bluuebunny/crossref_metadata_2025 huggingface dataset:
AN ATTEMPT TO STUDY THE EFFECTS OF CHEMICAL STRUCTURE ON THE AFFINITY AND EFFICACY OF COMPOUNDS RELATED TO ACETYLCHOLINE
Authors: BARLOW R. B. , SCOTT K. A. , STEPHENSON R. P.
Published: July 2012

Two sets of series of compounds, RN+Me3, RN+Me2Et, RN+MeEt2, RN+Et3, and R'N+Me3, R'N+Me2Et, R'N+MeEt2, R'N+Et3, have been prepared, in which R is a 2‐(diphenylacetoxy)ethyl, 2‐(benziloyloxy)ethyl, 2‐(2,2‐diphenylethoxy)ethyl, 3‐(diphenylmethoxy)propyl or 3,3‐diphenylbutyrylmethyl group, and R′ is a 2‐acetoxyethyl, 2‐ethoxyethyl, 3‐methoxypropyl or butyrylmethyl group: compounds of the first set therefore differ from those of the second set in that they contain a diphenylmethyl group (or a benziloyl group) in place of a methyl group. The former compounds are antagonists of acetylcholine whereas most of the latter act like acetylcholine. The affinity constants of the former compounds for the acetylcholine receptors of the guinea‐pig ileum have been determined and the equipotent molar ratios relative to acetylcholine have been measured for the latter compounds. The variation of the affinity constant with the constitution of the onium group in the antagonists (the diphenylmethyl compounds) was sufficiently consistent from one series to another for it to seem likely that corresponding changes in affinity with the constitution of the onium group would occur in the agonists. From the relative activity of the agonists and with this knowledge of relative affinity it was possible to assess the effects of their structure on efficacy. Substitution of one methyl in the onium group by an ethyl group in these compounds increased affinity but decreased efficacy. The replacement of a second methyl by a second ethyl group had little effect on affinity but decreased efficacy still further. The replacement of the ester link in acetylcholine by a 4‐ether oxygen atom (as in the diphenylmethoxypropyl and methoxypropyl compounds) did not appreciably reduce affinity but markedly reduced efficacy, whereas the replacement of the ester link by a 3‐ether oxygen atom (as in the diphenylethoxyethyl and ethoxyethyl compounds) markedly reduced affinity but did not reduce efficacy. The diphenylbutyrylmethyl compounds had low affinity and the butyrylmethyl compounds had low efficacy. We conclude that the action of acetylcholine at the postganglionic parasympathetic receptors in the guinea‐pig ileum depends upon the presence of the 4‐carbonyl group (and presumably the onium group) for affinity and on the 3‐ether oxygen atom and the trimethylammonium group for efficacy.
PREGANGLIONIC AND POSTGANGLIONIC STIMULATION OF THE GUINEA‐PIG ISOLATED VAS DEFERENS PREPARATION
Authors: BIRMINGHAM A. T. , WILSON A. B.
Published: July 2012

The isolated vas deferens of the guinea‐pig contracted when stimulated transmurally with parallel wire electrodes. These contractions persisted in concentrations of hexamethonium, pentolinium, nicotine and mecamylamine which at the same time abolished the responses to hypogastric nerve stimulation. Procaine and lignocaine in local anaesthetic concentrations abolished the responses to transmural stimulation but potentiated the contractions produced by added noradrenaline. Guanethidine and bretylium in concentrations specific for adrenergic neurone blockade abolished the contractions due to transmural stimulation without impairing the responses of the muscle to added noradrenaline or acetylcholine. In contrast, high concentrations of the adrenergic‐blocking agents phentolamine and dihydroergotamine were needed to block the contractions due to transmural stimulation; these concentrations also blocked the response to added noradrenaline but simultaneously reduced the responses to added acetylcholine or potassium chloride. Preparations from guinea‐pigs previously treated with reserpine at first responded normally to transmural stimulation; thereafter the contractions diminished progressively but were never abolished. Hyoscine and atropine produced a small decrease in the response to transmural stimulation when present in concentrations up to 1 × 10−5 and a larger decrease only in concentrations of 1 × 10−4 or greater. Hemicholinium produced a small decrease of the contractions due to transmural stimulation in concentrations up to 1 × 10−4; concentrations of 5 × 10−4 present for 1 hr produced only a slightly greater reduction in response. These experiments show that when the guinea‐pig vas deferens is removed without the hypogastric nerve and stimulated transmurally by the method described, contractions are produced mainly by excitation of postganglionic adrenergic nerves.
METABOLIC STUDIES WITH DI(AZIRIDIN‐I‐YL) SULPHOXIDE (DIETHYLENEIMINOSULPHOXIDE)
Authors: CRAIG A. W. , JACKSON H. , JAMES R. M. V.
Published: July 2012

