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1. Prostaglandins A(1), E(1), F(1alpha) and F(2alpha) were infused into the vertebral artery of the chloralose-anaesthetized greyhound and the resulting cardiovascular responses were compared with those obtained on intravenous and intracarotid infusions in the same dose range.2. Infusions of PGF(2alpha) intravertebrally (4-64 (ng/kg)/min) caused an increase of blood pressure, tachycardia and a fall of central venous pressure. Cardiac output was increased and peripheral resistance was essentially unchanged. There was never any response to intravenous or intracarotid PGF(2alpha) infusions in this dose range.3. PGF(1alpha) was found to have similar effects to PGF(2alpha) but it was much less potent.4. PGE(1) infusions (4-360 (ng/kg)/min) into the vertebral artery caused a tachycardia which was greater than that obtained with intracarotid or intravenous infusions, but there was no significant effect on blood pressure.5. Infusions of PGA(1) caused a small fall of blood pressure accompanied by an increase of heart rate and the dose response relationships were similar for all three routes of administration.6. It is concluded that some prostaglandins can activate cardioregulatory centres within the territory of distribution of the vertebral artery. Prostaglandin F(2alpha) is the most potent of these.

1. The intravenous infusion of pethidine or imipramine, in doses of 5 mg/kg, caused fatal hyperpyrexia in rabbits premedicated with pargyline. 2. The drug interaction was not antagonized when either reserpine or α-methyl-p-tyrosine were administered with pargyline. Neither reserpine nor α-methyl-p-tyrosine prevented the rise in brain stem 5-hydroxytryptamine content following monoamine oxidase inhibition, although the increase in catecholamines normally produced by pargyline was prevented. 3. The development of fatal hyperthermia was completely prevented when rabbits were treated with p-chlorophenylalanine prior to pargyline premedication. In these animals, the concentration of brain stem catecholamines, but not 5-hydroxytryptamine, was increased. 4. The results indicate that the hyperthermia evoked by pethidine or imipramine in combination with monoamine oxidase inhibitors can take place only in the presence of raised concentrations of 5-hydroxytryptamine in the brain stem.

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.

1. The effects of L-DOPA on postural hypotension and carotid occlusion pressor effect were studied, mainly in cats; the recovery of the blood pressure upon tilting was used as a measure of postural hypotension. 2. L-DOPA (30 mg/kg) partially depressed the carotid occlusion pressor effect and caused some degree of postural hypotension, L-DOPA (100 mg/kg) had more marked effects; the responses returned to control after 90 to 150 minutes. L-DOPA itself caused a pressor response in all cats. 3. The dopa decarboxylase inhibitor N1-(DL-seryl)-N2-(2,3,4-trihydroxybenzyl) hydrazine (RO4-4602, 50 and 10 mg/kg) had no effect itself on the tilt response but completely prevented the effects of L-DOPA on the carotid occlusion pressor effect and postural hypotension. 4. After RO4-4602 (3 and 1 mg/kg), L-DOPA (100 mg/kg) caused a brief rise of blood pressure followed by a longer lasting fall in horizontally-orientated cats (i.e. `supine' hypotension). No postural hypotension was observed after L-DOPA under these conditions. 5. Noradrenaline elicited only small and transient effects on postural hypotension, but dopamine's effects were more marked and longer lasting. Pressor dose-response relationships for noradrenaline were the same before and after L-DOPA, as well as in cats pretreated with L-DOPA for 4 days. 6. In cats with kidneys and intestines removed, the tilt reflex was still present. Dose-response curves to L-DOPA were the same as in normal animals. RO4-4602 (3 mg/kg) prevented postural hypotension and block of the carotid occlusion pressor effect; supine hypotension was also observed after L-DOPA. 7. The recovery response to tilting in spinal cats was markedly depressed or absent unless the blood pressure was elevated by angiotensin, in which experiments L-DOPA depressed the recovery upon tilting (i.e. induced postural hypotension). 8. Blood pressure responses to tyramine were increased after 10 mg/kg of L-DOPA, but depressed after 100 mg/kg. The response to tyramine was not depressed, however, when RO4-4602 was given to block the dopa-dopamine conversion. 9. The response to sympathetic stimulation in pithed rats was depressed after L-DOPA and dopamine, but not after α-methyldopa. 10. α-Methyldopa (300 mg/kg) given acutely caused a moderate degree of postural hypotension and a more marked postural hypotension if given for two days. 11. It is concluded that it is possible to differentiate between the supine and postural hypotension caused by L-DOPA and that supine hypotension is due to a central effect and postural hypotension to an extracerebral effect. Postural hypotension is discussed in relation to six hypotheses presented to explain its effect. Postural hypotension after L-DOPA is probably not due to a-adrenoceptor blockade, a central effect or any effect on the kidney. The most likely hypothesis is that L-DOPA forms dopamine which acts as a false transmitter in the peripheral sympathetic nervous system.

Summary 1 Experimental hypertension in the rat, induced either by renal artery stenosis or by treatment with deoxycorticosterone acetate (DCA) developed maximally over a period of 8 weeks. In both types of hypertension the rate of development was unaffected by immunosympathectomy or by chemical sympathectomy following the administration of 6-hydroxydopamine. 2 The effect of 6-hydroxydopamine on chronic renal hypertensive rats was to produce a hypotensive action of longer duration than when similarly administered to DCA-induced hypertensive or normotensive rats. Reserpine (5–10 mg/kg intraperitoneally) produced a more marked hypotensive effect on both types of hypertensive rats although it was of much shorter duration. 3 It is concluded that experimental hypertension of renal origin or induced by DCA treatment can develop even though most of the sympathetic nervous system has been destroyed. The maintenance of chronic hypertension in these conditions may depend on the adrenal glands or a hormonal system as yet undetected.

