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1 The effects of microiontophoretically applied morphine and its interactions with the effects of microiontophoretic applications of either acetylcholine, (-)-noradrenaline or 5-hydroxytryptamine have been studied on single neurones in the brain stem of rats anaesthetized with urethane. 2 Morphine excited or inhibited most neurones tested and the effects, especially excitation, were often extremely powerful. However, the time course of the excitatory and inhibitory effects were somewhat different. 3 Desensitization to the excitation produced by morphine was seen after repeated or prolonged applications and it is suggested that this phenomenon may be related to the tolerance which develops after chronic administration of morphine. No desensitization was observed to inhibition of neuronal activity by morphine. 4 Morphine usually reduced the excitation of neurones by acetylcholine, noradrenaline or 5-hydroxytryptamine but sometimes potentiated the effect, although not always on the same neurones. Inhibition of neuronal activity by these compounds was never modified by morphine and neither were the effects of glutamate or D,L-homocysteic acid when used as control agonists. 5 The in vitro release of morphine from six micropipettes was determined and the transport number was calculated to be 0.051 (s.d. 0.021). 6 The implications of these observations in explaining the pharmacological actions of morphine are discussed.

1 The possibility of a vasodilator innervation to the isolated and perfused central artery of the rabbit ear was examined. 2 Stimulation of the periarterial nerves in the presence of noradrenaline or other agonist used to maintain a partial constriction of the ear artery, led to a decrease in intraluminal flow followed after the cessation of stimulation by an increase in flow beyond the pre-stimulation level. 3 After blockade of adrenergic transmission with bretylium or guanethidine or of the α- and β-adrenoceptors with phentolamine and propranolol, stimulation of the periarterial nerves in the presence of a background tone, led to a clearly detectable vasodilatation. This dilatation was not blocked by treatment with atropine or mepyramine; nor was it enhanced by physostigmine. 4 Pretreatment of rabbits with reserpine (2 mg/kg) to deplete catecholamine stores, eliminated both the vasoconstrictor and vasodilator responses to nerve stimulation. However, a lower dose of reserpine (0.2 to 0.5 mg/kg) selectively eliminated the vasoconstrictor component of periarterial nerve activation. 5 The ear artery dilated in response to low concentrations of prostaglandin E1, and E2, in the presence of noradrenaline, but treatment with inhibitors of prostaglandin synthesis, indomethacin, aspirin or eicosa-5,8,11,14-tetraynoic acid did not reduce the vasodilator response. Attempts to extract a prostaglandin in the bathing medium were unsuccessful. 6 The involvement of a purine nucleotide appeared unlikely since the ear artery dilated only in response to fairly high concentrations of adenosine 5′-triphosphate (ATP), adenosine 5′-diphosphate (ADP) and adenosine 5′-monophosphate (AMP). Furthermore, dipyridamole, an inhibitor of adenosine uptake, enhanced dilatation due to exogenous ATP but not to periarterial nerve stimulation. 7 It is concluded that the central artery of the rabbit ear has a vasodilator innervation but the identity of the transmitter remains to be established.

1 Low doses of tiprenolol (0.01-0.02 mg/kg) and propranolol (0.05 mg/kg) abolished the ventricular arrhythmias produced by the intravenous injection of adrenaline in anaesthetized dogs respired with halothane.2 Larger doses of tiprenolol (2.0-4.0 mg/kg) restored sinus rhythm in four of five dogs with ventricular tachycardia produced by toxic doses of ouabain. Propranolol (2.0-4.0 mg/kg) had the same effect in each of four dogs.3 Both tiprenolol (4.0-8.0 mg/kg) and propranolol (4.0 mg/kg) increased the frequency of sinus beats and reduced the ventricular rate in dogs with ventricular tachycardia 20-44 h after ligation of a coronary artery.4 Practolol (0.5-16.0 mg/kg) did not reduce the ventricular rate or increase the frequency of sinus beats in dogs with ventricular tachycardia after ligation of a coronary artery.5 In dogs with ouabain-induced ventricular tachycardia mean arterial pressure was reduced after the administration of tiprenolol (0.5-8.0 mg/kg) or propranolol (4.0-8.0 mg/kg). Depression of sinus and atrioventricular nodal function, and of intraventricular conduction developed in some of the dogs given tiprenolol (4-8 mg/kg) or propranolol (8.0 mg/kg).6 The administration of tiprenolol (1.0-8.0 mg/kg) or propranolol (4.0-8.0 mg/kg) depressed the arterial pressure and caused the deaths of some dogs in which a coronary artery had been ligated. Such deaths did not occur in the group which had been given toxic doses of ouabain.

1 (±)-10-(3-Dimethylamino-2-methylpropyl)-2-valeroylphenothiazine hydrochloride (M & B 18,706) has been compared with dimethothiazine, chloropromazine, diazepam and baclofen for potency in reducing decerebrate rigidity in the cat and rat and for activity in causing ataxia or sedation. 2 When given intravenously M & B 18,706 had seven times the potency of dimethothiazine and one-half the potency of chlorpromazine in reducing the rigidity of the intercollicular decerebrate cat. When administered orally M & B 18,706 and chlorpromazine were equi-potent in reducing rigidity but M & B 18,706 was less effective than chlorpromazine in producing ataxia in this species. 3 In the rat, M & B 18,706 had one-quarter the potency of chlorpromazine for reducing decerebrate rigidity but had from 1/20th to 1/200th its potency in tests for sedative or tranquillizing activity. 4 M & B 18,706, like dimethothiazine and chlorpromazine, had little effect on the rigidity of ischaemic decerebrate cats and failed to inhibit polysynaptic spinal reflexes. 5 M & B 18,706 had intravenous potency comparable to chlorpromazine in reducing the pressor action of noradrenaline in the spinal cat.

1 In unanaesthetized pigeons, kept at room temperature (20-23 degrees C) the effects on cloacal temperature were examined of catecholamines, phenoxybenzamine and propranolol, injected into the cerebral ventricles.2 Noradrenaline, adrenaline, dopamine and isoprenaline caused a fall in cloacal temperature.3 Phenoxybenzamine produced a long-lasting small rise in cloacal temperature. This rise is attributed to removal of the hypothermic effect of noradrenaline released continuously from adrenergic neurones ending in the anterior hypothalamus. Propranolol produced a slight fall in cloacal temperature.4 The hypothermic effects of noradrenaline, adrenaline and dopamine were prevented by phenoxybenzamine but not by propranolol. They are therefore attributed to activation of alpha-adrenoceptors.5 The hypothermic effect of isoprenaline was not prevented by either phenoxybenzamine or propranolol. The effect can therefore not be attributed to activation of either alpha or beta-adrenoceptors. Propranolol actually accentuated the isoprenaline-induced hypothermia.