The work described was undertaken after the observation that the diuresis induced by several derivatives of ethyleneimine could be correlated with their content of ethyleneimine. The preparation of 35S‐labelled di(aziridin‐1‐yl) sulphoxide (diethyl‐eneiminosulphoxide) is described together with its metabolism in rat, mouse, rabbit and dog. The drug was completely metabolized in all species and, with the exception of the dog, most of the activity was excreted in the urine within 3 days. The main radioactive metabolite in all species was sulphate. In vitro studies demonstrated that the compound was slowly broken down to sulphite and free ethyleneimine; this hydrolysis was greatly accelerated in the presence of phosphate.
ANTIBACTERIAL ACTIVITY OF SOME DERIVATIVES OF 7‐AMINOCEPHALOSPORANIC ACID AGAINST STAPHYLOCOCCUS AUREUS AND SYNERGISM BETWEEN THESE AND OTHER ANTIBIOTICS
Authors: JAGO MARGARET
Published: July 2012

The N‐phenylacetyl derivative of 7‐aminocephalosporanic acid (cephaloram) had roughly the same activity as benzylpenicillin against a number of Gram‐positive organisms and about one‐eighth of the activity of benzylpenicillin against penicillin‐sensitive strains of Staphylococcus aureus. This derivative and the N‐α‐phenoxy‐propionyl derivative of 7‐aminocephalosporanic acid were 4 to 8 and 4 to 16 times as active as methicillin against penicillinase‐ and nonpenicillinase‐producing staphylococcal strains, respectively. Neither the presence of horse serum nor changes in inoculum size appreciably affected the activities of any of the derivatives of 7‐aminocephalosporanic acid which were tested. After forty‐eight subcultures in the presence of antibiotic the increase in minimum inhibitory concentration against the staphylococcus was about four‐times as great for cephaloram as for cephalosporin C. The resistant penicillinase‐producing strains remained stable after six subcultures in antibiotic‐free medium, and all the strains retained coagulase activity. Some degree of cross‐resistance was found between the derivatives of 7‐aminocephalosporanic acid and those of 6‐aminopenicillanic acid. Synergism was observed in vitro between certain derivatives of 7‐aminocephalosporanic acid and 6‐aminopenicillanic acid when they were tested together or with fusidic acid or cephalosporin P1 against a weak penicillinase‐producing strain of Staphylococcus aureus. Cephalosporin C and cephalosporin C (pyridine), each in combination with benzylpenicillin, showed a significant degree of synergism in protection experiments in mice infected with a strong penicillinase‐producing strain of Staphylococcus aureus.
VASOCONSTRICTOR ACTION OF TOLAZOLINE
Authors: BENFEY B. G. , VARMA D. R.
Published: July 2012

In cats treated with reserpine and anaesthetized with pentobarbitone sodium the adrenergic blocking drug, tolazoline, caused a rise of arterial pressure which was inhibited by previous administration of phenoxybenzamine. Tolazoline increased the contractions of the isolated papillary muscles of normal cats but not of cats treated with reserpine. Intra‐arterial injection of tolazoline into dogs treated with reserpine and anaesthetized with pentobarbitone sodium reduced the blood flow in the coeliac artery. It is considered that, following reserpine, tolazoline has a sympathomimetic vasoconstrictor action.
ACTIONS OF PROSTAGLANDINS E1, E2 AND E3 ON THE CENTRAL NERVOUS SYSTEM
Authors: HORTON E. W.
Published: July 2012

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.
CALCIUM IN RELATION TO THE ACTIONS OF OUABAIN AND ADRENALINE ON THE HEART
Authors: WALKER J. M. G. , WEATHERALL M.
Published: July 2012

Isolated pairs of rabbit auricles have been observed in media containing 6, 24 or 75 mm‐potassium, with corresponding reductions in sodium concentration. In 24 mm‐potassium, adrenaline restored beating and excitability, as did calcium chloride, but ouabain had no effect. In 75 mm‐potassium, adrenaline had no effect; calcium chloride caused a contracture; ouabain had no direct effect, but auricles which had been beating in the presence of ouabain contracted promptly on transfer to 75 mm‐potassium. Left auricles, which do not beat spontaneously, were less sensitive to calcium and to ouabain. The results showed a membrane stabilizing action of calcium and an action on muscular contraction, and suggested that cardiac glycosides acted by causing accumulation of calcium at the activator site in the tissue.
THE EFFECTS OF BETHANIDINE ON THE PERIPHERAL CIRCULATION IN MAN
Authors: FEWINGS J. D. , HODGE R. L. , SCROOP G. C. , WHELAN R. F.
Published: July 2012

Bethanidine has been administered intra‐arterially and intravenously into normotensive subjects and its effects on the limb blood vessels, arterial blood pressure, vascular sensitivity to noradrenaline and the degree and time course of sympathetic nerve blockade have been studied. The drug caused an initial constriction of hand and forearm vessels which is attributed to release of catechol amines since it is abolished by the prior administration of phenoxybenzamine. The constriction was followed by a sustained vasodilatation lasting between 5 and 20 hr. Sympathetic blockade of hand vessels commenced immediately on infusion and was complete within 1 hr of administration. Recovery occurred in about 5 hr. Sensitivity to intra‐arterial noradrenaline was increased within 10 to 15 min of infusion and before sympathetic blockade was complete. Intravenous administration caused a slight rise in blood pressure of supine subjects. Baroreceptor reflex responses of heart and of limb vessels elicited by tilting the subject feet downwards were abolished by bethanidine and postural hypotension occurred. Bethanidine is a potent sympathetic blocking agent in man with properties intermediate between those of bretylium and guanethidine.
A PRELIMINARY INVESTIGATION OF THE PHARMACOLOGY OF THE HUMAN ISOLATED TAENIA COLI PREPARATION
Authors: BUCKNELL ANNE , WHITNEY B.
Published: July 2012

