Showing papers in "British journal of pharmacology and chemotherapy in 1964"

The use of changes in capillary permeability in mice to distinguish between narcotic and nonnarcotic analgesics

Abstract: An extension of the “squirming test” is described which makes the method specific for nonnarcotic analgesics. The intraperitoneal injection of acetic acid causes squirming and an increase in capillary permeability that is measured by direct estimation of plasma-bound dye (Pontamine Sky Blue) which has leaked into the peritoneal cavity. Nonnarcotic analgesics inhibit squirming and leakage of dye. Values for the oral ED50s for both effects are given for a number of typical compounds. Narcotic analgesics, in doses that produce analgesia, inhibit squirming but do not significantly affect leakage of dye. Drugs that stimulate the central nervous system and also inhibit squirming have no significant effect on leakage of dye over the range of doses which inhibit squirming. Corticosteroids do not significantly inhibit either squirming or leakage of dye.

Stimulant actions of volatile anaesthetics on smooth muscle

Abstract: A number of volatile anaesthetics, and some compounds synthesized in the search for new anaesthetics, have been tested on guinea-pig intestinal smooth muscle in vitro. All the compounds produced a contractile response. This effect did not correlate well with convulsant activity in vivo among the compounds tested. Two kinds of stimulant effect were distinguishable: (1) Rapid, transient contractions, abolished by cocaine or lachesine; most of the anaesthetics in clinical use had this action. (2) Slow, sustained contractions, unaffected by cocaine or lachesine; this effect predominated among the fluorinated ring compounds. Hexamethonium and mepyramine did not affect the contractile response to any of the compounds. The first type of effect presumably represents excitation of postganglionic nerve cells, while the second type is a direct action on the muscle cell. The action of perfluorobenzene, which is of the latter kind, was studied further. Adrenaline and lack of calcium diminished the contraction in parallel with the contraction to histamine, which suggests that the cell membrane was the site of action; in contrast to the stimulant action of histamine or acetylcholine, the effect was highly temperature-sensitive, being almost abolished by cooling to 32 degrees C, and enhanced at 40 degrees C. The depressant action of anaesthetics on smooth muscle is affected very little by temperature changes. These findings are discussed in relation to other observations which suggest a stimulant action of volatile anaesthetics on excitable tissues. Protein denaturation is tentatively suggested as a mechanism of action.

A sensitive method for the assay of angiotensin.

Abstract: A method is described for the assay of angiotensin on the rat colon. Under the conditions of the assay, the preparation is sensitive to angiotensin and relatively insensitive to 5-hydroxytryptamine, to histamine and to other substances which might be present in blood. Bradykinin and catechol amines do not interfere with the assay. Evidence is given for the specificity of the angiotensin receptors.

Sodium sulphomethyl derivatives of polymyxins.

Abstract: Variations in the treatment of polymyxin B and polymyxin E (colistin) with formaldehyde and sodium bisulphite produce sulphomethyl derivatives which differ quantitatively in acute toxicity and in antibacterial activities in vitro and in vivo. The acute intravenous LD50 values of some sixty samples of these derivatives range from six- to more than eighty-fold those of the parent antibiotics; the in vitro antibacterial activities range from 2 to 12% and the in vivo activities from 20 to 50% of those of the parent antibiotics, with the most toxic derivatives showing the highest activities. When short and prolonged incubation methods are used, assays of the derivatives in solutions of different ages and of blood collected from man and dog after intramuscular injection, show that the antibacterial activities of these sulphomethyl derivatives depend on reversion to the unsubstituted form, and that the differences in the activities are due to variations in stability. These conclusions are supported by comparison of these sulphomethyl derivatives with stable acetyl derivatives. The lower in vivo activity is due, at least partly, to the high renal excretion of the substituted form. Electrophoresis shows that the derivatives are composite, the components corresponding to mono- to pentasulphomethyl polymyxin. Pain at the injection site is the most troublesome side-effect of polymyxin therapy, and this is avoided with these derivatives. In rats injected with quantities some twenty-times the usual human dose, the derivatives cause transitory decrease in urinary output and transitory proteinuria. After intramuscular injection of these derivatives into dogs, no antibiotic is detectable in the cerebrospinal fluid and concentrations present in the bile are not significantly different from those after injection of the parent antibiotic. When injected intracisternally into these animals, derivatives are less toxic than the parent compounds. These studies show that acute intravenous toxicity is a useful index of therapeutic efficiency and that derivatives with intravenous LD50 values of about 100 mg/kg are the most satisfactory ones. Because activity depends on reversion to the parent antibiotic, the use of these derivatives for topical application is contraindicated.