1 There is a growing concensus that myocardial performance in the early stages of experimental endotoxic and septic shock is relatively normal; however, recent reports have identified an intermediate phase of shock when myocardial dysfunction is clearly apparent.2 The mechanism of dysfunction has become a subject of intense investigation. A current view is that altered myocardial responsiveness to circulating catecholamines may play an important role in the dysfunction observed after endotoxin administration. The present studies, in which an isolated working heart preparation of the dog was used, were designed to test this hypothesis. This particular experimental preparation was selected to provide an adequate interpretation of results; cardiac output, afterload, and concentrations of adrenaline reaching the coronary vascular bed were controlled in all experiments. Responses to infusions of adrenaline were recorded in the ;steady-state' condition. Control (non-shocked) heart responses to adrenaline were highly reproducible in terms of inotropic, chronotropic and coronary vascular behaviour.3 Results from the study document myocardial dysfunction within 4-6 h following an LD(70) endotoxin administration on the basis of increased left ventricular end diastolic pressure (LVEDP), decreased cardiac power and myocardial efficiency, and depressed negative and positive dP/dt parameters.4 Findings suggest significantly altered responsiveness of the myocardium to infused adrenaline at rates of 1, 2, and 5 mug/min with concentrations between 10 and 1 ng/ml blood. LVEDP was elevated while calculated power and efficiency parameters remained significantly below control values during infusion of adrenaline in endotoxin-treated hearts. Depressions of responsiveness were interpreted to occur on the basis of failure to restore positive and negative dP/dt to normal values and depressed coronary blood flow responses during adrenaline administration. Increases in coronary flow were regularly less in experimental hearts than the controls. Heart rate responses to adrenaline in both failing and non-failing hearts were identical.5 In conclusion, it is suggested that myocardial contractile and relaxation characteristics and coronary vascular responses to adrenaline infusion are depressed in endotoxin shock during the period of demonstrated myocardial dysfunction. No distinct causal relationships were observed between the altered myocardial responsiveness and pathogenesis of heart dysfunction since myocardial dysfunction and altered responsiveness to adrenaline were generally observed together. Myocardial oedema formation after endotoxin as previously reported by this laboratory may bear a relationship to the depressed negative dP/dt response to adrenaline.

1 The amplitudes of the first positive and the first negative waves of cortical potentials evoked by electrical stimulation of the dental pulp in the rat were decreased following electrical stimulation of the peripheral cut end of the saphenous nerve. 2 This effect was greatly diminished when the stimulation of the saphenous nerve was performed with the saphenous or femoral veins ligated. 3 During stimulation of the saphenous nerve of a donor rat, the subcutaneous tissue in the area supplied by the nerve was perfused; when the perfusate (in which a permeability-increasing factor was detected) was injected intravenously into a recipient animal, a decrease in the amplitude of the evoked cortical potential of the recipient rat was also observed. 4 Intravenous injections of 5-hydroxytryptamine, histamine, bradykinin, prostaglandins or adenosine-triphosphate produced no effect on the evoked cortical potential, whereas large doses of acetylsalicylic acid caused a decrease. 5 It is suggested that a humoral factor, released during sensory nerve stimulation, may help to modulate the processing of afferent inputs from pain receptors.

1 The cardiovascular actions of 23 adenosine analogues have been examined in anaesthetized open thorax dogs; the analogues were substituted in the 2-position of the purine ring, or in the exocyclic amino group, or were modified in the imidazole or sugar rings. 2 The effects of these compounds on coronary blood flow, peripheral blood pressure, and heart rate were compared with those of adenosine. 3 9-β-D-Arabinofuranosyladenine had no cardiovascular action; the other analogues on intra-atrial administration caused an immediate increase in coronary blood flow, the magnitude and duration of which varied with the structures of the analogues. 4 2-Fluoro-, 2-bromo-, 2-isobutylthio-, 2-ethylamino-, and 5′-deoxy-5′-chloro- adenosines had coronary dilator potencies equal to or greater than that of adenosine. No relationship was found between the dilator potency of the adenosine analogues and their duration of coronary dilator action. 5 The coronary dilator action of adenosine was potentiated by inosine, 9-β-D-arabinofurano-syladenine, tubercidin, N6-methyladenosine and 2-trifluoromethyl-N6-methyladenosine. 6 There was no correlation between the substrate specificities of the shorter-acting analogues for adenosine deaminase or adenosine kinase and their duration of coronary dilator action. 7 It is proposed that in the anaesthetized dog, uptake into tissues is a more important mode of removal of adenosine and adenosine analogues from the vascular system than inactivation by adenosine deaminase, that the duration of coronary dilator action of the analogues is related primarily to their specificity for the carrier which mediates adenosine uptake, and that the adenosine carrier is not associated with kinase action.

1 The effects of tolamolol on haemodynamics and myocardial contractility were investigated in two groups of six patients undergoing diagnostic cardiac catheterization.2 The intravenous administration of tolamolol (0.15 mg/kg) produced a significant fall in heart rate from a control value (87 +/- 7 to 62 +/- 3 beats/min) 5 min after administration and a concomitant fall in cardiac output from 4.7 +/- 0.9 to 3.5 +/- 0.8 litres/minute. There was no significant change in systemic blood pressure, pulmonary artery blood pressure or stroke volume.3 There was no change in left ventricular end diastolic pressure after tolamolol. There was a fall in the maximum rate of rise of the left ventricular pressure (LV dp/dt(max)) and the derived index of the left ventricular contractile state (V(max)).4 These results suggest that tolamolol has a predominantly negative chronotropic but also a lesser negative inotropic action on the heart.

1 Noradrenaline and clonidine were applied by microiontophoresis to single neurones in the cerebral cortex and medullary reticular formation of anaesthetized rats.2 Of a total of 247 neurones studied, 79% of medullary units and 60% of cortical units responded in the same manner to both noradrenaline and clonidine. The usual response was a depression of neuronal firing rate.3 It proved possible to antagonize some responses to both substances by the microiontophoresis of bulbocapnine, whilst leaving unaffected similar responses to 5-hydroxytryptamine.4 On 13% of the cells, clonidine produced an increase of firing rate. This effect could not be attributed to a post-synaptic antagonism of tonically released endogenous noradrenaline, but may indicate a presynaptic action of clonidine, reducing noradrenaline release.5 These observations are thought to support the idea that clonidine may have an agonist action on noradrenaline receptors in the brain.