1. In cats under light allobarbitone anaesthesia, the effects of intravenous injections of narcotic and non-narcotic analgesics, of a general depressant, and of narcotic antagonists were investigated on the spontaneous release of acetylcholine (ACh) from the surface of the sensorimotor cortex.2. The narcotic analgesics morphine (0.1, 1.0 and 5 mg/kg), meperidine (1.0 and 2.0 mg/kg), methadone (1.0 mg/kg) and codeine (5.0 and 10.0 mg/kg) greatly reduced ACh release.3. The non-narcotic analgesics pentazocine (1.0 and 2.0 mg/kg) and propoxyphene (5.0 and 10.0 mg/kg) as well as the depressant chlorpromazine (0.25, 0.5 and 1.0 mg/kg) also greatly reduced ACh release.4. Two of the three narcotic antagonists examined, levallorphan (0.1, 1.0 and 5 mg/kg) and nalorphine (1.0 mg/kg) had the property of reducing ACh release. They were thus partial agonists. With levallorphan the greatest reduction occurred with the smallest dose injected and the effect was regularly obtained, whereas with nalorphine a reduction was obtained in some experiments only. The third, naloxone, was a specific narcotic antagonist and did not reduce the ACh release in any dose (0.01, 0.1, 0.5 and 1.0 mg/kg) examined. In a dose of 1.0 mg/kg it actually produced a small increase in Ach release.5. Naloxone (0.1-1.0 mg/kg) restored the reduction in ACh release produced by the narcotic analgesics and by the partial agonist levallorphan. It partially restored the reduction produced by the non-narcotic analgesics and by nalorphine, but had no effect on the reduction produced by chlorpromazine.6. The relevance of these results with regard to analgesia and to the narcotic abstinence syndrome is discussed.

Summary 1 The initial response after endotoxin administration (3 mg/kg) in cats involved pulmonary vasoconstriction. This was not seen when endotoxin was given by slow infusion and it could be prevented after a bolus injection of endotoxin by pretreatment of the cats with aspirin (10 mg/kg). Intense mesenteric vasoconstriction occurred in all the cats. 2 The mesenteric vasoconstriction was a specific response of the mesenteric blood vessels. At the time the mesenteric bed constricted, the renal bed dilated, the hepatic arterial bed remained unchanged and the smooth muscle of the intestinal wall relaxed. 3 Arterial blood from cats with a fully developed mesenteric vasoconstriction after endotoxin administration was perfused through a normal intestine. No immediate vasoconstriction developed but the perfused intestine constricted slowly over 60 minutes. This suggests that mesenteric constriction was not due to circulating vasoconstrictor factors or the intestinal innervation, but involved a slow local mechanism within the intestine. It could not be prevented or reversed by a variety of pharmacological agents. 4 These observations suggest that endotoxin caused a unique type of mesenteric vasoconstriction in cats by a local mechanism which took up to 60 min to develop, was sufficiently potent to reduce mesenteric flow to

1. Study of the delayed responses to lethal doses of endotoxin in cats is complicated by acute pulmonary vasoconstriction which results in hypotension, cardiac failure and pulmonary oedema. This acute response is abolished if the animal is pretreated with aspirin (10-100 mg/kg). In these cats, pretreated with aspirin, arterial pressure and right atrial pressure remain unchanged in the first 2 h after administration of endotoxin. Later, arterial pressure falls and the animals die but no haemorrhagic lung lesions are visible.2. These results confirm our previous conclusion that the delayed lethal response to endotoxin is an independent action and not a secondary consequence of the acute response. The mechanism of the action of aspirin is discussed and it is suggested that it prevents the release by endotoxin of vasoactive substances, possibly from platelets.3. In cats pretreated with aspirin, administration of endotoxin results in a marked mesenteric vasoconstriction. Although arterial pressure does not decrease significantly, superior mesenteric arterial flow decreases to 20% of control in the first hour after endotoxin and remains at this low level until the animal dies. Mesenteric ischaemia may contribute to the cat's death.4. The mesenteric vasoconstriction is not reduced by prior administration of phenoxybenzamine and is only slightly reduced after phenoxybenzamine, hypophysectomy and nephrectomy. It is concluded that catecholamines, vasopressin and angiotensin play at most a minor role in the mechanism of this vasoconstriction and that other unknown factors are predominant.

1. The β-adrenoceptor blocking properties of (±)-1-(2-acetyl-4-n-butyramidophenoxy)-2-hydroxy-3-isopropylaminopropane hydrochloride (M&B 17,803A) have been compared with those of practolol and propranolol in the guinea-pig, cat and dog. 2. Following either intravenous or oral administration in the cat or dog, M&B 17,803A and practolol had similar potency in antagonizing isoprenaline-induced tachycardia and both showed cardioselectivity, but both were less potent than propranolol. 3. M&B 17,803A and practolol had approximately one hundredth the intravenous potency of propranolol in increasing the severity of anaphylactic bronchospasm in the conscious sensitized guinea-pig. 4. M&B 17,803A possessed less marked intrinsic sympathomimetic activity than practolol but, like propranolol, it had significant local anaesthetic properties and increased the refractory period of rabbit isolated atria.

1. Inhibition of 5-hydroxytryptamine (5-HT) synthesis by p-chlorphenylalanine protected rabbits pretreated with pargyline from the fatal hyperthermic reaction which occurs on the intravenous injection of pethidine. 2. The development of tolerance to morphine did not protect against the fatal pargyline-pethidine hyperpyrexia. Moreover, the injection of nalorphine before or after pethidine conferred no protection. 3. Pethidine evoked a hyperpyrexia in rabbits pretreated with lithium sulphate or yohimbine. 4. Sodium diethyldithiocarbamate caused a fatal hyperpyrexia in rabbits pretreated with pargyline. 5. It is concluded that the pargyline-pethidine hyperthermic interaction might involve the relative concentrations of 5-HT and noradrenaline in the hypothalamus.

1. Experimental cardiac arrhythmias were produced in dogs anaesthetized with pentobarbitone. Ventricular arrhythmias were induced by strophanthin-K, light petroleum plus adrenaline or coronary ligation procedures. Atrial flutter was induced by an injury-stimulation technique. The acetylcholine and glycogen concentrations of the atria and ventricles were estimated.2. Physostigmine pretreatment (0.1 mg/kg) significantly reduced the incidence of ventricular arrhythmias after myocardial ischaemia but had no effect on any of the other arrhythmias.3. Physostigmine markedly increased the acetylcholine concentrations of atria and ventricles in control dogs, to nearly the same extent. Physostigmine had no effect on ventricular acetylcholine concentrations in dogs treated with strophanthin-K and light petroleum plus adrenaline but in the coronary ligation group it caused a significant increase in the acetylcholine concentrations of both atria and ventricles, and of atrial acetylcholine only in the injury-stimulation group.4. All the arrhythmias produced marked glycogenolysis of both the atria and the ventricles, to nearly the same extent. Although physostigmine produced marked glycogenolysis in the control dogs it significantly inhibited cardiac glycogenolysis after light petroleum plus adrenaline, atrial glycogenolysis after strophanthin-K-induced arrhythmias and ventricular glycogenolysis after myocardial ischaemia.5. There appears to be a possible correlation between the increase in the acetylcholine concentration of the ventricles and anti-arrhythmic actions of physostigmine, but there is a less clear correlation between changes in the glycogen concentration of ventricles and the anti-arrhythmic action.