The excitation and depression of mammalian cortical neurones by amino acids

Abstract: Amino acids related to L-glutamic and gamma-amino-n-butyric acid have been administered electrophoretically, and by pressure ejection, into the extraneuronal environment of single neurones in the pericruciate cortex of cats anaesthetized with allobarbitone or allobarbitone-urethane. Acidic amino acids related to glutamic acid, particularly N-methyl-D-aspartic acid, excited cortical neurones. Neutral amino acids related to gamma-amino-n-butyric acid, particularly 3-amino-1-propanesulphonic acid, depressed cortical neurones. Some of the depressants blocked the antidromic invasion of Betz cells by pyramidal volleys. There are no essential differences between the sensitivities of cortical and spinal neurones towards locally administered amino acids. A transmitter function of such amino acids within the mammalian central nervous system is considered unlikely.

Actions of prostaglandins e1, e2 and e3 on the central nervous system

Abstract: Prostaglandins E1, E2 and E3, injected into the cerebral ventricles of unanaesthetized cats, produced sedation, stupor and signs of catatonia. The threshold dose was 3 μg/kg. Slight sedation was also observed following an intravenous injection, but a dose of 20 μg/kg was required. In chicks, intravenous injections of prostaglandins (10 to 400 μg/kg) caused respiratory depression, profound sedation, loss of normal posture and, with the higher doses, loss of the righting reflex.

The inhibitory actions of prostaglandins on respiratory smooth muscle

Abstract: Prostaglandin E(1), in concentrations as low as 1 ng/ml., relaxed isolated tracheal muscle from cat, monkey, rabbit, guinea-pig and ferret. Tracheal muscle from the cat, monkey and rabbit did not exhibit inherent tone and the effect of prostaglandin E(1) on these preparations was seen only after a sustained contraction had been produced by a previous dose of acetylcholine or of another agonist. Prostaglandins E(2), E(3) and F(1alpha) also relaxed isolated cat tracheal muscle which had been stimulated by acetylcholine: their activities relative to that of prostaglandin E(1) were, respectively, 1.0, 0.2 and 0.002. In the anaesthetized cat prostaglandin E(1) increased lung "resistance to inflation" (presumably comparable to bronchial resistance) and the heart rate. In the anaesthetized rabbit and guinea-pig, prostaglandin E(1) antagonized the rise in resistance to inflation of the lungs obtained after vagal stimulation or after the intravenous injection of histamine; it sometimes lowered the resistance to inflation in these species. The possibility that prostaglandin may have a local physiological role in the control of bronchial smooth muscle tone is discussed.

Bronchoconstrictor action and antagonism of a slow-reacting substance from anaphylaxis of guinea-pig isolated lung.

Abstract: Slow-reacting substance produced in anaphylaxis (SRS-A) increased resistance of the lungs to inflation in the guinea-pig in vivo and caused isolated preparations of its tracheobronchial muscle to contract. SRS-A also contracted human isolated bronchial muscle and some but not all preparations of rabbit trachea. Nonsteroid anti-inflammatory drugs, which antagonize bronchoconstriction induced by kinins, but not that by histamine, acetylcholine, 5-hydroxytryptamine, substance P, angiotensin or lung prostaglandin, also antagonized the bronchoconstrictor action of SRS-A. This antagonism resembled that of kinins in being surmounted by higher doses of agonist, in the potencies of active drugs and in the types of drugs which were inactive. However, receptors in guinea-pig tracheobronchial muscle for SRS-A seem to be distinct from those for bradykinin, since preparations of this muscle could become unresponsive to either agent in vivo and in vitro, while remaining responsive to the other.