1 The effects of bicuculline on dorsal and ventral root activity and upon the depressant effect of gamma-aminobutyric acid (GABA) and glycine on ventral root responses have been studied on the isolated spinal cord of the frog.2 In the absence of stimulation, the alkaloid induced a variety of activity of which the most notable was phasic simultaneous slow wave depolarization in the dorsal and ventral roots which could be reduced or suppressed by magnesium.3 With low concentrations of bicuculline, the adjacent dorsal root response evoked by a single stimulus was depressed maximally before an increase in the ventral root response could be discerned.4 The bicuculline-induced dorsal root activity (in the absence of stimulation) was still apparent at times when the evoked dorsal root response was reduced.5 Bicuculline did not differentiate between the depressant effects of GABA and glycine on the evoked ventral root responses.6 The excitant effects of bicuculline reported here did not appear to be attributable to specific antagonism of the postsynaptic depressant action of GABA.

1 A method of stereotactic dissection followed by fluorimetric assay, has been used to determine the distribution of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT) within the preoptic hypothalamic area of rabbit brain. 2 The method involved subdividing the area into a number of thin slices cut with reference to stereotactic co-ordinates. The amine content of each slice was then determined fluorimetrically. 3 Noradrenaline was shown to be concentrated (>2.0 μg/g) in two areas within the preoptic hypothalamic area, both of which were adjacent to the mid-saggittal line: the first was close to the preoptic nucleus and the second immediately caudal to the main group of hypothalamic nuclei. 4 Dopamine was evenly distributed throughout the preoptic hypothalamic area. 5 5-HT was concentrated (>1.6 μg/g) towards the lateral borders of the area, principally in the region which joins the preoptic area to the anterior hypothalamus. 6 The relative merits of the stereotactic approach and the histochemical approach are discussed.

1 The shortening of cycle length (=positive chronotropic effect) by ouabain produced in isolated spontaneously beating atria of the guinea-pig was analyzed. 2 The action of ouabain was dose-dependent; threshold response was seen at 1 × 10-7 M, and maximal response occurred at 4 × 10-7 M. The half-time of the ouabain effect was about 20 minutes. 3 The positive chronotropic effect of ouabain was reduced to 40% by β-adrenoceptor blockade (3.3 × 10-9 M propranolol) or by reserpine-depletion of catecholamines. Incubation of reserpine-treated atria with noradrenaline partially restored the action of ouabain. 4 The effect of ouabain was greatly dependent upon the calcium concentration. The optimal calcium level was 2.5 × 10-3 M. Calcium and ouabain acted synergistically. 5 Increasing calcium concentrations inhibited the positive chronotropic effect of noradrenaline in a manner similar to increasing ouabain concentrations. 6 A hypothesis is proposed which explains the chronotropic effect of ouabain on the basis of two mechanisms: (1) increase of the catecholamine concentration affecting the pacemaker; (2) mobilization of calcium, i.e. increase of the biologically effective intracellular calcium level.

1 The relative potencies of methotrimeprazine, (+)-methotrimeprazine, (+/-)-10-(3-dimethylamino-2-methylpropyl)-2-valeroyl phenothiazine hydrochloride (M & B 18,706) and (+)-M & B 18,706 in reducing the pressor action of noradrenaline in the spinal cat, reducing intercollicular decerebrate rigidity, and muscle spindle afferent activity have been studied.2 Methotrimeprazine was eight times as potent as (+)-methotrimeprazine in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity. M & B 18,706 was also eight times as potent as (+)-M & B 18,706 in reducing the pressor action of noradrenaline and six times as potent in reducing decerebrate rigidity.3 For the above compounds and chlorpromazine there was a significant correlation between the effective doses for the inhibition of the pressor action of noradrenaline and for the reduction of decerebrate rigidity.4 The doses which reduced decerebrate rigidity were similar to those that reduced muscle spindle afferent discharge. It is likely that these drugs reduce decerebrate rigidity by inhibiting fusimotor activity.5 Desipramine increased decerebrate rigidity and increased spindle afferent discharge.6 It is thought that the phenothiazine derivatives studied reduce decerebrate rigidity and spindle afferent discharge by inhibiting receptors for noradrenaline in the central nervous system.

1 Effects of cholinomimetic agents, given into the IIIrd ventricle of adult fowls (Gallus domesticus) or infused into the hypothalamus of young chicks, were tested on behaviour, respiratory rate and body temperature. 2 Carbachol evoked behavioural and electrocortical arousal but lacked postural and respiratory effects. Contrariwise, pilocarpine increased respiratory rate and induced postural changes, i.e. abduction of the wings, but lacked other behavioural effects and did not alter electrocortical activity. Benzoylcholine induced tachypnoea, postural changes and brief electrocortical arousal. Acetylcholine was ineffective unless given with physostigmine, when electrocortical arousal, postural changes and tachypnoea developed. Methacholine induced tachypnoea and postural changes. 3 Effects of carbachol and pilocarpine were prevented by hyoscine and those of benzoylcholine by pempidine; hyoscine and pempidine were required together to prevent the effects of methacholine and to attenuate those of acetylcholine with physostigmine.

1 Three strains of rats spontaneously hypertensive (HRS), normotensive (NS) and hypotensive (HOS), were selected by repeated inbreeding. 2 In order to explain the different blood pressure levels observed, we have studied their vascular reactivity to noradrenaline and angiotensin II. Experiments were performed in anaesthetized ganglion-blocked, vagotomized rats. 3 The reactivity to noradrenaline was significantly higher in HRS than in NS and HOS rats. 4 The reactivity to angiotensin II appeared identical in the three strains used.

1 In unanaesthetized cats, the administration of 6-hydroxydopamine (6-OHDA), 750 mug, via the lateral cerebral ventricle produced a pronounced fall in rectal temperature but only a slight fall when repeated 7 days later. At this time hypothalamic noradrenaline concentration had diminished to 4% of control.2 In these animals, the hypothermic response to exogenous noradrenaline, 100 mug, given via the same route was uninfluenced by pretreatment with 6-OHDA.3 In unanaesthetized rabbits, intraventricular noradrenaline, 100 mug, produced a rise in rectal temperature and a biphasic effect on arterial pressure, a rise lasting 30 min followed by a fall.4 Intraventricular 6-OHDA, 750 mug, in unanaesthetized rabbits produced a rise in body temperature and a rise in arterial pressure. The same dose given to rabbits depleted of central noradrenaline with central 6-OHDA produced rises in body temperature and arterial pressure of similar magnitude, but of slower onset.5 These results suggest that intraventricular 6-OHDA releases noradrenaline from central neurones and that these neurones subserve thermoregulatory functions in both species. In the rabbit, central noradrenergic neurones can raise arterial pressure.