The effects of drugs on smooth muscle strips of human taenia coli, obtained from operation specimens, were studiedin 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 α‐ and β‐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.
CENTRAL CARDIOVASCULAR ACTIONS OF γ‐AMINOBUTYRIC ACID
Authors: BHARGAVA K. P. , BHATTACHARYA S. S. , SRIMAL R. C.
Published: July 2012

The vasomotor and cardiac effects of γ‐aminobutyric acid (GABA) administered by different routes were studied in cats and dogs. The cat was resistant to the action of GABA administered intravenously or into a vertebral artery. Intrathecal injection of GABA into the cat depressed the vasomotor reponse to spinal compression. In dogs, intravenous, intrathecal or intraventricular injection, or topical application of GABA to the floor of 4th ventricle consistently produced hypotension and depressed the reflex and direct excitability of the vasomotor neurones, located at the supraspinal and spinal levels. Bradycardia observed after intravenous and intraventricular injections of GABA into dogs was abolished by stellate ganglionectomy but not by vagotomy. It has been attributed to depression of the central sympathetic neurones.
SYMPATHOLYTIC DRUGS AND HYPERLIPAEMIA INDUCED IN RATS BY INTRAPERITONEAL INJECTIONS OF SURFACE‐ACTIVE AGENT
Authors: BRUS R. , CHRUŚCIEL M. , CHRUŚCIEL T. L. , PLECH A.
Published: July 2012

Hyperlipaemia and hypercholesterolaemia were induced in white rats by intraperitoneal injections of tyloxapol. Various sympatholytics and adrenolytics, including blocking agents of β‐receptors, were given simultaneously with tyloxapol. Bretylium tosylate prevented the increase in the serum levels of esterified fatty acids and cholesterol caused by tyloxapol. Phentolamine decreased the enhancement by tyloxapol of cholesterol and total lipid concentrations in the serum. Guanethidine and phenoxybenzamine reduced the increase in the concentration of esterified fatty acids, whereas dichloroisoprenaline insignificantly increased the tyloxapol‐induced hyperlipaemia. A small dose of pronethalol slightly increased the esterified fatty acid level in tyloxapol‐treated animals; a large dose significantly decreased the serum cholesterol concentration.
INHIBITORS OF HISTAMINE CATABOLISM AND THE ACTION OF GASTRIN IN THE RAT
Authors: AMURE B. O. , GINSBURG M.
Published: July 2012

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.
THE MECHANISM OF THE PRESSOR RESPONSES TO PHYSOSTIGMINE IN THE RAT AND THEIR MODIFICATION BY MEBUTAMATE AND AMYLOBARBITONE
Authors: BELLA D. DELLA , GANDINI A. , PRETI M.
Published: July 2012

Pressor responses to intravenous injections both of physostigmine and of pilocarpine were smaller in rats anaesthetized with either mebutamate or amylobarbitone than in rats anaesthetized with urethane. The response to electrical stimulation of the hypogastric nerve in the isolated hypogastric nerve‐vas deferens preparation was diminished by mebutamate and by amylobarbitone, but not by urethane. Similar results were obtained with the cat isolated splenic nerve‐spleen preparation. In the rat anaesthetized with urethane, pressor responses to physostigmine were only partially antagonized by hexamethonium but were completely abolished during “depolarizing” ganglionic block by nicotine or tetramethylammonium. It is suggested that, in addition to the central mechanism, there is a peripheral component in the pressor action of physostigmine and in the antihypertensive actions of mebutamate and amylobarbitone.
THE EFFECT OF SODIUM INTAKE ON THE URINARY HISTAMINE IN ADRENALECTOMIZED RATS
Authors: BJURÖ T. , WESTLING H.
Published: July 2012

The daily excretion (μg/day) of free histamine has been measured in bilaterally adrenalectomized or sham‐operated female rats. In rats developing adrenal insufficiency when kept on a “sodium free” diet, the output of free histamine in the urine fell progressively. The volume of urine was unchanged. In rats with adrenal insufficiency the oral administration of 0.9% saline caused an immediate rise in the urinary excretion of histamine. The rise was sustained for several days. Adrenalectomized rats consuming 43 mg/day of sodium chloride or less developed adrenal insufficiency and the daily output of urinary histamine fell progressively. A sodium chloride intake of 90 mg/day prevented this fall. Adrenalectomized rats kept on 0.9% saline showed no significant changes during the first 7 days after adrenalectomy. From the 8th day onwards the daily output of histamine in the urine rose progressively. After sham operation the daily output of histamine in the urine was not affected by the intake of sodium chloride. Adrenalectomized rats eat less food; a similar restriction of food intake in sham‐operated rats decreased the urinary excretion of histamine. The decrease was, however, not as pronounced as in adrenalectomized rats developing adrenal insufficiency. Other sodium salts, but not glucose, had the same effect as 0.9% saline on the urinary excretion of histamine in adrenalectomized rats.
THE EFFECTS OF SYNTHETIC ELEDOISIN ON THE SYSTEMIC AND CORONARY HAEMODYNAMICS AND METABOLISM OF THE INTACT DOG
Authors: MAXWELL G. M.
Published: July 2012