The influence of centrally acting cholinolytic drugs on brain acetylcholine levels

Abstract: A number of centrally acting cholinolytic drugs reduced levels of cerebral acetylcholine in the rat. Among its naturally occurring analogues, hyoscine had the greatest potency, producing a decrease of 31% at a dose of 0.63 mg/kg. Atropine methyl nitrate, which acts as a cholinolytic drug in the periphery, had no effect on brain acetylcholine levels. The fall in acetylcholine produced by hyoscine was greatest after 60 min and disappeared at about 120 min. The animals tended to show a partial tolerance to this effect of hyoscine when the drug was administered repeatedly. The reduction in acetylcholine after hyoscine was restricted to the cerebral hemispheres, and did not appear in subcortical regions of the brain. Hyoscine had no influence on the net synthesis of acetylcholine by acetone-extracted powder of rat brain. In a series of four synthetic cholinolytic drugs, only the two with conspicuous psychotomimetic actions in man produced a decrease in brain acetylcholine comparable to that seen with hyoscine and related alkaloids.

Angiotensin and peripheral sympathetic nerve activity.

Abstract: On the isolated vas deferens of the guinea-pig angiotensin potentiated strongly the height of contractions due to electrical stimulation of the hypogastric nerve; it did not affect the responses to noradrenaline and acetylcholine, nor did it elicit any contraction when given alone. Angiotensin likewise potentiated the responses of the cat spleen to nerve stimulation, but it also induced by itself strong contractions of the organ and reduction of the venous outflow. In experiments on the arterial blood pressure of anaesthetized and spinal cats, in which sympathetic postganglionic transmission was temporarily blocked by nicotine or tetramethylammonium, pressor responses to angiotensin were strongly reduced. As with some ganglion-stimulating drugs, the pressor responses, enhanced after a second series of nicotine injections, were reduced to the control level by hexamethonium. These findings indicate the involvement of peripheral sympathetic nerves in the action of angiotensin: the hypothesis is advanced that angiotensin acts at the peripheral nerve endings by promoting a greater output of noradrenaline.

Effects of central depressant drugs upon acetylcholine release.

Abstract: Several central depressant and other drugs have been examined for their effects upon acetylcholine release from the stimulated, perfused cat superior cervical ganglion and rat isolated phrenic nerve-diaphragm preparations. The acetylcholine released was assayed biologically. Amylobarbitone sodium, chloral hydrate, trichloroethanol, methylpentynol, methylpentynol carbamate, paraldehyde, procaine hydrochloride and troxidone reduced the presynaptic release of acetylcholine from the ganglion. They also exhibited a postsynaptic blocking action, this component of depressant activity being particularly prominent with paraldehyde and troxidone. Closely analogous findings were obtained at the neuromuscular junction with methylpentynol and its carbamate, paraldehyde, procaine hydrochloride, trichloroethanol and troxidone. At both sites the drug-induced depression, both of transmission and of acetylcholine output, was reversible. Whereas hexamethonium regularly blocked ganglionic transmission with no effect upon acetylcholine release, tetraethylammonium not only completely blocked ganglionic transmission but concomitantly augmented acetylcholine output. These results are discussed in relation to the electrophysiological and metabolic events associated with neuro-effector transmission.

A preliminary investigation of the pharmacology of the human isolated taenia coli preparation.