1 The actions of 5-methoxytryptamine (5-MeOT), N,N-dimethyltryptamine (DMT), 5-hydroxy-N,N-dimethyltryptamine (bufotenine, 5-HODMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), and their interactions with 5-hydroxytryptamine (5-HT), acetylcholine, (-)-noradrenaline, and glutamate were studied by microiontophoresis on single neurones in the brain stem of rats anaesthetized with urethane or decerebrate cats.2 Like D-lysergic acid diethylamide (LSD 25) the three psychotomimetic derivatives (DMT, 5-HODMT, 5-MeODMT) specifically antagonized 5-HT excitations of single neurones, but the non-psychotomimetic 5-MeOT had no antagonistic effects.3 In contrast to LSD 25, the psychotomimetic tryptamines only rarely antagonized glutamate effects, indicating that the excitatory 5-HT receptors and the glutamate receptors on the same neurones may be closely related spatially, but are separate.4 The methylated tryptamine derivatives were able to mimic the actions of 5-HT on neurones. The non-psychotomimetic 5-MeOT was most potent in this respect, while the other three derivatives which are psychotomimetic, were less active.5 The 5-HT mimicking actions of 5-MeOT were the same in rats pretreated with p-chlorophenylalanine or reserpine as in untreated rats. It therefore seems that the 5-HT mimicking actions are unlikely to be due to release of 5-HT, but are due to direct actions on 5-HT receptors.6 The evidence presented supports the hypothesis that LSD-like psychotomimetics act by an antagonism of 5-HT in the lower brain stem, and is not compatible with the suggestion that the psychotomimetic action of these drugs is related to 5-HT receptor stimulation.

1 Implantation of morphine into various parts of the corpus striatum of rats evokes only weak gnawing responses. 2 Deposition of apomorphine, morphine or methadone in the region of the nucleus ventralis thalami produces a biphasic response, i.e. general excitation, followed by a period of intense gnawing. 3 The effect of both apomorphine and morphine is blocked by chlorpromazine, haloperidol and pimozide. However, pretreatment with α-methyltyrosine methyl ester or α-methyldopa prevents only the gnawing response to morphine, but not to apomorphine. 4 Systemic nalorphine, morphine or pethidine suppress the gnawing response, evoked by thalamic implants of apomorphine or morphine. 5 Systemic amphetamine potentiates the effect of thalamic deposits of morphine. 6 Compulsive gnawing, following implantation of morphine into the ventral region of the thalamus, probably results from enhanced production and release of catecholamines.

1 The effects on tryptophan distribution and metabolism of drugs altering plasma unesterified fatty acid (UFA) concentration were investigated in the rat.2 UFA and plasma free (i.e. ultrafilterable) tryptophan altered in the same direction.3 Catecholamines and L-DOPA increased both plasma UFA and free tryptophan. L-DOPA also increased brain tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) but decreased brain 5-hydroxytryptamine (5-HT).4 Aminophylline increased plasma UFA and free tryptophan and also brain tryptophan, 5-HT and 5-HIAA. Food deprivation had qualitatively similar effects.5 Insulin decreased plasma UFA and free tryptophan in both fed and food-deprived rats. However, while in fed rats these changes were associated with small decreases of brain indoles, in food-deprived animals small increases occurred.6 Nicotinic acid had only small effects in fed rats but it opposed both the UFA and indole changes in food-deprived animals. Total plasma tryptophan increased in nicotinic acid treated, food-deprived rats.7 There was a tendency towards inverse relations between changes of plasma free and total tryptophan.8 The results suggest that drugs which influence plasma UFA through actions on cyclic AMP thereby alter the binding of tryptophan to plasma protein and that this leads to altered distribution and metabolism of tryptophan.

Summary 1 An investigation has been made of the effects of cadmium and zinc ions upon the contractile response of the guinea-pig isolated ileum to methacholine, histamine, potassium ion and a.c. field stimulation. The metal ions depress the response to all of these agents. 2 Radioisotope studies showed that cadmium and zinc ions have very much larger apparent volumes of distribution than sorbitol, both within whole ileum and within strips of the longitudinal smooth muscle layer. The results of these studies were indicative of surface binding and/or intracellular accumulation of these ions. 3 It is suggested that cadmium and zinc ions directly depress smooth muscle contractility in a non-specific manner. This action may result from their binding to or accumulation within the muscle cells.

Summary 1 . Castrated male rats and male rats that had been castrated as well as adrenalectomized, showed hypersexual behaviour 24 h after treatment with parachlorophenylalanine (PCPA), as did intact rats. 2 . A dose of PCPA 100 mg/kg was sufficient to induce mounting behaviour; this dose lowered the cerebral 5-hydroxytryptamine (5-HT) to about 50% in 24 h and further to 40% in 72 hours. 3 . Groups of juvenile male rats treated chronically with PCPA 100 mg/kg or 50 mg/kg, or with testosterone propionate 1·25 mg, showed hair loss after three weeks of treatment (6 injections), because of increased social interaction. 4 . Groups of intact male rats 9–11 weeks old given testosterone propionate 1·25 mg subcutaneously, showed mounting behaviour 3–5 h after the injection which was indistinguishable from the behaviour seen 24 h after treatment with PCPA 100 mg/kg. The 5-HT content of the brain was not altered by testosterone. 5 . The number of rats which showed mounting after PCPA treatment did not change with age, but the younger rats made more mounts in the observation time than rats more than three months old. 6 . The age of castration (3 weeks or 4 months) did not influence the results.

1. The haemodynamic effects of propranolol, practolol and 4-hydroxypropranolol have been compared in anaesthetized dogs both at free heart rates and at heart rates fixed by electrical pacing. All three drugs produced a fall in heart rate at the lowest dose of 0·09 mg/kg. 2. Practolol caused less change in dP/dt, cardiac output and blood pressure than did propranolol. 4-Hydroxypropranolol had intermediate effects. Since the changes in dP/dt caused by these three drugs were still present when the heart rate was fixed by pacing, it is concluded that these were independent of changes in heart rate. 3. The fact that practolol and 4-hydroxypropranolol cause less change in haemodynamic function than propranolol may be associated with the intrinsic sympathomimetic activity possessed by the first two of these drugs.