Cardiac output and coronary blood flow were measured before and after intravenous injection of eledoisin into anaesthetized dogs. The following changes, statistically significant at the 5% level, were found: increase of heart rate, and decreases in systemic and pulmonary arterial blood pressure, cardiac output, stroke volume, and in right and left ventricular work. Coronary flow decreased, cardiac oxygen extraction increased, and cardiac efficiency decreased. Many of these effects are similar to those caused by bacterial endotoxin.
THE EFFECT OF FASTING ON THE HYPERGLYCAEMIC RESPONSES TO CATECHOL AMINES IN RATS
Authors: FLEMING W. W. , KENNY A. D.
Published: July 2012

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 α‐ and β‐receptors and were consistent with the concept that, in the rat, liver glycogenolysis is mediated predominantly by α‐receptors and muscle glycogenolysis mainly by β‐receptors. In general the hyperglycaemic response in the fed rat is mediated predominantly by α‐receptors and in the fasted rat the response is mainly due to the activation of β‐receptors. A drug possessing both α‐ and β‐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.
Effects of metabolic inhibitors on contraction of rabbit detrusor muscle
Authors: PATON D. M.
Published: July 2012

. The contractile responses of rabbit detrusor muscle strips to acetylcholine are reversibly depressed but not abolished by 2,4‐dinitrophenol (0.1–1.0 mm) provided that d‐glucose or d‐mannose is present. l‐glucose, d‐2‐deoxyglucose, d‐galactose, d‐fructose, d‐xylose, maltose, lactose and sucrose are ineffective in this respect.

. The contractile responses are greatly reduced by iodoacetic acid (0.1–1.0 mm) in 30–60 min and eventually abolished. The depressant effect of iodoacetic acid (0.25 mm) can be partially reversed or retarded by pyruvate (20 mm).

. It is concluded that the energy for contraction of the detrusor muscle can be supplied by glycolysis alone. Because both d‐glucose and pyruvate can be utilized, it is assumed that the glycolytic route and Krebs cycle are available in the detrusor muscle cells.
Pharmacological modifications of sympathetic responses elicited by hypothalamic stimulation in the rat
Authors: MORPURGO CLARA
Published: July 2012

. The rise in blood pressure and the eyelid contractions elicited by electrical stimulation of the posterior hypothalamus in anaesthetized rats were studied for the assessment of drug effects on the sympathetic system. They were compared with the noradrenaline pressor effect and eyelid responses to cervical sympathetic nerve stimulation.

. Phentolamine caused a similar reduction of the pressor responses induced by hypothalamic stimulation and by noradrenaline. It also reduced the eyelid contractions elicited by central and by peripheral electrical stimulation.

. Guanethidine caused an immediate inhibition of the pressor response to hypothalamic stimulation, while it potentiated noradrenaline effects. Eyelid contractions elicited both by central and by peripheral electrical stimulation were inhibited.

. Chlorpromazine inhibited the pressor responses both to hypothalamic stimulation and to noradrenaline, but it caused a much greater reduction in the centrally evoked eyelid responses than in those due to peripheral stimulation.

. Diazepam caused a reduction of sympathetic responses to central stimulation but not to peripherally elicited responses.

. In unanaesthetized rats the rise in blood pressure induced by hypothalamic stimulation was accompanied by increased locomotor activity culminating in a flight reaction. In contrast to the pressor effect, which was reduced by all four of the above‐mentioned drugs, the flight reaction was not affected by phentolamine and guanethidine and only delayed by chlorpromazine and diazepam at dose levels which impaired the spontaneous locomotor activity.
Some studies on peripheral actions of mephenesin, methocarbamol and diazepam
Authors: CRANKSHAW D. P. , RAPER C.
Published: July 2012

. Mephenesin, methocarbamol and diazepam abolished polysynaptic reflex contractions of the cat tibialis anterior muscle elicited by stimulation of the homolateral femoral nerve.

. Mephenesin and methocarbamol caused a prolongation of the mean refractory period of directly or indirectly stimulated skeletal muscle. These effects were due to a direct action on the muscle fibres. There was no effect on responses to single stimuli.

. The increase in refractory period produced by mephenesin was greater in indirectly than in directly stimulated rat diaphragms. Experiments using the isolated phrenic nerve suggest that this difference is due to the local anaesthetic action of mephenesin.

. In the indirectly stimulated cat tibialis anterior muscle high frequency stimulation resulted in a non‐maintained tetanus in the presence of mephenesin and methocarbamol.

. Diazepam was without peripheral effects on the responses of skeletal muscle.

. The results with mephenesin and methocarbamol are discussed in relation to their mode of action in reducing muscle spasm.
The action of antidiuretic hormone on cell membranes. Voltage transient studies
Authors: CUTHBERT A. W. , PAINTER ELISABETH
Published: July 2012

The instantaneous impedance method has been used to study the effects of antidiuretic hormone (ADH) on frog skin.

The resting skin may be represented by a parallel RC network with a single time constant.

Antidiuretic hormone causes an increase in conductance and capacitance and in some cases the appearance of a polarization angle.

The structures in the skin responsible for the transients are located in the outermost membranes.

