Showing papers in "British Journal of Pharmacology in 1972"

Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment.

Abstract: 1. Effects of morphine sulphate (1·25, 2·5, 5, 10, 20 and 40 mg/kg i.p.) on locomotor activity of male rats were observed for 8 h after single doses in non-tolerant rats. The lower three doses had only an excitatory effect, whereas the higher three doses caused initial depression followed by a delayed excitatory effect. 2. The same doses of morphine were administered daily for 30 days. No tolerance developed within this time to the excitatory effect. The locomotor excitatory effect of the higher three doses of morphine became progressively more pronounced over treatment periods of 30 days (and 48 days for 20 mg/kg), while the latency to peak activity decreased. 3. An explanation of these results is suggested on the basis of two different central drug-receptor interactions affecting motility.

Atropine resistant excitation of the urinary bladder: The possibility of transmission via nerves releasing a purine nucleotide

Abstract: 1. The possibility that a purine nucleotide is involved in excitatory transmission to the urinary bladder has been tested. All the purine compounds tested which contained a pyrophosphate bond produced contraction, adenosine triphosphate (ATP) being the most potent. Adenosine and adenosine monophosphate caused relaxation. 2. The response to ATP closely mimicked the nerve-mediated contraction, both being characterized by a rapid contraction which was not maintained. A lack of sensitivity to ATP was noted in some preparations of the rat urinary bladder. 3. Both nerve-mediated contractions and contractions caused by ATP were blocked by quinidine, while the response to acetylcholine persisted. 4. Nerve-mediated responses were depressed during tachyphylaxis produced by high concentrations of ATP. Tachyphylaxis did not occur when low concentrations were used. Possible explanations for these results are discussed. 5. The results are consistent with the hypothesis that non-cholinergic excitatory nerves to the guinea-pig bladder release a purine nucleotide, but do not provide critical evidence for it.

Developmental characteristics of brain catecholamines and tyrosine hydroxylase in the rat: effects of 6‐hydroxydopamine

Abstract: Summary 1 Brain noradrenaline, dopamine and tyrosine hydroxylase were found in rat brain a few days before birth and increased progressively until reaching adult values. The most rapid period of growth for these substances seemed to occur between 7 and 18 days. 2 The intracisternal administration of 6-hydroxydopamine to rats 7 days of age reduced concentrations of noradrenaline, dopamine, and tyrosine hydroxylase by 72 hours. 3 The concentrations of noradrenaline, dopamine or tyrosine hydroxylase in rats that received 6-hydroxydopamine at 7 or 14 days of age remained markedly reduced when determined at adulthood, indicating that fibres did not continue to develop after the administration of this compound. The rats treated at 7 days also showed diminished concentrations of noradrenaline in heart. 4 Rats injected with 6-hydroxydopamine at 7 days had reduced body weight as well as a reduction of some organ weights. This growth deficit was not observed in animals that received this drug at 14 days of age. 5 The administration of ovine growth hormone to rats that received 6-hydroxydopamine at 7 days did not reverse the growth deficiency in these animals.

The ring test: a quantitative method for assessing the 'cataleptic' effect of cannabis in mice.

Abstract: 1. A bioassay for cannabis, called the ring test, has been developed in which the percentage of the total time spent on a horizontal wire ring during which a mouse remains completely immobile is recorded.2. The effect of cannabis on mobility is a dose-related, graded response.3. Threshold doses of cannabis extract are 12.5 mg/kg when injected intravenously, and 100 mg/kg when injected intraperitoneally or subcutaneously.4. The method provides a measure of the ;cataleptic' effect of cannabis. Chlorpromazine in doses of 1 mg/kg upwards also produces the effect but barbitone does not.5. It is concluded that Delta(1)-tetrahydrocannabinol (Delta(1)-THC) is largely responsible for the effect of cannabis extract on mobility; the potency ratio of Delta(1)-THC to cannabis extract is between 10 and 20. Delta(1)-Tetrahydrocannabidivarol (Delta(1)-THD) also affects mobility but is less active than Delta(1)-THC. Cannabidiol has no effect when injected intraperitoneally in doses up to 100 mg/kg.