1. Noradrenaline, dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid concentrations in the mouse brain were measured 30 min after subcutaneous injection of doses of morphine ranging from 0·1 to 100 mg/kg: motor activity was also measured. 2. The noradrenaline concentration in the mouse brain was reduced by moderate (2 to 20 mg/kg) but not by high (above 20 mg/kg) and low (below 2 mg/kg) doses of morphine. 3. The dopamine concentration in the mouse brain was reduced by moderate (1 to 20 mg/kg) doses but was raised by high doses (above 20 mg/kg) of morphine. 4. The 5-hydroxytryptamine concentration in the mouse brain was reduced by moderate (1 to 20 mg/kg) doses of morphine but not by high (above 20 mg/kg) and low (below 1 mg/kg) doses of morphine. 5. The 5-hydroxyindoleacetic acid concentration was not affected by low doses (0·1 to 2 mg/kg), raised by a dose of 5 mg/kg, lowered by doses of 10-50 mg/kg and not affected by 100 mg/kg of morphine. 6. These results are discussed with reference to the possible implication of changes in monoamines for the analgesic and behavioural effects of morphine.

1. Left atrial preparations isolated from rabbits were stimulated electrically at frequencies between 6 and 240/min. Tension-frequency curves were obtained from control preparations and preparations treated with ouabain and acetylcholine. Transmembrane potentials were recorded from single cells of the left atrium stimulated at different frequencies.2. The tension-frequency curve was moved downwards by acetylcholine (10(-6) g/ml). Ouabain (10(-6) g/ml) caused characteristic alterations in the tension-frequency relationship, enhancing the contractile tension at low but not high frequencies. The negative inotropic effect of acetylcholine was reduced by treatment with ouabain.3. Action potential durations were significantly influenced by alterations in frequency of contraction. The 10% duration increased with frequency within the range between 6 and 60/min but decreased at frequencies higher than 120/min. The 50% duration increased with frequency between 6 and 120/min but decreased at frequencies higher than 180/min. The dependence of the 50% duration upon frequency paralleled that of contractile tension. The 90% duration, the overshoot and the resting potential were not affected by frequency of contraction.4. Acetylcholine (10(-6) g/ml) shifted the 10%, 50% and 90% duration-frequency curves downwards, but did not significantly alter the overshoot and the resting potential. Ouabain (10(-6) g/ml) shifted the duration-frequency curves downwards and also reduced the size of the overshoot and the resting potential. Treatment of atrial preparations with 10(-6) g/ml ouabain potentiated the membrane effects of acetylcholine.5. The inhibition by ouabain of the negative inotropic effect of acetylcholine did not appear to be due to antagonism at the receptor level, but to interference with the mechanisms responsible for the mechanical events.

1. The effects of amino-oxyacetic acid (AOAA) on the central nervous system and on skeletal muscle have been examined in the chicken.2. AOAA had both anticonvulsant and convulsant effects, depending on the dose, as in other species.3. The convulsant effect, accompanied by EEG spiking, decreased rapidly with increase in age of young chicks.4. The convulsant effect was exerted primarily through supraspinal centres.5. Of control depressants tested, only troxidone and small doses of AOAA afforded significant protection against AOAA seizures.

Summary 1 A method is described for studying the peristaltic reflex in the guinea-pig or cat isolated colon, using a graded localized intraluminal stimulus consisting of a solid bolus. 2 The method gives an easy evaluation of propulsive activity and makes it possible to record simultaneously the segmental activity of the circular muscle in relation to the site of stimulation and the contractions and relaxations of the longitudinal muscle coat. 3 The velocity of propulsion, which is a reliable measure of propulsive activity, is dependent on the degree of distension and is easily affected by physical agents and nervous stimulation. A solid bolus is propelled only when there is simultaneous ascending contraction and descending inhibition of the circular musculature. 4 Since the peristaltic reflex could not be elicited from areas from which the mucosal and submucosal layers had been removed, these layers are essential for the triggering of the peristaltic reflex and for the propulsion of solid contents in the colon.

1. Changes in cutaneous water loss were followed by continuously monitoring total body weight loss. 2. Sweating was induced in normal subjects by raising the environmental temperature or by subjecting them to the emotional stress of mental arithmetic. 3. Propranolol in a dosage of 0·15 mg/kg body weight intravenously had no significant effect on either thermal or emotional sweating, whereas thermal sweating was completely blocked temporarily by administration of atropine 2·4 mg intravenously. 4. It is concluded that β-adrenoceptor blockade has no effect on physiological sweating in normal people.

1. Chronic administration of phenelzine to dogs caused 5-hydroxyindol-3-ylacetic acid (5-HIAA) concentrations in c.s.f. from the lateral ventricle to be maintained at 50% of their normal values, but did not alter the concentrations of 5-HIAA in c.s.f. from the cisterna magna. 2. Following 10 days treatment with phenelzine, the active transport of 5-HIAA from c.s.f. which normally occurs in the region of the fourth ventricle, was inhibited. This transport system was also inhibited by the addition of phenylacetic acid, the acid metabolite of phenelzine, to the fluid perfusing the cerebral ventricles. 3. After 10-12 days treatment with phenelzine all regions of brain showed concentration increases to approximately 300% for 5-HT and 150% for 5-HIAA, but no alteration in the tryptophan concentration. 4. Intravenous administration of tryptophan to dogs pretreated with phenelzine caused large increases in the concentration of tryptophan in brain and body fluids but did not alter either the concentrations of 5-hydroxytryptamine and 5-HIAA in brain or of 5-HIAA in c.s.f. 5. A model of the cerebral metabolism of 5-hydroxytryptamine is proposed and the results are interpreted to mean that phenelzine has inhibitory actions, either directly or in some instances indirectly, on intracerebral tryptophan 5-hydroxylase, monoamine oxidase and the transport of 5-HIAA from both brain and c.s.f.