The effects of ADH have been interpreted in terms of the formation of water‐filled sodium‐permselective pores in the outer facing membranes which occupy, at most, 0.3% of the skin surface. These pores constitute a parallel, and hence additive, capacitance with that of the normally ion impermeable parts of the cell surface, and in addition are responsible for the increase in conductance. The polarization angle is due to the polydisperse nature of the skin after hormone treatment.
Salbutamol: a new, selective β‐adrenoceptive receptor stimulant
Authors: CULLUM VALERIE A. , FARMER J. B. , JACK D. , LEVY G. P.
Published: July 2012

Salbutamol is a β‐adrenoceptive receptor stimulant. Its pharmacological actions are reduced or abolished by β‐receptor antagonists.

In anaesthetized animals, salbutamol, given intravenously, was slightly less active than isoprenaline in preventing spasm of bronchial smooth muscle but was considerably less active as a cardiac stimulant and vasodepressor substance. Its duration of action was about 2 to 3 times that of isoprenaline.

Salbutamol given by mouth or aerosol to conscious guinea‐pigs, greatly diminished bronchospasm caused by inhalation of acetylcholine. By mouth, salbutamol was more active and had a longer duration than isoprenaline or orciprenaline without affecting heart rate. By aerosol, salbutamol was approximately 10 times as active as isoprenaline and 100 times as active as orciprenaline. Its duration of action was much longer than that of isoprenaline or orciprenaline. Only isoprenaline produced an increase in heart rate by the aerosol route.

On isolated guinea‐pig trachea salbutamol had about 1/10 the activity of isoprenaline, on isolated atria about 1/2000.
The effect of catecholamines and sympathetic stimulation on the release of acetylcholine from the guinea‐pig colon
Authors: BEANI L. , BIANCHI CLEMENTINA , CREMA A.
Published: July 2012

In isolated guinea‐pig terminal colon, the effect of sympathetic stimulation on contraction and acetylcholine release elicited by pelvic and transmural stimulation was investigated.

Sympathetic stimulation reduced the nerve‐mediated contractile responses more than those produced by added acetylcholine.

Sympathetic stimulation also reduced the acetylcholine released during pelvic and transmural stimulation at low frequency. The inhibitory effect on acetylcholine released from resting colons is concealed by the simultaneous release of acetylcholine in considerable amounts from stimulated periarterial nerves which probably contain parasympathetic fibres.

The inhibitory effect of endogenous and exogenous catecholamines prevails when cholinergic neurones fire at low rates. It was confirmed that adrenaline is more active than noradrenaline.

The release of acetylcholine from unstimulated colons was for the most part maintained by nerve‐conducted activity, because tetrodotoxin was able to reduce it to about one‐tenth.

It is suggested that the sympathetic control of gastrointestinal tone and motility is exerted through two different routes: inhibition of intramural cholinergic plexuses and direct relaxation of smooth muscle cells.

The possible site and mechanism of action of catecholamines on intramural cholinergic structures is briefly discussed.
Effect of a new series of bicyclic compounds with potential thymoleptic properties on the reserpine‐resistant uptake mechanism of central and peripheral monoamine neuronesin vivoandin vitro
Authors: CARLSSON A. , FUXE K. , HAMBERGER B. , MALMFORS T.
Published: July 2012

Bicyclic compounds with potential thymoleptic properties (Lu‐compounds) have recently become available, and their effects on the membrane pumps of the central and peripheral monoamine neurones have now been tested and compared with those of the tricyclic antidepressant drugs.

Biochemical and histochemicalin vivostudies have been performed. The possible blocking action of Lu‐compounds on the noradrenaline (NA) and 5‐hydroxytryptamine (5‐HT) displacement caused by 4,α‐dimethyl‐meta‐tyramine (H 77/77) and 4‐methyl‐α‐ethyl‐meta‐tyramine (H 75/12), respectively, has been studied, and a positive result has been taken as evidence for membrane pump blocking activity. No certain effects were obtained on the 5‐HT displacement induced by H 75/12, whereas a partial blockade of the NA displacement by H 77/77 in central NA neurones was obtained after most of the Lu‐compounds (Lu‐3–010, 3–049, 3–092, 4–012) and especially after the thiophthalane derivative Lu 5–003. The ED50 of the latter drug was around 8 mg/kg, that is, somewhere between protriptyline (ED50 4 mg/kg) and desipramine (ED50 15 mg/kg) in potency.

Histochemicalin vivostudies on the rat iris revealed that Lu 5–003 and especially the corresponding phthalane derivative Lu 3–010 were potent in blocking the uptake of α‐methyl‐NA in the adrenergic nerve terminals of the iris. The other Lu‐compounds were less active. The releasing effects of the Lu‐compounds on the extragranular accumulation of α‐methyl‐NA in the adrenergic terminals were weak compared with membrane blocking activity.

In vitrostudies on the central and peripheral catecholamine (CA) neurones have also been performed. In the same way as, for example, protriptyline the Lu‐compounds only blocked accumulation of α‐methyl‐NA in the NA terminals but not in the dopamine (DA) nerve terminals. Lu 5–003 and Lu 3–010 were the most potent of the Lu‐drugs when addedin vitro. The Lu‐drugs were also injectedin vivoafter which the effect on the α‐methyl‐NA accumulation was studiedin vitro.In isotope experiments with labelled α‐methyl‐NA it was found that desipramine, Lu‐3–010, Lu 3–092 and Lu 4–012 were equally potent in blocking uptake in the central nervous system.