Pharmacology of AH 5158; a drug which blocks both α‐ and β‐adrenoceptors

Abstract: 1. AH 5158 differs from conventional adrenoceptor blocking drugs in producing competitive blockade of both alpha- and beta-adrenoceptors.2. AH 5158 is 5-18 times less potent than propranolol in blocking beta-adrenoceptors. It resembles propranolol in its non-selective blockade of beta(1)-cardiac and beta(2)-vascular and tracheal adrenoceptors and in its lack of intrinsic sympathomimetic activity.3. AH 5158 is 2-7 times less potent than phentolamine in blocking alpha-adrenoceptors. AH 5158 itself is more active on beta- than alpha-adrenoceptors.4. Blockade of noradrenaline vasopressor responses by AH 5158 in anaesthetized dogs was dose-dependent up to 1 mg/kg but no further blockade was obtained with larger doses of AH 5158. ;Self-limiting' blockade was not observed in dogs pretreated with cocaine, or in untreated dogs if the vasopressor agent was oxymetazoline instead of noradrenaline. A possible cause of ;self-limiting' blockade is discussed.5. In doses higher than those required for either alpha- or beta-adrenoceptor blockade, AH 5158 produced effects on cardiac muscle that are attributable to membrane-stabilizing activity. This was manifested as a negative inotropic action in spinal dogs and in guinea-pig left atrial strips, as a negative chronotropic action in syrosingopine pre-treated dogs, and as an increase in the effective refractory period of guinea-pig left atrial strips. AH 5158 was 3-11 times less potent than propranolol in these tests.6. In open chest dogs AH 5158 resembled propranolol in reducing cardiac output, rate and contractility, effects which are attributable to beta-adrenoceptor blockade. The drug differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger decreases in arterial blood pressure at equipotent beta-adrenoceptor blocking doses. These differences are attributable to the alpha-adrenoceptor blocking actions of AH 5158.7. In anaesthetized dogs, intravenously administered AH 5158 antagonized both catecholamine and ouabain-induced arrhythmias. Orally administered AH 5158 lowered systolic arterial pressure in conscious renal hypertensive dogs.8. These results show AH 5158 to possess a novel profile of activity. Possible uses of the drug in cardiovascular disorders such as hypertension, angina pectoris and cardiac arrhythmias are discussed.

Prostaglandins, oxygen tension and smooth muscle tone.

Abstract: 1. By using indomethacin to inhibit their intramural synthesis, we have investigated the contribution of prostaglandins to the maintenance of (a) the intrinsic tone of isolated smooth muscle preparations and (b) contractions produced by drugs or high oxygen concentration. 2. When treated with indomethacin, the rat stomach strip and chick rectum preparation slowly relaxed, whether they were bathed in Krebs solution or blood. Although their sensitivity to added prostaglandin was somewhat enhanced, they became insensitive to changes in oxygen or glucose concentration. However, another smooth muscle preparation, the rat colon, was neither relaxed by indomethacin nor contracted by high oxygen concentration. 3. These results support the hypothesis that intramural generation of prostaglandin maintains the tone of some smooth muscle preparations. 4. Contractions of the guinea-pig isolated colon were induced by histamine. These contractions were normally well maintained but in Krebs solution lacking either oxygen or glucose, only the initial spike contraction remained. In the presence of indomethacin the histamine contraction was also poorly sustained, but maintenance was restored by a low concentration of prostaglandin E2. 5. Thus, the effects on smooth muscle of oxygen or glucose lack may also be mediated by reduction in the synthesis or effects of an intramural prostaglandin. Extension of this hypothesis to intestinal and vascular smooth muscle in vivo is discussed.

Effects of amphetamine on the turnover rate of brain catecholamines and motor activity

Abstract: 1. Rats receiving (+)-amphetamine (either 0.3 or 0.2 mg/kg, i.v.) are anorexic. Only the former dose increases their motor activity. Both doses fail to change dopamine (DM) and noradrenaline (NA) concentrations in striatum and teldiencephalon. The turnover rate of striatal DM is increased only by 0.3 mg/kg of (+)-amphetamine; neither dose changes NA turnover rate in teldiencephalon.2. (-)-Amphetamine (1 mg/kg, i.v.) causes anorexia and hyperthermia in rats but it changes neither the steady-state concentration nor the turnover rate of striatal DM and tel-diencephalic NA. Motor activity is not increased by this dose of (-)-amphetamine.3. Cocaine (3 mg/kg, i.v.) increases motor activity and accelerates the turnover rate of striatal DM. This drug neither accelerates turnover rate of teldiencephalic NA nor causes anorexia.4. These observations suggest that the acceleration of striatal DM turnover rate elicited by (+)-amphetamine and cocaine may be associated with an effect on motor activity. In contrast, the increase of motor activity seems unrelated to the effects of these drugs on noradrenergic tracts of the teldiencephalon.

Dissociation of the behavioural and endocrine effects of lysine vasopressin by tryptic digestion.

Abstract: 1. Lysine vasopressin induces resistance to extinction of active avoidance behaviour (De Wied, 1971). 2. Digestion of lysine vasopressin with trypsin almost completely destroys the pressor-, antidiuretic-, oxytocic- and corticotrophin-releasing factor activities of lysine vasopressin, but does not materially influence its effect on the maintenance of an avoidance response.