1. Re-establishment of renal blood flow after total renal ischaemia of 4 h duration causes a pressor response in pentobarbitone anaesthetized rats and cats. 2. The pressor response is related to the release of renin from the ischaemic kidney. 3. Spinal section at any cervical level or stellate ganglionectomy abolishes the pressor response but spinal section caudad to the thorax or vagotomy and treatment with hexamethonium have no effect. 4. Spinal section and stellate ganglionectomy interfere with the release of renin and with the pressor response to angiotensin.

Summary 1 Exposure of depilated skin of guinea-pig to ultraviolet (u.v.) light for 20 s produces a prolonged inflammatory response. 2 The erythaema becomes evident within 15–30 min after the exposure and progressively increases in intensity reaching its maximum by 4–6 hours. The erythaema persists over 24 hours. 3 Increase in vascular permeability is biphasic with an early short-lived rise peaking at 0·5 h and a prolonged secondary response peaking at 9–12 h and lasting over 48 hours. 4 In presence of aspirin, phenylbutazone and indomethacin, administered prior to u.v. exposure, the inflammatory reaction is partially suppressed, depending upon the dose. The drugs are ineffective in aborting or minimizing the response when given after the inflammation is established. Corticosteroids fail to influence the u.v. inflammation in this test. The significance of these findings is discussed.

Summary 1 Urogastrone, an acid gastric secretion inhibitor extracted from human urine, was assayed in the anaesthetized rat by circulating through its stomach a succinic-propionic buffer and recording electrometrically the secretion of acid in response to carbachol, and inhibition of carbachol secretion by urogastrone. 2 Quantitative assay procedures are described requiring the administration of only one or two doses of urogastrone to each rat. 3 An extraction procedure for urogastrone is described based on the use of zeocarb, a cationic polystyrene resin. 4 The most purified samples contained 40–80 times the amount/milligram which was just detectable by the assay method.

1. Some spontaneously firing cells in the cerebral cortex of cats can be depressed by iontophoretically applied acetylcholine or acetyl-beta-methylcholine, and this depression is antagonized by atropine. Thirteen per cent of 101 spontaneously active neurones tested were depressed by cholinergic agents and 64% were excited.2. Single stimuli applied to the adjacent cortical surface excited 132 neurones orthodromically. Acetylcholine or acetyl-beta-methylcholine depressed this synaptic firing in 18% of the cells. The depression was blocked by atropine.3. The population of neurones in which cholinergic agents depressed spontaneous or synaptic firing was located within the superficial half of the cortex.4. Glutamate-induced firing was depressed by cholinergic agents in 41% of 211 cells tested; atropine and strychnine strongly antagonized this depressant action, while dihydro-beta-erythroidine was a weaker antagonist.5. Long duration inhibition of glutamate-induced firing evoked by repetitive stimulation of the cortical surface could be blocked by atropine or strychnine in both the intact and chronically isolated cortex. This provides strong evidence for a system of intracortical cholinergic neurones which make direct inhibitory contacts with neurones in the superficial layers of the cortex.

1. Isolated left-atrial strips of guinea-pigs were driven electrically at a constant rate and log-concentration curves were determined for the positive inotropic effect of noradrenaline and tyramine. 2. The atrial tissue from endotoxin-treated animals had a reduced sensitivity to noradrenaline and tyramine. 3. After endotoxin, the sensitizing effect of cocaine on the response to noradrenaline was normal but accumulation of 3H-noradrenaline in nerve terminals was markedly reduced. 4. Atrial tissue of endotoxin-treated guinea-pigs responded normally to stretch.

1. In cats anaesthetized with chloralose, repeated injections of 20 μg ouabain were made either into the cerebral ventricles, or into the ventromedial nucleus of the hypothalamus (VMH), or intravenously whilst the electrocardiogram, arterial blood pressure and respiration were recorded. 2. The injections produced cardiac arrhythmias preceded by sinus bradycardia, variable changes in arterial blood pressure and respiratory depression. Death occurred either from ventricular fibrillation or from cardiac arrest. 3. The arrhythmias which occurred after the injections into the cerebral ventricles were not peripheral effects produced after absorption of the ouabain into the blood stream, because with intravenous injections larger amounts were required to produce the arrhythmias and to cause death than with intraventricular injections. The arrhythmias which resulted in death were due to an action on the VMH. With microinjections of ouabain into this region of the brain death occurred earlier and after smaller doses than after intraventricular injections. 4. While sinus bradycardia was abolished by bilateral vagotomy other cardiac arrhythmias were prevented by acute cardiac sympathectomy and cervical cord transection. Thus both the sympathetic and parasympathetic nervous systems appear to be involved in the production of these arrhythmias. 5. Since some of the cardiac arrhythmias obtained with ouabain in anaesthetized cats resemble the cardiotoxic effects seen in clinical practice during treatment with digitalis glycosides it is concluded that these effects, too, are, at least in part, central in origin, caused by an action on the VMH and mediated mainly via the sympathetic nervous system.

1. The effects of a potential anti-Parkinson drug, benapryzine, have been compared with those of benzhexol, atropine and procaine on the excitatory responses induced by acetylcholine and L-glutamate on feline cortical neurones using the microiontophoretic technique.2. All the drugs tested reduced the excitatory responses evoked by acetylcholine and L-glutamate. However, benapryzine, benzhexol and procaine more effectively reduced the excitatory responses to L-glutamate than those to acetylcholine whereas atropine was more effective against acetylcholine-induced excitation.3. In the presence of procaine the amplitude of the extracellular spikes was decreased. This effect was also observed during applications of benapryzine and benzhexol.4. Tests on the isolated frog sciatic nerve indicated that benapryzine and benzhexol had local anaesthetic actions respectively greater than and equivalent to those of procaine.5. It was concluded that the effects of benapryzine and benzhexol on cortical neurones were probably related to their local anaesthetic properties. The possibility that a local anaesthetic action may account for the effects of these drugs and of many other commonly used anti-Parkinson drugs in Parkinson's disease is discussed.