In general the results obtained with the various models are in agreement. The high activity of Lu 5–003 on the central NA neurones may be related to its high heptane/H2O distribution coefficient.

It is concluded that the Lu‐compounds have a selective action on the membrane pump mechanism of the central and peripheral NA neurones. In these respects they behave like desipramine and protriptyline.
The effect of tropolone on the formation of 3,4‐dihydroxyphenylacetic acid and 4‐hydroxy‐3‐methoxyphenylacetic acid in the brain of the mouse
Authors: MURPHY G. F. , ROBINSON D. , SHARMAN D. F.
Published: July 2012

The development of a very sensitive and specific fluorimetric assay for 3,4‐dihydroxyphenylacetic acid has made it possible to measure how inhibitors of the enzyme catechol‐O‐methyl transferase affect the relative concentrations of this acid and its O‐methylated derivative 4‐hydroxy‐3‐methoxyphenylacetic acid (homovanillic acid) in the brains of mice treated with l‐3,4‐dihydroxy‐phenylalanine or probenecid.

It was found that tropolone and tropolone‐4‐acetamide reduce the concentration of homovanillic acid in the brains of the treated mice to an extent dependent on the dose.

The concentration of 3,4‐dihydroxyphenylacetic acid in the brain was increased by the administration of tropolone or tropolone‐4‐acetamide but the dose and response were not simply related to one another.

The results suggest that, in vivo, the formation of 3,4‐dihydroxyphenylacetic acid is not always a simple alternative to the formation of homovanillic acid when the enzyme catechol‐O‐methyl transferase is inhibited.
The influence of drugs on the uptake of acetylcholine by slices of rat cerebral cortex
Authors: POLAK R. L.
Published: July 2012

The acetylcholine content of cortical slices from rat brain, was determined after incubation for 30 min in a medium containing acetylcholine (4 μg/ml.). The cholinesterase activity of the slices had been inhibited by pretreatment with 3,3‐dimethyl‐n‐butyl 2‐methylphosphonofluoridate (soman).

Acetylcholine accumulated in the tissue slices, up to a concentration of about six times that in the medium.

The uptake of acetylcholine was partly inhibited by potassium in high concentrations.

Hemicholinium‐3, O‐ethyl S‐diethylaminoethyl ethylphosphonothiolate, physostigmine, atropine and choline, in that order of potency, inhibited the accumulation of acetylcholine in the cortical slices, but soman and ethyl N,N‐dimethyl phosphonoamidocyanate (tabun) had no effect on the uptake of acetylcholine.

Substances interfering with energy metabolism, such as 2,4‐dinitrophenol, oligomycin, sodium azide, amylobarbitone sodium and p‐chloromercuribenzoate inhibited the uptake of acetylcholine. Ouabain had little inhibitory effect.

In anaerobic conditions the accumulation of acetylcholine in the tissue slices was nearly blocked.

The uptake of acetylcholine in the tissue slices was dependent on temperature. The Q10 was about 2.

Autoradiography of sections from slices in which 3H‐acetylcholine had accumulated showed a diffuse distribution of radioactivity in the cytoplasm of all cells. There was no visible preference for certain cells or cell structures.
Regulation of metaraminol efflux from rat heart and salivary gland
Authors: COSTA E. , NEFF N. H. , NGAI S. H.
Published: July 2012

The turnover rate of noradrenaline (NA) in heart and submaxillary salivary gland was studied in rats exposed to 4° C or maintained at room temperature (22° C). Cold exposure increased the turnover of the NA store in heart but not in salivary gland.

In another series of experiments the decline of metaraminol (M) from heart and submaxillary salivary gland was studied in rats exposed to 4° C or maintained at room temperature. Cold exposure accelerated the efflux of M from heart, but not from salivary gland. It is concluded that the accelerated decline of M from heart is the consequence of selective activation of the sympathetic nerves that innervate the heart.

The turnover of NA was studied in rat heart after the administration of M (100 μg/kg intravenously) or its precursor α‐methyl‐meta‐tyrosine (200 mg/kg intraperitoneally). Turnover remained essentially normal after these drugs.

The administration of desipramine (DMI, 20 mg/kg intraperitoneally) 1 hr after M (100 μg/kg intravenously) induced a rapid sustained efflux of M from heart and salivary gland. The results of this study suggest that the slow decline of M from heart is the result of the great affinity of the amine retrieval mechanism in sympathetic nerve endings for M. DMI inhibits the retrieval mechanism, thus accelerating the efflux of M.
The characteristics of acetylcholine release mechanisms in the auditory cortex
Authors: HEMSWORTH B. A. , MITCHELL J. F.
Published: July 2012

The characteristics of the acetylcholine (ACh) release mechanism have been studied in the auditory cortex of rabbits on stimulation of the ipsilateral medial geniculate nucleus.

On stimulation of the medial geniculate nucleus the mean release of ACh from the auditory receiving cortex was 6.1 times the spontaneous release; the mean release from other parts of the cortex was 2.2 times the spontaneous release.

The frequency of stimulation most effective in evoking ACh release was found to be 10/sec.