Abstract: The effects of drugs on smooth muscle strips of human taenia coli, obtained from operation specimens, were studied in vitro. Both nicotinic and muscarinic sites of action of acetylcholine were demonstrated, the nicotinic effect being a relaxation. The sympathomimetic amines, adrenaline, noradrenaline, and isoprenaline produced a relaxation of the tissue by an action on adrenaline alpha- and beta-receptors. The presence of both types of receptor was demonstrated by selective adrenergic blockade with pronethalol or Hydergine. Pronethalol in high concentrations gave a nonselective adrenergic blockade. The ganglion-stimulating agents nicotine and dimethylphenylpiperazinium produced a relaxation of the tissue in all concentrations. This relaxation was inhibited by pronethalol or physostigmine but no contractile component to ganglion stimulation was revealed when these two drugs were present together. These results indicate the presence of either sympathetic ganglia in the intrinsic nerve plexuses, or adrenergic stores in the bowel wall. There is no pharmacological evidence for parasympathetic ganglia in human sigmoid colon. Histamine produced relaxant, contractile or biphasic responses. The type of response was independent of the "tone" of the preparation. The responses were not modified by procaine, hyoscine or pronethalol, which result indicates that both the contractile and relaxant responses to histamine were due to a direct action of the drug on smooth muscle. 5-Hydroxytryptamine produced either a contraction or a relaxation of the tissue. The relaxation was due to a direct effect of the drug, since hexamethonium, procaine or pronethalol did not affect the response. No conclusions have been drawn regarding the mechanism of the contractile response to 5-hydroxytryptamine. The nature of the responses of the tissue to drugs was independent of the disease for which the specimen of colon was removed.

SOME OBSERVATIONS ON THE PHARMACOLOGY OF α‐METHYLDOPA

Abstract: α-Methyldopa in high concentrations impaired the responses of rabbit isolated ileum and guinea-pig isolated vas deferens to stimulation of the sympathetic nerves and to noradrenaline, but these preparations taken from animals previously treated with α-methyldopa showed no sign of impairment. Contractions of the cat nictitating membrane were reduced but not abolished by α-methyldopa. In cats, dogs and rats, pressor responses to noradrenaline were usually slightly increased by α-methyldopa. Pressor responses to tyramine were not affected consistently. α-Methyldopa, α-methyldopamine and α-methylnoradrenaline behaved like dopa, dopamine and noradrenaline respectively in restoring the responses of tissues from reserpine-treated animals to stimulation of the sympathetic nerves to the rabbit ileum, the guinea-pig vas deferens and the cat nictitating membrane and in restoring responses to tyramine of the cat blood pressure and nictitating membrane, and the rat blood pressure. The potency of α-methylnoradrenaline relative to noradrenaline ranged from one-half to one-ninth on various preparations. The results are discussed in relation to the antihypertensive action of α-methyldopa.

Cobalt compounds as antidotes for hydrocyanic acid.

Abstract: The antidotal potency of a cobalt salt (acetate), of dicobalt edetate, of hydroxocobalamin and of cobinamide against hydrocyanic acid was examined mainly on mice and rabbits All the compounds were active antidotes for up to twice the LD50; under some conditions for larger doses The most successful was cobalt acetate for rabbits (5xLD50), which was effective at a molar cyanide/cobalt (CN/Co) ratio of 5, but had as a side-effect intense purgation Hydroxocobalamin was irregular in action, but on the whole was most effective for mice (45xLD50 at a molar ratio of 1), and had no apparent side effects Dicobalt edetate, at molar ratios of up to 2, was more effective for rabbits (3xLD50) than for mice (2xLD50), but had fewer side effects than cobalt acetate The effect of thiosulphate was to augment the efficacy of dicobalt edetate and, in mice, that of hydroxocobalamin; but, apparently, in rabbits, to reduce that of hydroxocobalamin Cobinamide, at a molar ratio of 1, was slightly more effective than hydroxocobalamin on rabbits and also less irregular in its action Cobalt acetate by mouth was effective against orally administered hydrocyanic acid The oxygen uptake of the body, reduced by cyanide, is rapidly reinstated when one of the cobalt antidotes has been successfully administered

Mechanism of the paralysing action of piperazine on ascaris muscle.