1. In cats anaesthetized with pentobarbitone, the fluid spaces in and around the brain stem were perfused from the third ventricle to the foramen magnum with artificial cerebrospinal fluid (c.s.f.) flowing usually at the rate of 5 ml/minute. Test solutions were substituted for the artificial c.s.f. without switching artifact for periods varying from 5 to 60 seconds. Observations were made on respiratory excursions, end-expiratory% CO2 and arterial blood pressure. 2. Perfusion with sucrose solution equiosmolar with the c.s.f. produced no respiratory or cardiovascular response. Replacement of sodium with potassium (60 to 133 mM) resulted in a prompt but mild respiratory stimulation and a delayed fall in blood pressure associated with a slowing of the heart beat. Replacement of sodium with magnesium (40 to 131 mM) resulted in a late prolonged apneustic depression of breathing and in an early but slight reduction in blood pressure. 3. Procaine (1 to 50 mg/ml) elicited a respiratory response similar to that of excess magnesium; however, an initial rise in blood pressure to as high as 200 mmHg was evoked with procaine. Nicotine (0·05 to 0·5 mg/ml) produced an immediate brief bradypnea followed by a vigorous and slowly reversing hyperpnea accompanied most often by a fall in blood pressure. Tachyphylaxis was observed in the response to nicotine. Noradrenaline (0·001 and 0·1 mg/ml) did not produce any effect, and it did not alter the responses elicited by procaine and nicotine given by perfusion either simultaneous with or subsequent to the noradrenaline. Acetylcholine (0·5 mg/ml) produced weak transient respiratory stimulation and a small fluctuation in blood pressure which disappeared in repeated tests. Methacholine (1 mg/ml) caused a brief hyperpnea and a fall in blood pressure both of which were abolished after atropine (0·2 mg) was injected into the third ventricle. Pilocarpine (10 mg/ml) elicited no change in respiration or blood pressure. Respiratory and cardiovascular effects produced by strychnine (1 mg/ml) were attributable non-specifically to convulsive movements of the animal. Ethamivan (1 mg/ml) produced a single deep breath and a slowly reversing rise in blood pressure. Cyanide (0·5 mg/ml) barely stimulated the respiration but it produced a long lasting rise in blood pressure. Ethyl alcohol (0·1 ml/ml) elicited brisk though brief respiratory stimulation and a short lasting fall in blood pressure. 4. It was shown that the effects of procaine and nicotine were not qualitatively altered when the perfusion effluent was collected through a ventral craniotomy instead of the cisterna magna.

Summary 1 The effects of α and β-adrenoceptor blockade, depletion of catecholamine stores, vagotomy, atropine, and ganglionic blockade on diazepam-induced vasodilatation were investigated in forty-six anaesthetized dogs. 2 Coronary blood flow was measured by timed collections of coronary venous efflux from fibrillating, decompressed ventricles; coronary and systemic vascular resistances were determined during total cardiopulmonary bypass under conditions of normothermia and constant aortic (coronary artery) pressure. 3 No significant alteration in the vasodilatation produced by diazepam was observed following either vagotomy or α-adrenoceptor blockade; partial inhibition of vasodilatation occurred after β-adrenoceptor blockade or catecholamine depletion, and nearly total inhibition was observed after small doses of atropine or ganglion-blocking agents. 4 The results suggest that diazepam may act as a specific ganglion-stimulant, causing active sympathetic and cholinergic vasodilatation.

1. Isoprenaline (0.02 to 2.0 mug kg(-1) min(-1)) inhibited gastric secretion in response to pentagastrin in both conscious and anaesthetized dogs and in response to feeding in conscious dogs.2. The inhibition was unaffected during cardiac beta-adrenoceptor blockade by propranolol.3. The inhibition was not due to decreased mucosal blood flow.4. This effect of isoprenaline is different from its effect on histamine-induced gastric secretion.5. Noradrenaline (0.05-2.0 mug kg(-1) min(-1)) also decreased gastric secretion but it was less effective than isoprenaline.6. The mechanism of action of noradrenaline is probably a decrease in mucosal blood flow.

1. The effects of some rapidly metabolized sympathomimetic amines, such as β-phenylethylamine and p-tyramine, in eliciting hypertensive responses to reserpine in the anaesthetized rat, have been studied. 2. Retardation of metabolism, by pretreatment with the monoamineoxidase inhibitors iproniazid or phenelzine, causes β-phenylethylamine (which in untreated rats has no effect) to induce hypertensive responses to reserpine. Tyramine and other hydroxy substituted phenylethylamines are much less active in this respect, probably because of relatively poor lipid solubility. 3. Hypertensive responses to reserpine are due to catecholamine release, which is believed to be from stores made accessible to indirectly acting sympathomimetic amines with high lipid solubility by an action of reserpine on cell membranes.

1. Pressor responses to sympathetic outflow stimulation, noradrenaline and angiotensin have been recorded in pithed rats. 2. Disulfiram (50 mg/kg) and sodium diethyldithiocarbamate (DDC) (5-100 mg/kg) both caused an initial increase in the pressor response to all three procedures followed by a selective inhibition of the angiotensin responses. 3. Penicillamine (1-100 mg/kg) and ascorbic acid (1-500 mg/kg) increased the pressor responses to all three procedures without any subsequent blocking action. 4. Reserpine (5 mg/kg daily for 3 days) abolished responses to sympathetic outflow stimulation but did not impair angiotensin or noradrenaline responses. 5. In reserpinized rats, the initial enhancement of angiotensin responses after disulfiram and sodium diethyldithiocarbamate was absent or reduced and the onset of the subsequent block was accelerated. 6. Possible mechanisms for the angiotensin-blocking action of disulfiram and sodium diethyldithiocarbamate are discussed.

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.