Fluorometric estimation of 4-hydroxy-3-methoxyphenylethyleneglycol sulphate in brain

Abstract: 1. A simple, sensitive, and selective method was developed for the fluorimetric estimation of 4-hydroxy-3-methoxyphenylethyleneglycol sulphate (MOPEG-SO(4)) in rat brain.2. MOPEG-SO(4) was isolated on a DEAE Sephadex column. Fluorescence was measured at 465 nm (excitation at 320 nm) after heating the column eluate with acid and reheating after adding ethylene diamine.3. The concentration in brain of MOPEG-SO(4) increased after blockade of its transport from brain by treatment with probenecid and decreased after inhibiting its synthesis by treatment with alpha-methyltyrosine or pargyline.4. Our studies suggest that measurement in changes in the rate of formation of MOPEG-SO(4) may be a useful index of noradrenaline turnover.

Long‐lasting peripheral and central effects of 6‐hydroxydopamine in rats

Abstract: 1. In newborn rats treated with 6-hydroxydopamine hydrobromide (6-OHDA) (50-150 mg/kg on 5-7 days) a widespread and long-lasting dose related sympathectomy was demonstrated.2. When rats given 6-hydroxydopamine (100 mg/kg, seven treatments) in the neonatal period were killed at 10 weeks the concentration of noradrenaline (NA) in the heart, mesentery and vas deferens was significantly reduced. There was no alteration in the catecholamine content of the adrenal glands.3. The amplitude of the responses of perfused mesenteric arteries from 6-hydroxydopamine treated rats to intra-arterial noradrenaline was not increased, compared with controls, but the duration of responses was increased.4. 6-Hydroxydopamine given to newborn rats caused a long-lasting depletion of noradrenaline in three of the five regions of the central nervous system (cortex, cerebellum and spinal cord) studied. The concentration of noradrenaline in the pons-medulla was increased, but in the thalamic region was unchanged. The treated rats showed significantly lower exploratory activity.5. Treatment of newborn rats with 6-hydroxydopamine thus has striking and long-lasting effects on peripheral and central adrenergic systems.

Metabolism of isoprenaline in dog and man

Abstract: 1. The metabolism of isoprenaline has been studied in man and dog following intravenous and oral or intra-duodenal administration.2. Intravenous isoprenaline was excreted largely unchanged in urine in both species. Only one-third of the radioactivity in urine was in the form of the O-methyl metabolite.3. After oral doses in man or intraduodenal doses in dogs, plasma radioactivity was almost entirely as conjugated isoprenaline and this metabolite accounted for more than 80% of radioactivity in urine.4. Catechol-O-methyl transferase may be less important than Uptake(2) in limiting the pharmacological action of isoprenaline.5. Pharmacological response (heart-rate increase) was related to plasma concentration of isoprenaline only after rapid intravenous injections. In dogs, following prolonged infusion or intraduodenal doses, heart rate returned to base-line values when plasma concentrations of isoprenaline were high.

Effect of cannabis and certain of its constituents on pentobarbitone sleeping time and phenazone metabolism

Abstract: 1. Cannabis extract prolonged sleeping time in mice in a thermally neutral environment (30-32 degrees C) in which hypothermia does not occur. The prolongation was dose related, just detectable at 50 mg/kg, and 4-fold at 500 mg/kg.2. Under these conditions, ether sleeping time was not prolonged.3. Cannabis extract inhibited the aerobic metabolism of phenazone by a microsome-rich 9,000 g supernatant of mouse liver homogenate capable of nicotinamide adenine dinucleotide phosphate (NADPH) generation.4. Delta(1)-Tetrahydrocannabinol (Delta(1)-THC) prolonged pentobarbitone sleep and inhibited phenazone metabolism, but its action was limited, and could not account for the effect of the extract. The carotenes and water-soluble fractions of the extract were inactive on pentobarbitone sleep.5. Cannabidiol was strongly active by both tests; in vivo 39.8 muM/kg (12.5 mg/kg) prolonged sleep by 190%, and in vitro 12.7 muM inhibited phenazone metabolism 20%. These actions were dose related, and could account for the effect of the extract.6. The prolongation of pentobarbitone sleep by cannabis extract in a dose of 200 mg/kg, intraperitoneally, was maximal when given 30 min before the pentobarbitone, still present at 3 h, but undetectable at 24 hours. No phase of enhanced metabolism at 24 or 48 h after single cannabis injection was detected.7. It is concluded that cannabis extract inhibits microsomal activity of mouse liver, chiefly by virtue of its cannabidiol content. It is probable that cannabis consumption by man could lead to altered disposal of many other drugs, used in medicine or otherwise.