Abstract: The effects of piperazine on Ascaris muscle cells have been investigated with electrophysiological techniques. These cells have an average resting potential of about 30 mV interrupted by rhythmic spikes of myogenic origin (1 to 7 spikes/sec). With piperazine (10-3, w/v), the average resting potential increases above 40 mV and the pacemaker activity is suppressed. These changes are similar to those temporarily produced in the same cells by the electrical stimulation of inhibitory nerve fibres. Electrophoretic application of piperazine to different areas of the muscle cells shows that this drug hyperpolarizes their membrane only when applied to the region where both excitatory and inhibitory neuromuscular synapses are located. The degree of muscle hyperpolarization induced by piperazine depends upon the extracellular chloride concentration, decreasing when a fraction of the chloride ions is replaced by the larger, supposedly nonpenetrating, sulphate anions. Piperazine may, therefore, be regarded as a pharmacological analogue of a natural inhibitory transmitter.

The action of morphine‐like drugs on impulse transmission in mammalian nerve fibres

Abstract: Experiments on nerves in situ and on isolated nerves provide no evidence that morphine interferes with impulse transmission in myelinated or nonmyelinated nerve fibres. The concentrations used in experiments on isolated nerves were 10- to 100-times as high as those required to depress transmission at autonomic nerve-effector cell junctions. Examination of the resting membrane potential, the action potential and the positive after-potential, the conduction velocity, the time courses of the recovery of the size of the action potential and of the excitability after a conditioning stimulus, the ability of the axons to sustain repetitive activity and the posttetanic hyperpolarization gave no indication that morphine affects either the mechanisms involved in the initiation of the propagated impulse or those leading to restoration of the resting state after activity. Analgesic drugs, such as pethidine and methadone which have a local anaesthetic action, may cause a reversible decrease in the size of the compound action potential and in the conduction velocity of A-B and C fibres.

A comparison of imipramine, chlorpromazine and related drugs in various tests involving autonomic functions and antagonism of reserpine.

Abstract: Seven structurally-related compounds consisting of three antidepressant drugs (imipramine, desmethylimipramine and amitriptyline), three tranquillizing agents (promazine, chlorpromazine and chlorprothixene) and a hybrid, desmethylpromazine, have been examined in a series of tests involving autonomic functions and antagonism of reserpine. Activities of the compounds in antagonizing reserpine-induced ptosis in rabbits and prolongation of alcohol hypnosis in mice give good correlation with their clinical actions, whilst their activities in augmenting excitation of rats by amphetamine and yohimbine toxicity in mice, and in reversing reserpine-induced bradycardia in rats offer further evidence for drug-induced sensitization to adrenergic or tryptaminic mechanisms, which is not however specific for antidepressant agents. No evidence has been obtained to indicate that a central parasympatholytic action is an important component of the antidepressant activity of imipramine and related drugs.

An electrophysiological investigation of the actions of some autonomic blocking drugs on transmission in the guinea-pig vas deferens.

Abstract: Membrane potentials have been recorded from the guinea-pig isolated vas deferens with intracellular and sucrose-gap electrodes during stimulation of the hypogastric nerve and of intramural nerve fibres. Atropine had no detectable effect on the excitatory junction potentials in response to nerve stimulation or on the spontaneous discharge of small potentials. High concentrations of adrenolytic drugs, acting on α-receptors were needed to block the response to nerve stimulation and the spontaneous discharge. During the onset and recovery from yohimbine blockade, junction potentials in response to repetitive stimulation were not sustained. Bretylium initially reduced both the junction potentials and the spontaneous discharge. However, after 30 min exposure, the spontaneous discharge increased in frequency although the response to nerve stimulation was abolished. Block of the junction potentials by procaine was rapid in onset compared with that by bretylium and guanethidine, but the spontaneous discharge was not abolished. These results are discussed in relation to the mechanism of transmission from sympathetic nerve to smooth muscle.

Effect of hexadimethrine bromide on plasma kinin formation, hydrolysis of p-tosyl-l-arginine methyl ester and fibrinolysis.