Both the spontaneous and evoked release of ACh were reduced by 40–65% in the absence of calcium from the solution bathing the auditory cortex, and increased by 15–25% when the calcium concentration in the bathing solution was doubled.

The presence of low concentrations of magnesium in the fluid bathing the cortex was essential for the optimal release of ACh, but high magnesium concentrations lowered this release.

The presence of triethylcholine (TEC) in the fluid bathing the auditory cortex reduced both the spontaneous and evoked release of ACh. This reduction was reversed in the presence of choline.

The effects of calcium, magnesium and TEC on the ACh release mechanism in the cerebral cortex and at the neuromuscular junction are compared.
The pharmacology of salivary myoepithelial cells in dogs
Authors: EMMELIN N. , OHLIN P. , THULIN A.
Published: July 2012

. Pressure changes in the submaxillary and parotid ducts of dogs, induced by nerve stimulation or intravenous injection of drugs, were studied.

. Pressure rises could be elicited by parasympathetic stimulation and by acetylcholine and methacholine, even when no secretion was evoked. These effects were abolished by atropine.

. Similarly, sympathetic stimulation, adrenaline, noradrenaline and phenylephrine raised the pressure in both glands, also in the absence of secretion. Dihydroergotamine abolished these effects. Isoprenaline increased the pressure in the submaxillary duct, but only when it caused secretion. This effect was abolished by propranolol. In the parotid gland isoprenaline caused neither secretion nor pressure rise. It is concluded that the myoepithelial cells of the two glands are supplied with α‐adrenoceptors.

. Doses of histamine, bradykinin, kallidin and physalaemin which caused no salivary secretion raised the duct pressure even when dihydroergotamine, propranolol and atropine had been given.

. Angiotensin and 5‐hydroxytryptamine increased the pressure only in some experiments. Oxytocin caused very little or no pressure rise. Vasopressin had no effect of its own but reduced the pressure raising effects of nerve stimulation or drugs.
Prostaglandins A1, A2 and 19‐hydroxy A1; their actions on smooth muscle and their inactivation on passage through the pulmonary and hepatic portal vascular beds
Authors: HORTON E. W. , JONES R. L. , HOPKIN JUDY M. , HORTON E. W.
Published: July 2012

. Prostaglandins A1, A2 and 19‐hydroxy A1 have qualitatively similar actions to prostaglandin E1 on smooth muscle.

. The prostaglandins A have little activity on gastrointestinal, respiratory and reproductive smooth muscle but are potent depressors of the systemic arterial blood pressure of the dog, cat and rabbit.

. Our experiments support the view that the depressor action of the prostaglandins E and A is due to a direct dilator action on many peripheral vascular beds and not due to changes in nervous tone to these beds.

. A single passage through the pulmonary circulation of the cat or dog causes substantial loss of the vasodilator activity of prostaglandin E1 but little if any loss of the vasodilator activity of the prostaglandins A.

. A single passage through the hepatic portal circulation of the cat causes substantial loss of the vasodilator activity of prostaglandins E1, A1 and A2.

. The cat blood pressure and rat fundal strip would be a suitable combination for the parallel biological assay of the prostaglandins A1 and A2.
ACTH and decubitus ulceration: an experimental study
Authors: BARTON A. A. , BARTON MARY
Published: July 2012

. Ulcers due to neurectomy with excision of the sciatic nerve are more severe than those due to tenotomy and can be inhibited by a single dose of ACTH.

. Timing and mode of administration of ACTH to prevent decubitus ulceration is critical and depends on its ability to prevent the separation of endothelial cells.
Role of catecholamines in centrogenic cardiac arrhythmia induced by aconitine
Authors: BHARGAVA K. P. , KOHLI R. P. , SINHA J. N. , TAYAL G.
Published: July 2012

. Injection of 20 μg of aconitine into the lateral ventricle of dogs anaesthetized with pentobarbitone regularly induced cardiac irregularities and hypertension. The cardiovascular changes appeared within 5 min and lasted for about 90 min. Tachyphylaxis to the aconitine‐induced cardiovascular effects was observed.

. The aconitine‐induced arrhythmia and hypertension were centrogenic, for they were abolished or prevented by spinal transection (C2) or ganglionic blockade.

. Bilateral vagotomy as well as bilateral stellate ganglionectomy merely raised the threshold for arrhythmia without affecting the blood pressure response. The neural supply to the heart, therefore, does not seem to be the major pathway concerned in the genesis of the centrogenic cardiovascular effects of aconitine.

. The centrally evoked release of endogenous catecholamines from the adrenal glands was responsible for the aconitine‐induced arrhythmia, since the arrhythmia could be blocked or prevented by prior reserpinization, bilateral adrenalectomy or thoracic splanchnic nerve section.

. α‐ and β‐adrenoceptive receptor blocking agents prevented or abolished the aconitine‐induced arrhythmia in a manner similar to the catecholamine‐induced arrhythmia.
Microelectrode studies in the frog isolated spinal cord during depression by general anaesthetic agents
Authors: RICHENS A.
Published: July 2012

. Extracellular and intracellular potentials have been recorded from the isolated spinal cord of the frog during depression of synaptic transmission by volatile and barbiturate general anaesthetic agents.