1. The peristaltic reflex in the colon was elicited by a localized intraluminal stimulus. The contractile response of the longitudinal coat, which consists of two phases, begins before the start of propulsion. Although the contractions of the longitudinal and circular musculature are usually associated, they may be independent of each other. In particular, the longitudinal contraction does not seem to be necessary for propulsion. 2. Both the longitudinal reflex contraction and the segmental responses of the circular muscle to distension, namely a contraction above and a relaxation below the bolus, are abolished by tetrodotoxin and ganglion blocking agents. 3. In the guinea-pig, longitudinal and circular reflex contractions are usually resistant to antimuscarine, antihistamine and antitryptamine drugs but in the cat they are abolished by antimuscarine drugs. In both species, however, atropine and hyoscine can impair propulsion by blocking selectively the descending inhibition. In the cat, it is possible to find doses which abolish the descending inhibition without affecting the contractile responses of the longitudinal and circular muscle. 4. Sympathetic denervation and pretreatment with reserpine do not affect the propulsive activity. The maintenance of the descending inhibition in denervated organs suggests that the inhibitory neurones to the circular muscle are not adrenergic. 5. On the basis of the effects of drugs, the possible nervous mechanism subserving the polarity of propulsion has been examined. Such a mechanism seems to require an inhibitory pathway involving muscarinic receptors at some point. 6. Pelvic nerve stimulation facilitates propulsive activity. The effect of transmural stimulation is different at low and at high frequencies of stimulation. The inhibitory effect of sympathetic stimulation on the reflex responses seems to be due mainly to an action on intrinsic nervous structures.

1. 5-Hydroxytryptamine (5-HT), acetylcholine (ACh), noradrenaline (NA), glutamate, D,L-homocysteic acid (DLH), glycine and gamma-aminobutyric acid (GABA) were applied to single neurones in the brain stem of decerebrate cats by microiontophoresis. The abilities of D-lysergic acid diethylamide tartrate (LSD 25), methysergide maleate (UML 491) and 2-bromo-lysergic acid diethylamide (BOL 148) to antagonize the actions of these compounds were studied.2. LSD 25 antagonized 5-HT excitation of single neurones when applied iontophoretically or administered intravenously. LSD 25 also antagonized glutamate excitation of neurones which could be excited by 5-HT. Inhibitory effects of 5-HT, the action of glutamate on neurones which could be inhibited by 5-HT and the actions of all the other compounds tested were unaffected by LSD 25.3. Iontophoretically applied UML 491 was also a specific antagonist to 5-HT and glutamate excitation but was less potent than LSD 25, and BOL 148 rarely exhibited antagonism.4. It is suggested that antagonism to 5-HT and glutamate excitation of brain stem neurones may be the basis of the psychotomimetic action of LSD 25. It is also suggested that there may be similarities in the mechanisms by which 5-HT and glutamate produce excitation where they act on the same neurone.

1. In agreement with previous findings on whole brain, the intraperitoneal injection of hydrocortisone, DL-α-methyltryptophan or L-kynurenine decreased the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxy-indoleacetic acid (5-HIAA) in different regions of the rat brain. 2. Hydrocortisone caused similar decreases in the concentrations of both 5-HT and 5-HIAA, suggesting decreased 5-HT synthesis. 3. Changes in the concentration of 5-HIAA after hydrocortisone corresponded significantly to those after α-methyltryptophan. Changes in the concentration of 5-HT did not correspond, possibly due to falsely high 5-HT values because of interfering material derived from α-methyltryptophan. 4. In general, kynurenine caused larger decreases in the concentration of 5-HT than in the concentration of 5-HIAA. 5. In agreement with previous findings with whole brain, immobilization of rats for 5 h decreased the concentration of 5-HT and increased that of 5-HIAA in most brain regions. 6. The order of the percentage decreases in the concentrations of 5-HIAA 6 h after hydrocortisone injection was, in decreasing order: hypothalamus, striatum, cerebellum, mid-brain, pons + medulla and cortex. The percentage increases after immobilization for 5 h were in the reverse order. 7. The differences between the percentage decreases in the concentration of 5-HIAA after hydrocortisone and the percentage increases after immobilization were very similar in all regions except the hypothalamus. This is consistent with immobilization stress increasing the firing rate of 5-hydroxytryptaminergic neurones similarly in different regions. 8. During the first 3 h of immobilization the concentrations of 5-HIAA in the hypothalamus and in the rest of the brain increased approximately in parallel. Between 3 and 5 h, 5-HIAA returned to control concentrations in the hypothalamus while continuing to rise in the rest of the brain. 9. Relative changes in the concentration of 5-HT in particulate and supernatant fractions after the various treatments were comparable except 2 h after kynurenine injection when the concentration 5-HT fell in the particulate but not in the supernatant fraction. The concentration of 5-HT did fall in the latter, though more slowly than in the former fraction, suggesting a concentration of amine synthesizing organelles in particulate material.

1. In anaesthetized cats, intravenous adenosine infusions decreased resistance to blood flow in the myocardial vascular bed. This effect of adenosine was augmented during the 60 min following the intravenous injection of dipyridamole (1 mg/kg). 2. In different experiments, intravenous infusions of noradrenaline caused either a slight increase or a slight decrease in myocardial vascular resistance. The dilator component of the action of noradrenaline was not augmented by dipyridamole. 3. Isoprenaline infusions decreased the resistance of the myocardial bed. This effect was unaltered after dipyridamole. 4. These results do not support the hypothesis that part of the effect of catecholamines on myocardial vascular resistance involves the release of adenosine from hypoxic myocardial cells.

1. L7810 (4-carbamoyloxy-1-(4-(4-fluorophenyl)-4-oxobutyl) decahydroquinoline, has a local anaesthetic action on frog nerve 1·75 times that of procaine. 2. L7810 protected anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation and increased the lethal dose of ouabain. 3. L7810 reduced the rate of rise of intracellularly recorded action potentials in rabbit isolated atria; the resting potential was not affected, but the duration of the action potential was prolonged. 4. Unlike most drugs with local anaesthetic properties L7810 did not depress contractions in isolated atria but increased them. 5. L7810 reduced the spontaneous frequency, maximum follow frequency and conduction velocity of rabbit isolated atria. 6. L7810 had no blocking action on the chronotropic or positive inotropic actions of isoprenaline on isolated atrial muscle. 7. In anaesthetized dogs L7810 caused a small dose-related bradycardia, and a large dose-related decrease in peripheral vascular resistance. There was no blockade of the effects of isoprenaline on heart rate or peripheral blood flow.