Occurrence of bombesin and alytesin in extracts of the skin of three European discoglossid frogs and pharmacological actions of bombesin on extravascular smooth muscle

Abstract: 1. Methanol extracts of the skin of Bombina bombina and Bombina variegata variegata, two European discoglossid frogs, contain an active tetradecapeptide, bombesin. Alytesin, a tetradecapeptide strictly related to bombesin is present in extracts of the skin of Alytes obstetricans, another European discoglossid frog. The American frog Rana pipiens, contains in its skin ranatensin, an endecapeptide related to bombesin and alytesin. 2. Passage of crude skin extracts of Bombina through a column of alumina yields eluates which may be considered free of other peptide contaminants and are suitable for the isolation of bombesin in a pure form. 3. Bombesin has a stimulant action on several preparations of intestinal, uterine and urinary tract smooth muscle. Sometimes the effect is easily repeatable and shows a fair proportionality to the dose, but at other times a prompt and intense tachyphylaxis is observed. Other smooth muscle preparations are poorly sensitive or insensitive to bombesin. The rat uterus, the kitten small intestine, the guinea-pig colon and the rat urinary bladder may be used for the quantitative bioassay of bombesin. 4. Bombesin-like peptides may easily be distinguished from all other naturally occurring peptides by parallel assay. They constitute a new group of active peptides possessing a peculiar spectrum of activity.

A comparison of the excitatory and inhibitory effects of non‐adrenergic, non‐cholinergic nerve stimulation and exogenously applied ATP on a variety of smooth muscle preparations from different vertebrate species

Abstract: 1. The responses to non-adrenergic, non-cholinergic nerve stimulation have been compared with those to exogenously applied ATP on seventeen different tissues from a number of vertebrate classes.2. Stimulation of all the mammalian gut preparations studied (with the exception of the guinea-pig ileum) after blockade of the effects of adrenergic and cholinergic nerve stimulation by guanethidine (3.5 muM) and hyoscine (1.3 muM) caused inhibition; exogenously applied ATP mimicked this inhibitory response.3. Stimulation of the guinea-pig ileum in the presence of hyoscine and guanethidine, usually caused a diphasic response, relaxation followed by contraction; exogenously applied ATP mimicked this response, in contrast to acetylcholine and noradrenaline which caused excitation and relaxation respectively.4. Stimulation of preparations of lower vertebrate gut and guinea-pig bladder in the presence of hyoscine and guanethidine caused contraction; exogenously applied ATP mimicked this contractile response.5. In each preparation the time course of the response to ATP was similar or identical to the response to non-adrenergic, non-cholinergic nerve stimulation.6. The results are consistent with the hypothesis that a purine nucleotide may be the transmitter substance released from non-adrenergic, non-cholinergic nerves supplying smooth muscle preparations from a number of vertebrate classes.

Effects of catecholamines and adenosine derivatives given into the brain of fowls

Abstract: 1. Adult fowls (Gallus domesticus) with cannulae chronically implanted into the IIIrd cerebral ventricle and various other sites of the brain received microinfusions or injections of catecholamines, adenosine, 3′,5′-cyclic AMP or its dibutyryl derivative. The effects of these substances on behaviour, electrocortical activity and body temperature were studied. 2. Behavioural and electrocortical sleep with fall in body temperature were obtained with intraventricular noradrenaline, α-methylnoradrenaline and isoprenaline; dopamine was ineffective. The doses required to elicit sleep were smaller than those affecting body temperature. Following mebanazine, the effects of noradrenaline were prolonged and doses of dopamine, previously ineffective, lowered body temperature and induced behavioural and electrocortical sleep. 3. Noradrenaline, α-methylnoradrenaline, isoprenaline and dopamine infused into the hypothalamus induced sleep and lowered body temperature. Effective doses of noradrenaline, α-methylnoradrenaline and isoprenaline infused into the hypothalamus were one-twentieth to one-fifth those for intraventricular injection. Tachypnoea developed with isoprenaline and dopamine. Additionally with dopamine, there was deviation of the head to the contralateral side, together with repetitive jerking movements of the head. These effects were prolonged and intensified by mebanazine, whereas the involuntary movements with dopamine were greatly reduced by haloperidol. 4. Involuntary movements, but without sleep, were induced by infusing dopamine into the paleostriatum augmentatum; noradrenaline infused into this site was ineffective. 5. In three of five fowls pretreated with aminophylline, 3′,5′-cyclic AMP infused into the hypothalamus induced behavioural and electrocortical sleep; without aminophylline pretreatment, 3′,5′-cyclic AMP was ineffective. Adenosine infused into the hypothalamus, following pretreatment of fowls with aminophylline, consistently induced behavioural and electrocortical sleep. Dibutyryl cyclic AMP infused into the hypothalamus of intact fowls elicited behavioural arousal, followed by bursts of electrocortical spikes (6 Hz) over both cerebral hemispheres, spikes subsequently becoming regular at 1 Hz. Clonic limb and body movements occasionally accompanied the bursts of spike activity, infrequently developing into convulsions. In fowl encephale isole preparations, in which dibutyryl cyclic AMP was infused into the hypothalamus, spike activity was confined to the ipsilateral hemisphere.