Summary 1 . Arvin stimulated the reticulo-endothelial uptake of colloidal carbon in rabbits. The onset of effect after intravenous administration was immediate and the minimum stimulant dose by this route was very low—0·05 unit/kg (0·1 μg protein/kg). 2 . Carbon opsonized in vitro with serum taken 4 h after an intravenous injection of Arvin was cleared more rapidly than carbon treated with control serum. Serum collected 10 min after Arvin did not promote carbon uptake. 3 . Reticulo-endothelial block with Thorotrast or excess carbon did not prevent the stimulant effect of Arvin but prevented the stimulant effect of opsonization with 4 h serum. 4 . The reticulo-endothelial stimulant effect of Arvin appears to be unrelated to its coagulant action on fibrinogen. The mechanism may involve a direct action on phagocytic cells and an effect on colloidal particles via serum opsonins.

1. (+)-Amphetamine mimicked the excitatory and inhibitory actions of (-)-noradrenaline on single neurones in the brain stem of acute halothaneanaesthetized rats when these compounds were applied by iontophoresis. (+)-Amphetamine had no actions on neurones unaffected by (-)-noradrenaline. 2. These mimicking actions of (+)-amphetamine could not be observed 20 h after treatment of the animals with reserpine 5 mg/kg. 3. The enzyme inhibitors α-methyl-p-tyrosine and FLA 63 also greatly reduced the number of (-)-noradrenaline-mimicking responses to (+)-amphetamine. 4. In animals pretreated with α-methyl-p-tyrosine, but not in those pretreated with FLA 63, excitatory actions of (+)-amphetamine on neurones excited by (-)-noradrenaline could be elicited 45-90 min after systemic injection of L-DOPA. 5. These results indicate that (+)-amphetamine can release noradrenaline from presynaptic sites in the brain stem, which may be a basis for its alerting actions.

1. Small doses of (-)-[(3)H] noradrenaline were injected into the lateral cerebral ventricles in rats to label radioactively the endogenous noradrenaline (NA) stores.2. Intraventricular injection of 25 mug atropine methonitrate at the same time inhibited the increased rate of disappearance of [(3)H] NA from the hypothalamus at an environmental temperature of 9 degrees C, when compared with the values at 24 degrees C, without impairing temperature regulation.3. At 32 degrees C, 25 mug atropine methonitrate caused a lethal hyperthermia. A dose of 5 mug was not lethal and did not inhibit the increased rate of disappearance of [(3)H] NA from the hypothalamus.4. It is concluded that the pathway which stimulates an increased turnover of NA in the cold contains an atropine sensitive synapse but is not the principal pathway of heat production. The increased turnover of NA in the heat probably does not involve an atropine sensitive synapse.

1. The effects of electrical stimulation and solutions containing a high concentration of potassium on the efflux of [14C] glycine from slices of rat spinal cord have been studied. 2. Slices of cord were incubated with [14C] glycine which rapidly accumulated in the tissue. The slices were then superfused in a small chamber and the radioactivity released from the tissue was measured. After superfusion for 60 min, 98% of the radioactivity remaining in the tissue was present as unchanged glycine. 3. The spontaneous efflux of [14C] glycine consisted of an initial rapid phase followed by a much slower release of [14C] glycine. After superfusion for 60 min, more than 65% of the radioactivity taken up during the incubation period was retained by the tissue. 4. When the slices were depolarized by electrical stimulation or by solutions containing a high concentration of potassium (40 mM), a striking increase in the efflux of [14C] glycine was produced. This effect was not reduced by the absence of calcium ions in the superfusion medium. 5. Electrical stimulation produced similar increases in the efflux of [3H] GABA and [14C] glutamate from slices of cord but had no significant effects on the efflux of [3H] alanine or [14C] urea. 6. The results are consistent with the suggestion that glycine may be an inhibitory synaptic transmitter substance in the mammalian spinal cord.

Summary 1 . In conscious rabbits, the rapid intravenous injection of levodopa alone does not have any significant effects on the blood pressure in doses up to 10 mg/kg. 2 . After inhibition of monoamine oxidase, levodopa induces a sustained pressor response. 3 . This response can be blocked by inhibition of extracerebral decarboxylase. 4 . Possible mechanisms for these interactions are discussed, together with their therapeutic implications in Parkinsonism.

Summary 1 . (–)-Noradrenaline, (–)-α-methylnoradrenaline and (–)-isoprenaline were infused into various brain regions of 12–21 day chicks. When infused into the hypothalamic area, but not the cerebral hemisphere or posterior mesencephalon, these amines produced behavioural sleep, lowered temperature and blood pressure and reduced oxygen consumption; electrocortical sleep activity usually ensued but this was not marked and frequently dissociation between electrocortical activity and behaviour occurred. After monoamine oxidase inhibition, which prolonged the action of noradrenaline, dopamine had similar effects. 2 . The effects of the catecholamines were prevented or substantially reduced by pretreatment with phenoxybenzamine given intravenously or into the hypothalamus but not by intravenous injection of propranolol. However, intrahypothalamic infusion of propranolol prevented the temperature, but not the behavioural effects of noradrenaline. The implications of this are discussed. 3 . That the effects were similar but more intense, apart from electrocortical changes, and of longer duration than those seen after intravenous injection of catecholamines suggests that in young chicks these amines penetrate from the blood into the brain and elicit their effects through a localized region, presumably the hypothalamus.

1. Oxotremorine exerts an action on peripheral cholinoceptors in the anaesthetized rat. After the blockade of peripheral cholinoceptors with the quaternary atropine derivative, atropine methylbromide, oxotremorine produced a rise in arterial blood pressure and tachycardia. 2. The rise in arterial pressure and tachycardia was absent in rats that had been pithed or had undergone high spinal cord transection. 3. A non-quaternary atropine derivative antagonized these cardiovascular effects. 4. Drugs which inhibit activity of the sympathetic nervous system antagonized the oxotremorine-induced hypertension and tachycardia. 5. It is concluded that the rise in arterial pressure and tachycardia seen in the anaesthetized rat treated with a quaternary derivative of atropine is due to an action of oxotremorine on the central nervous system at a supraspinal level, resulting in an increase in activity of the efferent sympathetic nervous system.