Abstract: The antiheparin agent hexadimethrine bromide, in concentrations of 20 to 200 mug/ml., inhibited the activation by active Hageman factor of the plasma enzyme which releases kinin from substrate. Once activated, this kinin-forming enzyme was not consistently inhibited by hexadimethrine in a concentration of 1 mg/ml. Surfaces which induce kinin formation by activating Hageman factor in plasma (glass, kaolin, celite, barium carbonate and carboxymethylcellulose) were inactivated by bathing in aqueous solutions of hexadimethrine. The effects of hexadimethrine on Hageman factor and on glass were not abolished by amounts of heparin which neutralize most other actions of hexadimethrine. Hexadimethrine prevented the activation by kaolin, but not by streptokinase, of p-tosyl-L-arginine methyl ester-splitting and fibrinolytic factors in plasma; once these enzymes were activated by kaolin, they could not be inhibited by hexadimethrine. Hexadimethrine, given locally or intravenously into guinea-pigs, reduced the increase in capillary permeability produced by intracutaneous injections of kaolin suspensions.

The effect of fasting on the hyperglycaemic responses to catechol amines in rats

Abstract: The relative activities of adrenaline, noradrenaline and isoprenaline in producing hyperglycaemia and glycogenolysis in skeletal muscle have been studied in both fed and fasted rats, 1 hr after subcutaneous injection of the catechol amines. The relative hyperglycaemic activities of the three catechol amines depended greatly upon the prandial state of the rats and on the dose range used. In fed rats the relative potencies were in the descending order of potency, adrenaline-noradrenaline-isoprenaline, irrespective of the dose range. Isoprenaline had no hyperglycaemic activity in fed rats even at doses as high as 2 mg/kg. In fasted rats the order of potency depended on the dose. At low doses (0.005 to 0.02 mg/kg) the descending order was isoprenaline-adrenaline-noradrenaline. At higher doses (0.1 to 1 mg/kg) the descending order was adrenaline-isoprenaline-noradrenaline. The relative activities of the three catechol amines in causing glycogenolysis in muscle was independent of the dose range or the prandial state of the rats. Under all conditions the descending order of potency was isoprenaline-adrenaline-noradrenaline. The results are discussed with reference to Ahlquist's (1948) hypothesis of alpha- and beta- receptors and were consistent with the concept that, in the rat, liver glycogenolysis is mediated predominantly by alpha-receptors and muscle glycogenolysis mainly by beta-receptors. In general the hyperglycaemic response in the fed rat is mediated predominantly by alpha-receptors and in the fasted rat the response is mainly due to the activation of beta-receptors. A drug possessing both alpha- and beta-receptor activity elicits an exception to this rule in the fasted rat. Several perturbing problems in the literature, particularly with regard to the hyperglycaemic activity of isoprenaline and to the difficulty in blocking the hyperglycaemic response, can now be explained in the light of these findings.

Quantitative studies of the antagonism by nalorphine of some of the actions of morphine-like analgesic drugs.

Abstract: A quantitative investigation has been made of the antagonism by nalorphine of the analgesia and lenticular opacity produced in mice by a number of compounds. ED50 values have been obtained for each drug in the absence and in the presence of increasing doses of nalorphine, and from these, appropriate dose-ratios have been calculated. It has been possible to derive the equivalent of a pA(2) value for each drug with nalorphine and, since these are almost identical, it may be concluded that all the drugs combine with similar receptors. Nalorphine antagonizes both actions by competing for the receptors. It was not possible to antagonize quantitatively the analgesic action of pethidine with nalorphine, although the lenticular effect could be abolished. The effect of nalorphine on the change in skin temperature in mice induced by some of the analgesic drugs was also investigated.

The part played by calcium in determining the response to stimulation of sympathetic postganglionic fibres

Abstract: The inhibition of the pendular movements in a loop of rabbit ileum caused by stimulating the periarterial nerves in the mesentery depends on the calcium concentration in the bathing fluid. The inhibition is small when the concentration is low, and increases as the concentration rises. In the lower ranges of calcium concentration there is rarely any change in the response to noradrenaline, so that the increase in inhibition is due to an increase in the amount of noradrenaline released. The effect of calcium is antagonized by magnesium. In the presence of hyoscine, nicotine inhibits the ileum, and this inhibition also depends on the concentration of calcium. Acetylcholine can sometimes be shown to cause inhibition, and again this inhibition depends on the concentration of calcium. These and other experiments show a close similarity between the release of catechol amines from the adrenal medulla by acetylcholine and the release of noradrenaline from the postganglionic fibre by stimulation or by nicotine. In both instances the calcium concentration plays a decisive part.