Evaluation of mechanisms controlling the release and inactivation of the adrenergic transmitter in the rabbit portal vein and vas deferens

Abstract: 1. A method is described for the detection and assay of picogramme quantities of noradrenaline. This involves transferring Krebs solution containing noradrenaline to a cascade system where the catecholamine may be bioassayed on superfused preparations of the rabbit aorta and iliac artery. 2. Electrical field stimulation of the rabbit vas deferens and portal vein caused the release, into the bathing medium, of a material which was identified by pharmacological and chemical tests as noradrenaline. 3. Cocaine (0·3-5 μg/ml) caused a marked increase in noradrenaline output after electrical stimulation of the portal vein and vas deferens. This effect appeared to be maximal at a concentration of 2·4 μg/ml; when the cocaine concentration was increased above 10 μg/ml the noradrenaline output was greatly reduced. 4. Phenoxybenzamine (5 μg/ml) caused a 4-8 times greater increase in noradrenaline output than cocaine; however, the increase in output due to phenoxybenzamine was much smaller in tissues pretreated with cocaine. 5. Corticosterone (20 μg/ml) increased noradrenaline output by 30-40% in untreated vas deferentia, but caused a 300% increase in output in tissues pretreated with cocaine. Cocaine also caused a much greater increase in output in tissues pretreated with corticosterone than in untreated tissues. 6. Treatment with pargyline plus tropolone caused a 100-200% increase in noradrenaline output; this effect was not modified by cocaine, but was abolished when the tissues were pretreated with either phenoxybenzamine or corticosterone. 7. When tissues were stimulated for 240 pulses at 1-16 Hz, the output per pulse of noradrenaline increased linearly with the logarithm of the frequency of stimulation. This relationship between frequency and output was seen in both untreated tissues, and in tissues treated with cocaine, phenoxybenzamine, corticosterone or pargyline plus tropolone. 8. It is concluded that cocaine enhances output by blocking the neuronal reuptake of noradrenaline, and corticosterone by blocking the extraneuronal uptake and subsequent metabolism of noradrenaline. Phenoxybenzamine acts by blocking both neuronal and extraneuronal uptake mechanisms. There appears to be a dynamic balance in the distribution of noradrenaline between the two uptake mechanisms after the release of the transmission from the nerve endings. 9. It is calculated that more than 90% of the noradrenaline released by nerve stimulation (240 pulses at 2-16 Hz) is inactivated by neuronal and extra neuronal uptake mechanisms. 10. It is calculated that the fraction of the total noradrenaline store that is released by one pulse at 2 Hz is 6·6 × 10-5 in the portal vein and 5·6 × 10-5 in the vas deferens; the corresponding values at 16 Hz were 15·9 × 10-5 and 16·2 × 10-5.

The occurrence of tolerance to a central depressant effect of nicotine.

Abstract: Summary 1 . Rats were injected with 0·8 mg nicotine/kg, 0·8 mg amphetamine/kg or with saline immediately before being tested for 30 min in activity boxes. 2 . During the first 3 trials the nicotine group were less active than the controls but from trial 5 onwards nicotine had a stimulant effect. The stimulant effect of the amphetamine did not alter with repeated injection.

Effects of clozapine on cerebral catecholaminergic neurone systems

Abstract: Summary 1 . Clozapine, a dibenzodiazepine derivative claimed to possess antipsychotic properties in man without producing extrapyramidal disorders, greatly increased the turnover of cerebral dopamine in the rat. 2 . The drug itself was virtually devoid of cataleptigenic activity in rats; however, it antagonized prochlorperazine-induced catalepsy. 3 . It is proposed that clozapine causes a blockade of striatal dopamine receptors which is of the surmountable type in contrast to that produced by cataleptigenic neuroleptics. In addition, clozapine may also increase the turnover of cerebral noradrenaline.

Output of prostaglandins from the rabbit kidney, its increase on renal nerve stimulation and its inhibition by indomethacin.

Abstract: Summary 1 . In each of six experiments, prostaglandins were identified in the renal venous blood of the rabbit. The concentrations in renal venous blood were up to 45 times higher than in aortic blood, suggesting that most of the prostaglandins originate from the kidney. 2 . Prostaglandins E2, F2α and a prostaglandin of the A, C or B series were estimated by biological assay after solvent partition and column or thin-layer chromatography. 3 . Prostaglandins E2 and F2α were identified conclusively by combined gas chromatography-mass spectrometry. 4 . Electrical stimulation of the renal nerve increased the output of prostaglandins. 5 . Indomethacin (10 mg/kg) injected intravenously, reduced the output of prostaglandins into renal venous blood and prevented the increase in output on renal nerve stimulation.