Summary 1 An increase in the concentration of glycogen occurs in the mouse brain after depletion of cerebral catecholamines by alpha methyl-p-tyrosine methylester (H44/68), diethyldithiocarbamate, or reserpine. 2 Depletion of cerebral 5-hydroxytryptamine with parachlorophenylalanine (PCPA) does not result in a change in the concentration of brain glycogen. 3 When H44/68 is administered together with reserpine to inhibit the synthesis and storage of cerebral catecholamines, and thus bring about their total depletion from the brain, the cerebral glycogenolytic effect of amphetamine is abolished. 4 Amphetamine-inducing glycogenolysis is only partially antagonized if only one of the catecholamine-depleting agents H44/68, diethyldithiocarbamate, or reserpine is injected prior to the amphetamine. The persistence of this glycogenolytic effect of amphetamine is possibly due to the presence of residual stores of catecholamines available for release by the stimulant drug. 5 Depletion of cerebral 5-hydroxytryptamine by PCPA does not result in any antagonism of amphetamine-induced glycogenolysis. 6 The results suggest that amphetamine depletes brain glycogen by the release of central catecholamines rather than by a direct action at receptors.

1. As a local anaesthetic on frog nerve, LB46 had 0.4 times the activity of procaine and 2 times that of INPEA.2. In reducing the maximum rate of depolarization (MRD) of intracellularly recorded cardiac action potentials, LB46 was 20 times more potent than INPEA.3. As an antagonist of the chronotropic effect on atrial muscle and of the inotropic effects on ventricular muscle of isoprenaline the pA(2) values for LB46 were 9.05+/-0.15 and 9.30+/-0.06 respectively, and for INPEA 6.00+/-0.16 and 6.10+/-0.12.4. LB46 was 8 times more active than racemic propranolol in blocking the effects of isoprenaline on isolated cardiac muscle, and since its direct action on the cardiac membrane was only 0.1 times that of propranolol, there was a net gain of 80 times in the specificity of LB46 for class 2 (antisympathetic) over class 1 (depression of MRD) antidysrhythmic actions.5. INPEA was 2.5 times less active as a beta-adrenoceptor blocking drug on cardiac muscle than (+)-propranolol, and 1,300 times less active than LB46.6. INPEA, but not LB46, prolonged the duration of both atrial and ventricular intracellular action potentials.

Summary 1 Intraperitoneal injection of graded doses of ketamine produced a dose-dependent fall in body temperature of rats. Similarly, intracerebral injection of much smaller doses produced hypothermia. 2 Pretreatment of the rats with p-chlorophenylalanine (PCPA) greatly attenuated the hypothermic response to ketamine whereas the intraperitoneal injection of 5-hydroxytryptophan in PCPA-treated rats restored the hypothermic effect of ketamine. 3 Depletion of the brain monoamines by reserpine completely prevented the ketamine-induced hypothermia. Treatment with sodium diethyldithiocarbamate (DEDTC), however, did not modify the hypothermic effect of ketamine. 4 Pretreatment of the rats with pargyline potentiated the ketamine-induced hypothermia. 5 Depletion of brain monoamines by reserpine in combination with inhibition of noradrenaline biosynthesis (DEDTC) resulted in a long lasting fall in temperature which was not modified by ketamine. 6 When the ambient temperature was raised from 26° C to 32° C, ketamine-induced hypothermia was much reduced and superimposed on a hyperthermia which occurred in all animals. 7 It is concluded that ketamine produces hypothermia in rats possibly through the release of 5-hydroxytryptamine in the hypothalamus and that this effect is similar in some respects to that produced by morphine in non-tolerant rats.

1. The electrolytic brain lesion technique was used to evaluate the role of the substantia nigra in the mediation of the locomotor stimulant effect of (+)-amphetamine in the rat. The effect upon the results of variations in strain and basal activity levels of the rats was assessed.2. In the immediate postoperative phase the lesioned animals developed spontaneous stereotyped behaviour patterns which were more intense in rats of initially high basal activity. Activity was depressed at this stage and only that of the low activity animals was stimulated by amphetamine.3. After the 2nd postoperative day rats with lesions of the substantia nigra developed hyperactivity, but this was only maintained in rats initially of low basal activity. During this stage the locomotor stimulant effect of amphetamine (1.0 mg/kg) was apparent and after the 9th postoperative day animals generally displayed an increased sensitivity to the drug effect.4. The involvement of the substantia nigra with the control of locomotor activity is indicated but its integrity would not appear essential for the mediation of the locomotor stimulant effects of amphetamine.

1. The abilities of some pyrimidopyrimidines (including dipyridamole) and pteridine derivatives to potentiate heart block produced by adenosine in the guinea-pig and to produce coronary dilatation in kitten hearts were investigated.2. The results demonstrated a correlation between adenosine potentiating and coronary dilating activities of the compounds studied, and are therefore compatible with the concept that compounds of the dipyridamole type owe their coronary dilator activity to potentiation of endogenous adenosine.

1. The effect of intravenous infusions of various ions on the antidiuretic action of antidiuretic hormone has been studied in rats.2. Lithium (13 mmol/l.) reversibly inhibits the antidiuretic responses. Similar concentrations of potassium, rubidium, strontium, magnesium, choline and calcium do not. Lithium has a similar effect on the antidiuretic activity of oxytocin.3. The inhibition is not simply related to blood nor whole body lithium concentrations.4. Lithium (2 mmol/l.) in contact with the serosal surface also inhibits the transport of water facilitated by either 0.5 U/l. antidiuretic hormone or 1.1 mmol/l. cyclic adenosine monophosphate in the isolated toad bladder.5. Choline (2 mmol/l.) on the serosal surface also inhibits the transport of water facilitated by vasopressin in the toad bladder.

1. The effects of intracerebroventricular administration of some α- and β-adrenoceptor stimulants and antagonists on the body temperature of rabbits were investigated. 2. Noradrenaline produced a dose dependent rise in body temperature. Other catecholamines were less active. 3. The noradrenaline response was blocked by α-adrenoceptor blocking agents while β-adrenoceptor antagonists had no effect. 4. α-Methyl-noradrenaline and metaraminol had some hyperthermic effect, but significantly reduced the response of noradrenaline. 5. The possible presence of α-adrenoceptors in the central thermoregulatory mechanisms is suggested.