Inhibitors of histamine catabolism and the action of gastrin in the rat.

Abstract: A method is described for the partial purification of hog's antral gastrin by gel filtration and ion-exchange chromatography. Gastrin was assayed by its effect on the pH of the effluent fluid from the perfused lumen of the stomach of the anaesthetized rat. The latency of the response to gastrin given intravenously was shorter than the latency to a similar dose of histamine. The response to gastrin injected into the arterial circulation of the stomach appeared sooner than the response to gastrin injected intravenously. Iproniazid and aminoguanidine potentiated responses to gastrin. Incubation in vitro with monamine oxidase or diamine oxidase did not inactivate gastrin. Chlorpromazine and bromolysergic acid diethylamide, in doses which enhance the effects of histamine on acid gastric secretion, did not affect responses to gastrin.

Studies on the hyperglycaemia induced by chlorpromazine in rats

Abstract: Chlorpromazine induces in rats a marked and long-lasting hyperglycaemia which (a) is more marked at low than high room temperatures, (b) is inhibited by phentolamine but not by dibenamine, and (c) is prevented by adrenalectomy, by removal of the adrenal medullae and by treatment of the rats with reserpine. Other experimental results suggest that there is a correlation between the hyperglycaemia and the hypothermia induced by chlorpromazine and by its congeners. The hyperglycaemia seems to be the result of at least two factors: an activation of the adrenergic mechanisms and an impaired peripheral utilization of glucose.

Secretory responses of extramedullary chromaffin tissue.

Abstract: When the isolated inferior mesenteric ganglion of the dog was perfused with Locke solution, the effluent fluid contained noradrenaline and adrenaline. At rest the output of noradrenaline ranged from 0.7 to 40 ng/min, and that of adrenaline from 0.7 to 25 ng/min. Electrical stimulation of the inferior splanchnic nerves did not alter the catechol amine content of the perfusate, and stimulation of the ascending mesenteric nerves caused an increase to little more than twice the resting value. When acetylcholine or dimethylphenyl-piperazinium iodide was infused into the preparation, the catechol amine content of the effluent fluid was 6- to 100-times the resting level. Two drugs with muscarinic action (pilocarpine and 3-acetoxy-1-benzyl-1-methylpyrrolidinium bromide) produced only very small increases in catechol amine release. Angiotensin, in doses ranging from 20 ng to 2 μg, inhibited release of catechol amines, and bradykinin had a weak stimulatory effect. It is suggested that the catechol amines released into the effluent fluid were derived from chromaffin tissue in the ganglion; evidence for innervation of this tissue was unobtainable, but its catechol amines were readily released by the injection of nicotinic drugs.

A comparison of the ganglion potentials and block produced by acetylcholine and tetramethylammonium.

Abstract: Potentials recorded from the surface of the superior cervical ganglion of cats after an intra-arterial injection of acetylcholine were characterized by a complex waveform which depended on the amount of drug administered. Small doses of acetylcholine evoked a potential consisting of low amplitude hyperpolarization followed by low amplitude depolarization. Somewhat larger doses of acetylcholine caused a triphasic potential containing an initial period of depolarization in addition to the periods of hyperpolarization and delayed depolarization. Still larger doses of acetylcholine produced usually a monophasic wave of depolarization. Small doses of atropine prolonged the initial period of depolarization and prevented the hyperpolarization and delayed depolarization. Hexamethonium reduced or abolished the initial depolarization and enhanced or unmasked the hyperpolarization. The block of transmission occurring during the falling phase of the initial depolarization or during the hyperpolarization was antagonized by atropine. Unlike acetylcholine, tetramethylammonium produced only a prolonged ganglion depolarization which was unaffected by atropine and blocked by hexamethonium. The block of transmission by tetramethylammonium was partially prevented by atropine. These findings support the proposals that three pharmacologically distinctive cholinoceptive sites are present in sympathetic ganglia and, further, that activation of a cholinoceptive site sensitive to atropine may be involved in the block of transmission produced by acetylcholine and related drugs.