The release of prostaglandins and rabbit aorta contracting substance (RCS) from rabbit spleen and its antagonism by anti-inflammatory drugs

Abstract: 1. Slices of rabbit spleen generate rabbit aorta contracting substance (RCS) and a prostaglandin of the E series when they are vibrated or stirred. 2. The release of both substances is increased by arachidonic acid and inhibited by aspirin-like drugs. 3. When the spleen effluent containing RCS and prostaglandin E is incubated for a further 3 min, the prostaglandin concentration increases and the RCS concentration declines. 4. RCS may therefore be an unstable intermediate in the biosynthesis of prostaglandins.

Relative activities on and uptake by human blood platelets of 5-hydroxytryptamine and several analogues.

Abstract: 1. The specificity of platelet receptor sites for 5-HT uptake and for the rapid morphological change and aggregation was investigated with 5-hydroxy-tryptamine (5-HT) and seventeen analogues as well as with some antagonists of 5-HT.2. The analogues, with the exception of 5-hydroxy-N'N'-dibutyltryptamine, caused the rapid morphological change in platelets. In concentrations below those needed to produce the agonistic action (viz. 0.05-2.0 muM), these analogues themselves inhibited competitively the shape change caused by 5-HT.3. The velocity of change in shape caused by 5-HT was reduced in low Na media.4. Ten analogues produced platelet aggregation; three of these, viz. 5-methoxy-alpha-methyltryptamine, 5-hydroxy-alpha-methyltryptamine and 5-hydroxy-N'N'-diisopropyltryptamine), were approximately equipotent with 5-HT. Six analogues did not induce platelet aggregation.5. All the analogues which prevented the initial change in shape of platelets caused by 5-HT also inhibited its aggregating effect, apparently competitively with low K(i) values (0.02-1.6 muM).6. As with the inhibition of shape change, the inhibition of aggregation shows relatively low structural specificity of the receptor site.7. Methysergide was a potent inhibitor of shape change and aggregation (K(i) approximately 0.03 muM); imipramine was much less inhibitory (K(i) approximately 5-10 muM).8. Only one analogue (5-hydroxy-alpha-methyltryptamine) was taken up like 5-HT by platelets. All the other analogues inhibited the uptake of 5-HT by platelets (K(i)=0.2-2.7 muM).9. Methysergide was a weak inhibitor of 5-HT uptake (K(i) approximately 125 muM) whereas imipramine was very effective (K(i) approximately 0.3 muM).10. Our results show that the initial change in shape of platelets is required for and precedes aggregation. The structural specificity of the platelet receptor concerned with shape change and aggregation caused by 5-HT appears low whereas the uptake mechanism is a highly specific one. The uptake probably proceeds through more than one step, the relationship between the steps is not yet clear.

Anterograde amnesic effects of pethidine, hyoscine and diazepam in adults.

Abstract: 1. The intravenous administration of 5 and 10 mg of diazepam caused anterograde amnesia in 50 and 90% of adults, the peak effect occurring in 2-3 min and action persisting for 20-30 minutes.2. Hyoscine (0.4 and 0.6 mg) caused amnesia in 35 and 50% of patients with peak effect not occurring until 50-80 min after injection and action persisting for at least 120 minutes.3. With neither drug was there any relationship between the incidence of amnesia and the degree of drowsiness.4. Amnesia was not observed after saline or after 50 mg pethidine.5. On questioning 6 h after a short operation many patients had no memory of an object which they clearly recognized and described 1 h after surgery.

Metabolism of amylobarbitone in patients with chronic liver disease

Abstract: 1 A single dose of amylobarbitone (3·23 mg/kg) was given by intravenous injection to each of ten healthy controls and two groups of five patients with chronic liver disease A curve of serum amylobarbitone concentration against time was prepared for each subject and the proportion of the serum amylobarbitone bound to protein determined The urinary excretion of the metabolite hydroxyamylobarbitone, ethyl (3 hydroxyisoamyl) barbituric acid was measured 2 The degree of protein binding of serum amylobarbitone was reduced in the five patients (group I) with abnormally low concentrations of albumin in serum ( 3·5 g/100 ml) 3 The equation for a double exponential decay was fitted to the concentration/time curves for amylobarbitone free in the serum water The mean intercepts and rate constants were used to calculate the dimensions of mathematical models based on a two compartment open system 4 The five patients (group I) who had abnormally low concentrations of albumin in serum showed impairment of amylobarbitone metabolism; the rate constant β(h-1) for the second exponential decay of serum amylobarbitone concentration was reduced (P<0·01), the urinary excretion of hydroxyamylobarbitone was reduced (P<0·001) and the mean serum water clearance (C, ml/min) representing amylobarbitone elimination by metabolism was reduced 5 The five patients (group II) who had normal concentrations of albumin in serum showed no impairment of amylobarbitone metabolism Within the total patient group there were strong and significant positive correlations between the serum albumin concentration and each of the indices of the rate of amylobarbitone metabolism 6 Both patient groups showed an increase in the first dispositional rate constant α(h-1) and in the clearance (Ct ml/min) representing transfer between central and peripheral compartments The physiological basis for this observation is uncertain 7 The clinical response to the single intravenous dose of amylobarbitone was not significantly greater (P=0·11) in the patient group (I) with slow amylobarbitone metabolism than in the patient group (II) with a normal rate of amylobarbitone metabolism