1. The effects of intravenous injection of lignocaine and propranolol were studied in dogs. 2. Ventricular ectopic beats produced by intravenous injection of adrenaline in anaesthetized dogs respired with halothane were abolished in four out of six dogs by lignocaine. Propranolol was effective in all three dogs tested. 3. Intravenous infusion of lignocaine at (0·2 and 1·0 mg/kg)/min to total doses of 3·0 ± 1·0 and 2·2 ± 0·5 mg/kg, respectively, abolished the ventricular tachycardia produced in anaesthetized dogs by ouabain. A similar effect was produced by infusion of propranolol at (0·2 mg/kg)/min to a total dose of 1·9 ± 0·4 mg/kg. Intravenous injection of single doses of lignocaine (4·0-8·0 mg/kg) also abolished the arrhythmia. 4. The frequency of the ventricular ectopic beats occurring in conscious dogs 20-44 h after ligation of the anterior descending branch of the left coronary artery was reduced, with an increase in the number of sinus beats, after intravenous injection of lignocaine (8·0 mg/kg). Larger doses produced excitement. Propranolol (4·0 mg/kg) had a greater effect than the same dose of lignocaine but after 8·0 mg/kg, three of the four dogs died. 5. Propranolol was more effective than lignocaine in abolishing the three different types of arrhythmia. 6. Dose-response curves showed that lignocaine was more active in abolishing the ouabain induced arrhythmia than the halothane-adrenaline arrhythmia and was least active on the arrhythmia caused by ligation of the coronary artery.

1. The vasoactivity of a number of phosphodiesterase inhibitors in the auto-perfused splanchnic region and hindquarters of the cat have been investigated. 2. Theophylline, dipyridamole and 4-(3,4-dimethoxybenzyl)-2-imidazolidinone (Ro 7-2956) and its analogues were more potent vasodilators in the splanchnic region than in the hindquarters, whereas papaverine was a potent vasodilator in both these vascular beds. 3. The vasodilator response to the phosphodiesterase inhibitors in the splanchnic region and hindquarters was not susceptible to β-adrenoceptor blockade. 4. Infusion of dibutyryl cyclic AMP into the superior mesenteric artery increased vascular conductance of the splanchnic region. This effect was enhanced by Ro 20-1724 in doses below those in which this compound affected conductance. 5. These results are consistent with the hypothesis that accumulation of cyclic AMP in vascular smooth muscle mediates the vasodilator response to phosphodiesterase inhibitors.

1. In cats anaesthetized with intravenous chloralose, microinjections of tubocurarine, leptazol, strychnine or picrotoxin, in a volume of 1 μl, were made into the grey matter of the cerebral cortex and the electrical activity was recorded from the site of injection with the microinjection cannula which, insulated except at its tip, served as recording electrode. 2. Routinely the injections were made into the gyrus splenialis or into the underlying gyrus cinguli close to the mid-line, because the injections would then most likely be in grey and not in white matter. Injected in this way all four drugs set up foci of excitation which gave rise to synchronous firing of a large number of neurones with the result that high voltage negative spikes were recorded from the microinjection cannula. 3. On injection into the gyrus splenialis the threshold dose was about 0·04 μg for picrotoxin, about 0·2 μg for tubocurarine, about 5 μg for strychnine and 25 to 50 μg for leptazol. Following the injection of larger doses the spike discharge continued for a few hours after picrotoxin and tubocurarine, for over an hour after strychnine, but for a few minutes only after leptazol. On injection into the gyrus cinguli the threshold doses were slightly greater and with larger doses the spikes occurred at greater frequency but were of lower voltage than in the gyrus splenialis. 4. With large doses of picrotoxin injected into the gyrus splenialis the spikes developed an after-positivity and an after-discharge which sometimes passed into a short period of fast activity. 5. The foci of excitation set up by the drugs were restricted to the site of injection because on raising or lowering the microinjection cannula the spikes recorded from it quickly decreased in voltage and then disappeared. When the injections were made close to a sulcus and the microinjection cannula, on being lowered, traversed the sulcus, the spikes changed their polarity. 6. The spike discharge appears to be a consistent response to the injections of the drugs into grey matter of any part of the cerebral cortex since it was also obtained on their injection into the pyriform cortex, amygdala and area retrolimbica anterior, but not on their injection into white matter or caudate nucleus, thalamus or hypothalamus.

Summary 1 Morphine, oxotremorine and physostigmine showed antinociceptive activity in mice using the hot plate reaction time test. 2 The action of morphine, but not that of oxotremorine, was antagonized by naloxone and by nalorphine, whereas the effect of physostigmine was unaffected by naloxone and increased by nalorphine. 3 The antinociceptive effects of morphine and of physostigmine were increased by procedures reported to increase the ratio of 5-hydroxytryptamine to dopamine in the brain. It was decreased by procedures reported to cause a fall in brain 5-hydroxytryptamine or a rise in dopamine relative to 5-hydroxytryptamine. 4 The antinociceptive effect of oxotremorine was potentiated by procedures reported to decrease brain noradrenaline and was unaffected by procedures altering brain 5-hydroxytryptamine. 5 The results suggest differences in the mode of action of morphine and physostigmine on the one hand and of oxotremorine on the other.

1. Chemical sympathectomy with 6-hydroxydopamine (6-OHDA) prevented the development of renal hypertension in 80% of weanling male rats of the C.F. strain. 2. Adult male rats treated with 6-OHDA developed hypertension on bilateral clamping of the renal arteries. 3. Demedullation of the adrenal glands followed by 6-OHDA treatment in adult rats prevented the development of hypertension in 75% of them. 4. Weanling rats treated with 6-OHDA did not have any measurable catecholamines in their hearts up to 72-78 days after treatment. 5. Unlike the weanling rats, the hearts of adult rats (demedullated or with intact medulla) showed significant refilling (40-50%) of catecholamine stores 60 days after 6-OHDA treatment. 6. It is concluded that the functional sympathetic nervous system is important in the development of renal hypertension in the rat.

