocine and nalorphine was found in the dorsal half of the spinal cord but not in the ventral half.4 The increase in the concentration of NM induced by morphine, pentazocine or nalorphine was completely suppressed by naloxone (1 mg/kg, s.c.) given 5 min before the administration of these drugs.5 When the spinal cord was transected at C1, the NM increasing effect of morphine disappeared, yet when the brain stem was transected at the inter-collicular level, the effect remained.6 In morphine-tolerant rats, the concentration of NM in the spinal cord was almost the same as that observed in normal rats, but the increase in the concentration of NM in the spinal cord after the acute administration of morphine did not take place.7 The NM concentration in the spinal cord of normal rats was not modified by aminopyrine (75 mg/kg, s.c.), chlorpromazine (10 mg/kg, s.c.), mephenesin (100 mg/kg, i.p.) or naloxone (25 mg/kg, s.c.).8 The possible relation between morphine analgesia and the descending noradrenergic neurones in the spinal cord of rats is discussed. (+info)
Noradrenaline release in rats during prolonged cold-stress and repeated swim-stress.
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1 Plasma noradrenaline concentration in rats was measured during prolonged cold-stress and repeated swim-stress. 2 Cold exposure for 6 h caused a rise in plasma noradrenaline which reached a peak at 4 h. 3 Administration of desmethylimipramine and normetanephrine to block neuronal and extra-neuronal uptake of noradrenaline raised plasma noradrenaline concentration without changing the pattern of the response to cold exposure. 4 Repeated cold exposure on subsequent days produced no change in the pattern of plasma noradrenaline concentration. 5 Five successive 1-min swims at 30-min intervals caused a rise in plasma noradrenaline concentration which was maximal after the third swim. 6 It is suggested that prolonged and repeated activation of sympathetic nerve terminals leads to a decline in noradrenaline release. (+info)
The separation of epinephrine from norepinephrine and dopamine from DOPA on Sephadex G-10.
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Epinephrine and norepinephrine were separated by acid elution through a Sephadex G-10 column with high recovery (better than 90%), excellent reproducibility, and little overlap (less than 10%). Once packed, the columns could be re-used indefinitely. Total elution time was about six hours and the columns could be left untended since the gravity flow stops automatically once the level of the eluant reaches the gel bed. The resulting dilution was five-fold. 3,4-Dihydroxyphenylalanine (DOPA) was completely separated from 3,4-dihydroxyphenylethylamine (dopamine) by the same procedure. (+info)
Further evidence for a central hypotensive action of alpha-methyldopa in both the rat and cat.
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1. alpha-Methyldopa (300 mg/kg i.p.) produced a fall in blood pressure in conscious genetic hypertensive rats. Pretreatment with intraventricular 6-hydroxydopamine prevented this hypotensive effect of alpha-methyldopa, whilst intravenous 6-hydroxydopamine reduced but did not prevent the hypotension.2. The hypotensive effect of alpha-methyldopa was prevented or reversed by intraventricular injection of phentolamine (200 mug/rat).3. Pressor responses obtained by stimulation of the entire sympathetic outflow in the Gillespie & Muir preparation, were unaffected by pretreatment with alpha-methyldopa (300 mg/kg i.p.).4. Vasoconstrictor responses to periarterial nerve stimulation of the isolated renal artery preparation of the rat were markedly reduced by pretreatment with alpha-methyldopa. Furthermore, alpha-methylnoradrenaline was found to have one-eighth the vasoconstrictor potency of noradrenaline in this particular artery preparation.5. Pressor responses obtained by stimulation of the posterior hypothalamus or midbrain reticular formation in the rat anaesthetized with urethane were markedly reduced by pretreatment with alpha-methyldopa. FLA-63, a selective dopamine-beta-hydroxylase inhibitor, prevented the reduction of the pressor responses to hypothalamic stimulation produced by alpha-methyldopa.6. Stimulation of the posterior hypothalamus in the anaesthetized cat caused both an increase in sympathetic nerve activity and a rise in blood pressure. These responses were markedly reduced 3-4 h after the injection of alpha-methyldopa (100 mg/kg i.v.).7. These results strongly suggest that the central actions of alpha-methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded. (+info)
The removal of noradrenaline in the pulmonary circulation of rat isolated lungs.
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1. Removal of noradrenaline by isolated lungs of the rat, perfused via the pulmonary artery with Krebs bicarbonate solution has been studied.2. A constant removal (40.2%) was observed over a concentration range of 2-50 ng noradrenaline/ml (12-300 nM). At 100 ng/ml (600 nM), the removal is significantly reduced to 33.5%.3. The removal of noradrenaline was inhibited by cocaine (1 muM), but not by normetanephrine (5 muM), metaraminol (10 muM), phenoxybenzamine (10 muM) and 5-hydroxytryptamine (110 and 560 nM).4. We conclude that the removal of noradrenaline in the lungs does not involve an uptake process comparable with those previously described for this amine. The uptake process for noradrenaline in the lung is similar to that for 5-hydroxytryptamine and may be unique to this tissue. (+info)
Permanent alterations in catecholamine concentrations in discrete areas of brain in the offspring of rats treated with methylamphetamine and chlorpromazine.
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Methylamphetamine hydrochloride (80 mg/l.) and/or chlorpromazine hydrochloride (200 mg/l.) have been administered in the drinking water of female Wistar rats during pregnancy and suckling. The offspring were weaned at 21 days and thereafter received no drugs. Nine months later, male offspring were killed and noradrenaline and normetanephrine concentrations were determined in eight discrete areas of the brains: neocortex, hippocampus, striatum, thalamus, hypothalamus, corpora quadrigemina, pons/medulla, and amygdala region. Both drugs appeared to have permanently altered catecholamine concentrations in several areas of the brain. There was evidence of antagonism between the effects of the two drugs in the hippocampus, striatum, thalamus, and corpora quadrigemina, where the individual drugs produced altered noradrenaline concentrations but a combination of the two had no effect. (+info)