Central cholinergic and adrenergic mechanisms in the release of antidiuretic hormone

Abstract: 1. Studies on the urine outflow, blood ADH concentration and electrolyte excretion were carried out in alpha-chloralose anaesthetized hydrated dogs; the agonists and antagonists of specific cholinoceptors and adrenoceptors were injected by the intracerebroventricular technique, to delineate the role of the C.N.S. receptors in the control of ADH secretion.2. Central injection of acetylcholine elicited a dose-dependent antidiuretic response which was associated with an increase in the blood ADH titre. Central atropinization partially blocked the antidiuretic response. The remaining antidiuretic response was reversed to a diuretic one by further pretreatment with phenoxybenzamine. The diuretic response thus obtained could be blocked by propranolol.3. The alpha-adrenoceptor agonists, phenylephrine and noradrenaline, induced dose-dependent antidiuretic responses with a concomitant rise in blood ADH concentration. Their effect could be blocked by pretreatment centrally with phenoxybenzamine. Low doses of adrenaline induced a diuretic response and a decrease in blood ADH concentration, higher doses elicited a dose-dependent antidiuretic response and increase in the titre of ADH in blood. Central phenoxybenzamine pretreatment reversed the antidiuretic effect of high doses of adrenaline to a diuretic effect which could be blocked by propranolol.4. Isoprenaline elicited a dose-dependent diuretic response and a decrease in blood ADH titre and propranolol competitively blocked the effect of isoprenaline.5. It is concluded that central muscarinic cholinoceptors and the alpha-adrenoceptors are concerned in the release of ADH, whereas the beta-adrenoceptors are concerned with inhibition of ADH release.

Control of pancreatic amylase release in vitro: effects of ions, cyclic AMP, and colchicine

Abstract: 1. The time course and concentration-response relationship of amylase release from pieces of guinea-pig pancreas in vitro in response to bethanechol and pancreozymin was determined. 2. Removal of Ca++ from the medium had no effect on basal amylase release but abolished the stimulating effect on release of bethanechol. 3. Elevation of the concentration of Mg++ in the medium increased basal amylase release and reduced the response to bethanechol. 4. Elevation of the concentration of K+ in the medium increased amylase release; this effect was blocked by a concentration of atropine which blocked also the response to bethanechol. 5. Cyclic AMP, dibutyryl cyclic AMP and theophylline failed to stimulate amylase release. Pancreatic cyclic AMP concentrations were found not to be increased by bethanechol, pancreozymin or an elevated concentration of K+ in the medium. 6. Colchicine had no effect on basal amylase release or the response to bethanechol or pancreozymin. 7. It is concluded that the coupling of stimulus to secretion involves ionic control but that neither cyclic AMP production nor microtubular mechanisms play a major role in controlling exocytosis in the pancreatic acinar cell. These findings are discussed in relation to the stimulus-secretion coupling processes in other cells.

The hyperglycaemic effect of morphine

Abstract: 1. In the unanaesthetized cat, an injection of 0·75 mg of morphine into a lateral cerebral ventricle produced strong hyperglycaemia; on intravenous injection, 10 to 30 times larger doses were required. Other effects produced with both injections were shivering, pupillary dilatation, opening of the eyes, miaowing, periods of excitation, and analgesia. Between the periods of excitation the cat did not react to objects moving in front of its eyes and it had a vacant stare. 2. Noradrenaline, adrenaline, and 5-hydroxytryptamine (5-HT) injected intraventricularly (250 μg, twice) depressed the hyperglycaemia due to intraventricular morphine, and noradrenaline also depressed the hyperglycaemia due to intravenous morphine. Adrenaline produced the strongest and 5-HT the weakest depression. 5-HT did not depress the other effects of morphine, but the catecholamines depressed most of them; only analgesia and the vacant stare appeared to be unaffected. 3. Reserpine injected intraventricularly (0·5 mg, twice) greatly accentuated the hyperglycaemia as well as the other effects produced by intraventricular morphine, but pupillary dilatation and opening of the eyes no longer occurred; the protrusion of the nictitating membranes produced by the reserpine persisted. 4. Pentobarbitone sodium injected intraperitoneally in an anaesthetizing dose practically abolished the morphine hyperglycaemia, but injected intraventricularly in a dose of a few milligrammes, it had a two fold effect: depression followed by enhancement of the morphine hyperglycaemia. The enhancement may be due to sensitization of the effect of the adrenaline released by morphine, since adrenaline hyperglycaemia was enhanced as well. 5. Morphine did not seem to act on structures in the walls of either the lateral or third ventricle when producing its hyperglycaemic effect on intraventricular injection. The action may therefore be on more caudally situated parts of the neuro-axis, on the central grey, on structures in the floor of the fourth ventricle or of the lateral recesses, or even on structures near the ventral surface of the brain stem.