1. Centrally administered sodium diethyldithiocarbamate (DDC) produced hypothermia, central nervous depression and potentiation of the antinociceptive effect of morphine. These effects resemble those seen with centrally administered ouabain. Furthermore, the interactions of (+)-amphetamine, desmethylimipramine and nialamide with DDC and ouabain were similar.2. 6-Hydroxydopamine by the same route also produced central nervous depressant effects including hypothermia, decreased locomotor activity and catalepsy but not ptosis.3. Both ouabain and chlorpromazine produced similar effects on behaviour and body temperature including selective abolition of a conditioned avoidance response.4. Although centrally administered tetrabenazine produced ptosis, decreased locomotor activity and catalepsy, it had no significant effect on body temperature. However, the hypothermia produced by peripherally administered reserpine was reversed by centrally administered dibutyryl cyclic 3',5'-adenosine monophosphate.5. Centrally administered cocaine and desmethylimipramine produced no depressant effects but an increased excitability and responsiveness were apparent in both cases.6. Although the observed behavioural depression and hypothermia can occur independently both seem to involve an interference with dopaminergic systems.

Summary 1 Both MJ 1999 and AH 3474 protected guinea-pigs anaesthetized with urethane against ouabain-induced ventricular fibrillation. 2 MJ 1999 had 1/90, and AH 3474 1/30, of the activity of procaine in reducing the height of the action potential of frog sciatic nerve. 3 MJ 1999 and AH 3474 reduced the rate of rise of intracellularly recorded action potentials at concentrations in excess of 160 × 10−6m (50 mg/l.). It was concluded that direct depression of depolarization could have contributed little to the protection against ouabain-induced fibrillation. 4 MJ 1999, but not AH 3474, greatly prolonged the duration of the action potential in acute experiments on isolated atrial and ventricular muscle, and prolonged the Q-Tc interval of the electrocardiogram in anaesthetized guinea-pigs. It is suggested that this effect contributes to anti-arrhythmic activity. 5 At concentrations up to 80 × 10−6m AH 3474 had positive chronotropic and inotropic effects on isolated rabbit atrial muscle, but at higher concentrations these were superseded by negative effects. MJ 1999 was depressant at all concentrations studied, the threshold concentrations being 19 × 10−6m for chronotropic, and 162 × 10−6m for inotropic effects.

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 GillespieMuir 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.

Summary 1 In a preparation consisting of the myenteric plexus and the longitudinal muscle layer removed from a segment of guinea-pig ileum, spontaneous action potentials occurred which were unaffected by tetrodotoxin but suppressed by Mn2+ and were therefore myogenic. 2 A single current pulse of 0·1 ms duration evoked a response consisting of an early action potential followed after a delay of about 200 ms by a complex of biphasic spikes. The first action potential was conducted for no more than 15 mm and the second complex for 30–70 mm. 3 Since the first action potential was unaffected by hyoscine or Mn2+ but abolished by tetrodotoxin, it was due to excitation of nerve fibres. The later complex of spikes was suppressed by hyoscine and Mn2+ and therefore due to excitation of smooth muscle. It was also inhibited by adrenaline or morphine, compounds which depress acetylcholine release. The evoked smooth muscle response was followed by absence of spontaneous electrical activity for 2–4 seconds. 4 The nerves travelling in a longitudinal direction had a mean maximum conduction velocity of 0·65 m/s, an absolute refractory period of 2·8 ms and a relative refractory period of about 20 ms. 5 The conduction velocity of the smooth muscle response evoked by stimulation of the nerve with a single pulse was 0·16 m/second. After a single pulse the muscle was inexcitable for 0·7–1·3 s; the delay of transmission from nerve to muscle was 210 ms. When instead of a single pulse a train of two—five pulses at 20 ms intervals was applied, the size, conduction distance and conduction velocity of the evoked smooth muscle response were increased.

1. The effects of dimethothiazine have been studied on the response of afferent fibres from primary and secondary endings of muscle spindles in the soleus muscle of the decerebrate cat during stretching of the muscle under controlled conditions. 2. Dimethothiazine in doses of 1 to 4 mg/kg intravenously reduced the discharge frequency of primary and secondary endings. Higher doses of dimethothiazine had little further significant effect on the discharge frequency. 3. The discharge frequency recorded from de-efferented muscle spindles in soleus of the decerebrate cat were similar to the discharge frequencies obtained in preparations with intact ventral roots which had received a high dose of dimethothiazine. 4. Dimethothiazine had little significant effect on the discharge frequency of afferent fibres from muscle spindles in the soleus muscle of decerebrate preparations where the ventral roots were cut. 5. These effects of dimethothiazine on muscle spindle activity were not related to any changes in blood pressure of the decerebrate cat. 6. Dimethothiazine appears to reduce the effects of both the dynamic and static fusimotor fibres on the spindle. 7. The doses of dimethothiazine which effect spindle discharge frequency are similar to those required to reduce decerebrate rigidity.

Summary 1 Propranolol, as the racemate and the (+)- and (–)-isomers (400 μg/l.) and practolol (50 mg/l.) were tested for their effects on atrial and ventricular rates and on the duration of overdrive suppression (ODI) in isolated perfused cat hearts with surgically-induced heart block. 2 Racemic propranolol and the (+)- and (–)-isomers prolonged ODI and slowed the rate of the ventricular pacemaker; the (+)- and (–)-isomers also reduced the rate of the atrial pacemaker. Practolol shortened ODI and increased the rate of the atrial and ventricular pacemakers. 3 The (+)- and (–)-isomers were more potent than the racemate; the (–)-isomer was more potent than the (+)-isomer. The results suggest there is a stereospecific mechanism involved in the biological distribution of propranolol. 4 Twenty-four hours after reserpine treatment (5 mg/kg, i.p.) practolol continued to increase the rate of the atrial and ventricular pacemakers but did not shorten ODI. 5 The mechanism by which these agents affect myocardial excitability and automaticity is discussed.

1. Convulsant and anticonvulsant effects of gamma-hydroxybutyrate (GHB) have been studied in chicks. 2. When administered alone, GHB produced weak myoclonic seizures accompanied by electrocortical synchrony and spikes. 3. GHB was found to protect chicks against leptazol- and picrotoxin-induced seizures. A slight potentiation of strychnine-induced seizures was evident.

1. In the neuronally isolated cortex of the cat, local application of diphenhydramine, promethazine, gammahydroxybutyrate, gammabutyrolactone, gamma aminobutyric acid, hyoscine and pethidine, and the intravenous injection of diazepam and meprobamate depressed or abolished the surface negative and surface positive response to direct stimulation and raised the stimulus threshold of the positive burst response. These effects were the same as previously demonstrated for general and local anaesthetics on the same preparation. 2. Chlorpromazine produced a similar depression in small concentrations but caused spontaneous activity in higher concentrations. 3. In contrast to local application, pethidine when given by intravenous injection in a high dose produced convulsant activity in the isolated cortical slab. The possibility was suggested that the convulsant activity was produced by a metabolite of pethidine. 4. The results of this investigation suggest that the central depression produced by a number of structurally unrelated drugs is indicative of an anaesthetic-like property of these drugs.