The influence of phenoxybenzamine on the storage of noradrenaline in rat and cat tissues

Abstract: In the cat, phenoxybenzamine prevented the uptake of noradrenaline by the kidney but not by the uterus; dichloroisoprenaline prevented the uptake of noradrenaline by the uterus but not by the kidney. In the rat, a single dose of phenoxybenzamine prevented the uptake of noradrenaline by the heart, spleen and uterus and reduced the uptake by the duodenum. Prolonged treatment with phenoxybenzamine prevented the uptake by the heart and uterus but not by the spleen or duodenum. Both phenoxybenzamine and dichloroisoprenaline lowered the noradrenaline content of some tissues of the rat. Phenoxybenzamine did not antagonize the responses to noradrenaline of the nonpregnant cat uterus in situ, not the responses of rat isolated ventricles, uterus or duodenum. It is concluded that the way in which these noradrenaline antagonists affect the storage sites for noradrenaline varies between organs. The effects of the drugs on the receptors for noradrenaline are not related to their effects on storage sites.

Observations on the significance of 5-hydroxytryptamine in relation to the peristaltic reflex of the rat

Abstract: Peristalsis of normal rats, and of rats fed either on a control diet or on a tryptophan-free diet (5-hydroxytryptamine-depleted rats), was studied in vitro and in situ to test the hypothesis that 5-hydroxytryptamine functions as a local hormone in the intestine and may be essential for initiation of the peristaltic reflex. A tryptophan-free diet depleted intestinal 5-hydroxytryptamine by a mean value of 90%; in some rats, the depletion appeared to be complete. Peristaltic responses, even of rats with complete depletion, were qualitatively similar to, and quantitatively not statistically different from those of normal or of pair-fed control animals whose intestinal mucosa contained high concentrations of 5-hydroxytryptamine. Intraluminal and serosal 5-hydroxytryptamine produced effects in 5-hydroxytryptamine-depleted rats similar to those in the normal and in the control animals. Furthermore, the maximal stimulatory effects of 5-hydroxytryptamine on peristaltic performance were not greater than spontaneous variations in performance in any group of animals, except with tryptophan-fed control rats, when the effects of the amine on peristalsis in situ were greater than spontaneous variation. It was therefore concluded that 5-hydroxytryptamine is not essential for peristalsis in the rat.

The effects of adrenaline and other drugs affecting carbohydrate metabolism on contractions of the rat diaphragm

Abstract: The ability of several drugs to restore directly elicited twitches of the rat diaphragm depressed by excess potassium chloride has been studied. The drugs found to be effective were sympathomimetic amines, insulin, glucagon, caffeine, theophylline, calcium chloride and hexosephosphates. The effects of the sympathomimetic amines and glucagon were blocked by beta-receptor blocking agents. Phloridzin blocked the effect of insulin and depressed that of glucagon. The increase in twitch tension still occurred under anaerobic conditions and was not abolished by the glycolytic inhibitor, iodoacetate. All of the effective drugs are known to affect carbohydrate metabolism and the suggestion by Ellis (1955) that the effect on contractions may be a result of increased intracellular hexosephosphate levels is discussed.

A quantitative study of the effect of cocaine on the response of the cat nictitating membrane to nerve stimulation and to injected noradrenaline.

Abstract: Results are reported of a quantitative study of the potentiating effect of cocaine on the responses of the cat nictitating membrane to intravenously and intra-arterially injected noradrenaline, as well as to different types of sympathetic nerve stimulation. Responses of the membrane to noradrenaline were potentiated more with intravenous than with close-arterial injections. From studies of the responses of the nictitating membrane to various forms of sympathetic nerve stimulation before and after injection of cocaine, conclusions are drawn as to the extent to which the transmitter amine liberated by nerve activity is normally removed and its effect thereby limited in duration and extent. This uptake was greatest at low stimulus frequencies. The mechanism by which cocaine potentiates sympathetic responses is discussed.