A metabolic interaction in vivo between cannabidiol and Δ1‐tetrahydrocannabinol

Abstract: The effect of pretreatment with cannabidiol (CBD; 50 mg/kg i.p.) on the distribution of radioactivity in chromatograms of ethyl acetate extracts of the brains of mice injected with tritiated Delta(1)-tetrahydrocannabinol ((3)H-Delta(1)-THC; 1.0 mg/kg i.v.) was determined. The pretreatment with CBD produced significant increases in the levels of radioactivity in the brain assigned to Delta(1)-THC and its centrally active metabolite 7-hydroxy-Delta(1)-THC: the changes produced were respectively 1.4 and 2.0 fold.Pretreatment with CBD did not bring about any detectable change in the degree of 'catalepsy' produced by Delta(1)-THC. This negative finding may have been due to the wide limits of error that were obtained in the bioassay.

A comparison of the pharmacological and biochemical properties of substrate‐selective monoamine oxidase inhibitors

Abstract: 1. MB (ii) increasing brain levels of noradrenaline (NA) and 5-HT and (iii) antagonizing tetrabenazine-induced sedation.2. Concentrations of MB (b) the rise in brain 5-HT levels rather than NA levels.

Investigations of the mode of action of a new antidysrhythmic drug, Kö 1173.

Abstract: 1. Ko 1173, 1-(2',6'-dimethyl-phenoxy)-2-amino-propane, was equal to lignocaine in potency as a local anaesthetic on stripped frog sciatic nerve at pH 7·5. 2. In anaesthetized guinea-pigs in which ventricular fibrillation had been produced by an intravenous infusion of ouabain, intravenous administration of Ko 1173 caused reversion to sinus rhythm in ten out of ten animals. The mean dose of Ko 1173 required was 3·3 mg (15·3 μmol)/kg. When the ouabain infusion was continued, ventricular fibrillation did not recur, and the lethal dose of ouabain was greater than in controls. 3. Pretreatment with Ko 1173, however, did not influence the toxicity of ouabain infusion, implying great brevity of action. 4. Ko 1173 given intravenously caused a bradycardia which was maximal in 2-3 min, and which did not last more than 5 minutes. 5. Ko 1173 reduced the maximum driven frequency of isolated rabbit atria, raised electrical threshold, slowed conduction velocity and depressed contractions. 6. Ko 1173 reduced the maximum rate of depolarization of intracellularly recorded rabbit atrial and ventricular potentials, but did not affect the resting potential or the duration of the action potential.

Monoamine mediation of the morphine-induced activation of mice.

Abstract: Summary 1 . The dose-response relationship for hyperactivity in grouped mice following the injection of morphine sulphate has been established. 2 . The activation response can be modified by drugs which affect either catecholamines or indoleamines. 3 . The monoamine precursors l-DOPA and 5-hydroxytryptophan potentiate the response. 4 . The monoamine synthesis inhibitors α-methyl-p-tyrosine and p-chlorophenylalanine reduce the response. 5 . Inhibition of monoamine oxidase activity by pargyline caused a great increase in the response. The simultaneous administration of reserpine resulted in a further potentiation. 6 . Reserpine blocked the response whenever it was given alone, either before, with or after the injection of morphine. 7 . Blockade of α-adrenoceptors with phentolamine or phenoxybenzamine reduced the response. 8 . Blockade of tryptaminergic receptors with methysergide or cinanserin also antagonized the response. 9 . The major tranquillizers haloperidol and chlorpromazine reduced the response. Haloperidol was especially effective in this regard. 10 . The tricyclic antidepressant drug imipramine potentiated the response. 11 . The morphine antagonist nalorphine completely prevented the response. 12 . The anticholinergic agent atropine and the antihistaminic drug mepyramine did not affect the response. 13 . We conclude that dopamine, noradrenaline and 5-hydroxytryptamine are all involved in the normal activation response of grouped mice to morphine, with dopaminergic mechanisms being of primary importance.