1. Chronic administration of phenelzine to dogs caused the concentrations of homovanillic acid (HVA) in c.s.f. from both the lateral ventricle and cisterna magna to fall to new low levels at which they were maintained.2. After 10-12 days treatment with phenelzine the caudate nucleus had elevated concentrations of dopamine and 3-methoxytyramine and lowered concentrations of 3,4-dihydroxyphenylacetic acid and HVA.3. Intravenous administration of tryptophan to dogs pretreated with phenelzine caused in c.s.f. an increase in the concentrations of HVA and in the caudate nucleus a decrease in dopamine concentration and an increase in the concentrations of its metabolites, 3-methoxytyramine, 3,4-dihydroxyphenylacetic acid and HVA.4. A model is proposed for the cerebral metabolism of dopamine and some of the points at which tryptophan and its metabolites may interact with dopamine metabolism are discussed.

1. A method of recording the peristaltic frequency and the rate of transport of fluid (perfusion rate) in the rat ureter in vivo is described.2. Acetylcholine and atropine did not alter ureteral activity. Histamine increased the rate of peristalsis by up to 15% and the rate of perfusion by up to 10%. Low doses of 5-hydroxytryptamine increased peristaltic frequency whereas high doses decreased peristaltic frequency; all doses reduced the rate of perfusion.3. Morphine reduced the rate of perfusion by 5-10% at all dose levels, but only the highest dose used reduced the frequency of ureteral peristalsis.4. (-)-Adrenaline, (-)-noradrenaline and (+/-)-isoprenaline reduced the frequency of peristalsis. The order of potency was isoprenaline>noradrenaline>adrenaline. The response was dose-related and blocked by propranolol, which itself did not affect ureteral activity.

1. Previous work in acute experiments has shown that the main pharmacological action of oxyfedrine is stimulation of β-adrenoceptors, yet there have been clinical reports that the drug is beneficial in the treatment of angina pectoris. 2. In the present experiments rabbits and guinea-pigs were treated for several weeks with daily i.p. injections of oxyfedrine. 3. A daily dosage of 15 mg/kg oxyfedrine had no effect on growth rate for 4 weeks, but thereafter the growth rate of treated animals fell below that of controls. 4. The heart weights of the treated animals, expressed as a percentage of body weight, were significantly lower than those of controls. 5. Measurement of intracellular potentials in hearts taken from treated rabbits showed that the main effects were a reduction in the maximum rate of depolarization and a prolongation of the plateau of the action potential. 6. Guinea-pigs treated for 6 weeks with 15 mg/kg oxyfedrine daily i.p. were protected to some extent from the toxic effect of ouabain infused intravenously.

1. The analgesic activity of sympathomimetic drugs does not appear to involve a peripheral component. 2. Drugs causing changes in morphine analgesia have similar effects on the analgesia produced by methylamphetamine. 3. The analgesia produced by morphine and methylamphetamine is increased by drugs which increase the ratio of brain 5-hydroxytryptamine (5-HT) to dopamine. 4. The analgesia is decreased by drugs causing a fall in brain 5-HT or a rise in dopamine relative to 5-HT.

1. Chronotropic dose-response curves (non-cumulative) for β-adrenoceptive antagonists were constructed from results in rats anaesthetized with pentobarbitone and depleted of catecholamines by pre-treatment with syrosingopine. 2. Depletion of catecholamines lowered resting heart rate and reduced the threshold to the chronotropic action of isoprenaline by about 50%. Eight β-adrenoceptive antagonists produced a dose-dependent chronotropic response but the maximum response was in all cases smaller than that obtained with isoprenaline. The order of activity was dichloroisoprenaline>LB 46>practolol>INPEA>oxprenolol>pronethalol>alprenolol>I.C.I. 45,763 (Ko 592). Propranolol and sotalol were without significant activity. The duration of the chronotropic response to the antagonists was more prolonged than that to isoprenaline. Propranolol caused a parallel shift to the right of the dose-response curves for the agonist effects of the antagonists. 3. Estimation of β-adrenoceptor blocking activity in anaesthetized cats gave an order of activity dissimilar to that found for maximum agonist responses: LB 46 > oxprenolol > alprenolol > propranolol > I.C.I. 45,763 > practolol > dichloroisoprenaline > sotalol > INPEA > pronethalol. 4. Consideration of chemical structure and physico-chemical properties did not explain the differences between the agonist activities of the adrenoceptive antagonists.

1. Effects of L-dopa and dopamine on the secretion of pancreatic juice were investigated in preparations of the isolated blood-perfused canine pancreas.2. Dopamine (1-10 mug) given intra-arterially caused a profuse flow of juice.3. The secretory activity of dopamine (3 mug) was approximately equal to that of secretin (0.1 unit).4. L-Dopa (10-100 mug) given by a single intra-arterial injection was ineffective, but infusion at 100 mug/min for 10 min caused a marked increase of secretion after a delay of a few minutes.5. Intravenous administration of either L-dopa (3 mg/kg) or dopamine (10-100 mug/kg) elicited a marked increase of pancreatic secretion, but was definitely less effective than intra-arterial injection.6. Dopamine-induced secretion was not modified by atropine, phentolamine, propranolol, guanethidine or tetrodotoxin.7. It is concluded that dopamine acts directly on the exocrine cells in the pancreas.

1. The antihypertensive action of methyldopa was investigated in the light of the prevailing false sympathetic neurotransmitter hypothesis of Day & Rand (1963). Immunosympathectomized and normal animals were used for the investigation. 2. Methyldopa in a single injection significantly decreased the blood pressure in control hypertensive, immunosympathectomized normotensive, and normal rats. Guanethidine did not decrease the blood pressure of immunosympathectomized rats; it decreased the blood pressure of control and control hypertensive rats. 3. The hypotensive effect of methyldopa was not antagonized by adrenoceptor and ganglion blocking agents or by the inhibition of dopamine β-oxidase. 4. High doses of methyldopa produced less hypotension than relatively low doses. This might be due to an antagonism of the hypotensive effect by methylnoradrenaline, which is formed from methyldopa. 5. The antihypertensive action of methyldopa could not be correlated with any change in aortic sodium or potassium. 6. It is concluded that methyldopa does not exert its hypotensive effect by producing a weakly active false sympathetic neurotransmitter.