Summary 1 The fall in arterial blood pressure with bradycardia that occurs on injection of clonidine into the cerebral ventricles and into the cisterna magna is attributed to an action on ‘chemosensitive zones’ situated at the ventral surface of the brain stem. This conclusion is based on the following results obtained in cats anaesthetized with pentobarbitone sodium. 2 The fall in blood pressure no longer occurs on injection of clonidine (10 to 100 μg) into the cerebral ventricles when the passage of clonidine into the subarachnoid space is prevented by cannulation of the aqueduct. In this condition, the injections produce instead a rise in blood pressure. 3 Applied bilaterally, by means of perspex rings, to the ventral surface of the brain stem, clonidine (10 μl of a 50 to 1,000 μg/ml solution placed in each ring) produces a fall in blood pressure with bradycardia, but only when the perspex rings cover the ‘chemosensitive zones’ from which changes in blood pressure and heart rate are obtained with various drugs.

1. A technique for the perfusion of the rabbit liver with Krebs solution is described: the hepatic nerves were monitored for centripetal action potentials. Spontaneous afferent activity, and a good response to stimulating agents persisted for 7 h or longer. 2. Action potentials were elicited by injections or infusions of acetylcholine, 5-hydroxytryptamine, bradykinin, phenyldiguanide, adrenaline and various other compounds. From comparison with experiments carried out in vivo by other authors, it would appear that most of the nerves stimulated were afferent. 3. Inhibition of action potentials, either those occurring spontaneously or those elicited by injections, was produced by aspirin, paracetamol, mepyramine, chlorpheniramine, procaine and lignocaine but not by morphine or atropine. Pentolinium produced some inhibition, as did hexamethonium in concentrations of about 7·5 μg/ml. 4. Three methods for using the preparation for the assessment of local anaesthetic action are described. 5. Lobeline, potassium cyanide and 2,4-dinitrophenol stimulated nerve bundles which were not stimulated by anoxia or hypoxia.

1. Injection of 0.5-2.0 units of vasopressin or 25-100 mug of adrenaline into the peritoneal cavity of pregnant rats produced a transient slowing of the foetal heart. The bradycardia could be induced in foetuses after 15-21 days of gestation. Foetal heart rates dropped from normal values of 140-180 beats/min, often to less than 20 beats/minute. The period of bradycardia was dose dependent and ranged from 30 to 65 minutes.2. Maternal injection of the hormones produced a fall in foetal blood pressure from an average of 54, often to less than 20 mm of water, in 17-day foetuses. Direct injection of the hormones into the pericardial sac of the foetuses had the opposite effect and pressures rose an average of 15 mm of water 1 min after the injection.3. During the period of bradycardia, the potassium concentrations in foetal serum rose from an average value of 8.9 mequiv/1. to an average of 17.3 mequiv/litre. Concentrations of serum sodium fell from 126.2 to 121.4 mequiv/1. during the bradycardia. No changes were detected in the concentrations of either calcium or chloride. Foetal P(O2) levels fell from 25 to 15, P(CO2) rose from 61 to 89 or more, and pH fell from 7.19 to 6.86 during the bradycardia.4. Maternal death and uterine clamping caused foetal bradycardia and a rise in foetal serum potassium to an average of 20.2 mequiv/litre.5. It is concluded that interruption of normal uterine blood flow by vasoconstruction (adrenaline or vasopressin) or direct blockage (uterine clamping) results in a transient hypoxia, bradycardia, and serum ion changes in foetuses.

1. The inotropic activity of glucagon was compared with catecholamines and cardiac glycosides by in vitro procedures which were able to differentiate between the activities of the latter two groups. 2. The frequency-force curve for glucagon resembled that of noradrenaline at low stimulation frequencies (1 and 2/min) and that of ouabain at more rapid frequencies of stimulation. 3. Noradrenaline and adrenaline increased the amplitude of contraction of cat papillary muscles and markedly shortened the time to reach peak tension. Ouabain and glucagon increased tension without any change in the time to peak tension. 4. Noradrenaline caused a rapid onset and rate of rise of contraction of cat aortic strips, whereas the response to ouabain was slow in onset and rate of development. Glucagon had no effect on this preparation, even at high concentrations. 5. Manganese ions caused a shift of the dose-response curve to ouabain and glucagon, but not to noradrenaline or calcium. In 0·5 mM Ca media, the response to ouabain was abolished and the curve to noradrenaline shifted. 6. When glucagon was added to an atrial preparation, the time to the initial increase in tension and the time to maximal tension was intermediate between that necessary for noradrenaline and that necessary for cardiac glycosides. 7. Propranolol blocked the inotropic response to noradrenaline, but not to either ouabain or glucagon. 8. A relative measure of contraction-dependency was described. Cardiac glycosides exhibited a greater degree of contraction-dependency than either noradrenaline or glucagon. 9. Adrenaline elevated the depressed plateau of the action potential from calf and sheep Purkinje fibres, but ouabain and glucagon were without effect. 10. Electrophysiological measurements demonstrated that moderate concentrations of glucagon exerted only a small effect in prolonging atrial and ventricular action potentials. 11. Several pharmacological blocking drugs and other inotropic agents did not potentiate or block the inotropic response to glucagon. Reserpine pretreatment increased the response to glucagon. 12. It was concluded that glucagon has its own spectrum of inotropic activity and does not completely mimic the effects of either ouabain or noradrenaline.

1. The effects of adenosine on systemic blood pressure, coronary blood flow and cardiac contractility and rate were studied in anaesthetized open-thorax dogs.2. The potency and duration of action of substituted adenosine analogues were compared with that of adenosine.3. With the exception of 2-chloroadenosine, in which coronary dilator activity was enhanced, substitution in the 2-position of the adenosine molecule reduced activity.4. In all cases 2-substitution prolonged the duration of the coronary dilator activity of adenosine.5. N(6)-Methylation of adenosine and 2-chloroadenosine reduced their coronary dilator activities, but had no effect on the duration of the response.6. Comparison of the coronary dilator potencies and hypotensive activities of 2-ethylaminoadenosine and 2-methoxyadenosine indicates that these analogues have some specificity for the coronary bed.