. Volatile agents did not impair conduction in presynaptic terminals in concentrations which completely blocked synaptic transmission.

. Methohexitone consistently impaired conduction in presynaptic terminals long before transmission through polysynaptic pathways was blocked.

. Volatile agents depressed the excitability of the motoneurone membrane, as evidenced by impaired antidromic invasion, reduced excitability to direct stimulation, depression of the synaptic potential and elevation of firing threshold. It is concluded that these actions are responsible for the depressant effect of volatile agents on spinal reflexes.

. Methohexitone produced an increase in the excitability of the motoneurone membrane, as evidenced by enhanced antidromic invasion, increased excitability to direct stimulation and potentiation of short latency responses. Despite this excitatory action, the polysynaptic pathways through the cord were depressed by an action of the drug on conduction in presynaptic terminals.

. It is suggested that the sensitivity of the motoneurone membrane to volatile agents may contribute to the good muscle relaxant properties of these drugs in clinical use.
Studies on the action of acetylcholine on the sino‐auricular node of the dog
Authors: DUTTA S. N. , SANYAL R. K. , TRIPATHI O. N.
Published: July 2012

. The response of the sino‐auricular node to direct injection of acetylcholine in the artery supplying the node has been studied in the dog.

. Acetylcholine in graded doses (2, 5, 10 μg) caused acceleration of the sinus rhythm.

. The time course of the positive chronotropic action of acetylcholine resembled that produced by adrenaline or noradrenaline.

. The positive chronotropic action produced by acetylcholine was blocked by dichloro‐isopropylnoradrenaline and pronethalol and potentiated by cocaine.

. In reserpinized dogs, acetylcholine in similar doses produced sinus bradycardia. The positive chronotropic response could be temporarily restored by infusion of adrenaline or noradrenaline.

. Atropine blocked both the positive and negative chronotropic actions of acetylcholine.
Effect of reserpine on the subcellular distribution of 3H‐α‐methylnoradrenaline in the mouse heart
Authors: LUNDBORG P.
Published: July 2012

. Mice were injected with reserpine (0.5 mg/kg or 2.5 mg/kg) at various intervals after an intravenous injection of 3H‐α‐methylnoradrenaline (3H‐α‐MeNa), 20 μg or 100 μg/kg. The effect of reserpine on the content of labelled amine in the subcellular fractions of the heart was studied.

. In most experiments reserpine caused a pronounced decrease in the 3H‐α‐MeNA content of the particulate fraction (P). The decrease was most pronounced when the higher dose of reserpine and lower dose of α‐MeNA were used. In most experiments, the 3H‐α‐MeNA content of the supernatant fractions was unchanged and, therefore, the P/(P + S) ratio was decreased.

. It is concluded that the effect of reserpine is a releasing effect on the particulate (granular) fraction, probably by blocking the re‐uptake of the amine leaked from the granules. No support was found for the hypothesis that reserpine acts by inhibition of release of amines from the nerve granules.
The uptake of cardiac glycosides by intestinal smooth muscle of the guinea‐pig in relation to digitalis receptors
Authors: GODFRAIND T. , LESNE M.
Published: July 2012

. The accumulation and release of 3H‐digitoxin, 3H‐digoxin and 3H‐ouabain by isolated guinea‐pig intestinal smooth muscle has been studied and compared with a pharmacological action due to inhibition of the sodium pump.

. The uptake of labelled cardiac glycosides can be described by means of an exponential function. The t of uptake was similar for the three compounds and did not depend on the concentration.

. Analysis of the curve relating the uptake of cardiac glycosides at equilibrium to the bath concentration enabled a non‐saturable and a saturable binding site to be distinguished.

. In contrast to the uptake observations, the onset of the pharmacological effect was dependent on the concentration, and furthermore the t½; for this effect was shorter.

. The release of cardiac glycosides proceeded more slowly than the uptake.

. The uptake of a labelled glycoside was reduced in the presence of another glycoside. The amount of displaceable glycoside was nearly equivalent to the capacity of the saturable binding site.

. The significance of these results is discussed.
Pharmacological significance of biogenic amines in the lungs: 5‐hydroxytryptamine
Authors: SADAVONGVIVAD CHIRAVAT
Published: July 2012

. A technique for the spectrofluorometric analysis of 5‐hydroxytryptamine, histamine, noradrenaline and dopamine in a single lung sample has been developed. The method is a combination of the extraction procedure of Shore & Olin (1958), plus the modification introduced by Hogans (1967) for the analysis of three of the four amines. The fourth amine, histamine, was analysed by the method of Shore, Burkhalter & Cohn (1959), which was combined with the analysis of the other three amines. The combined procedure consisted principally of disintegrating the lung tissue in butanol and subsequent separation of amines for measurement of fluorescence, either directly, as for 5‐hydroxytryptamine, or after formation of fluorophores, as for histamine, noradrenaline and dopamine. It has been possible to analyse all four amines from a sample of the lung in which the bronchopulmonary responses have been investigated.

. The concentration of 5‐hydroxytryptamine in the lung of seven species ranges from about 0·5 μg/g in the guinea‐pig, dog and man to about 7 μg/g in the rabbit. The pulmonary resistance is increased after an injection of 5‐hydroxytryptamine in the rat and guinea‐pig.

. The guinea‐pig is more sensitive to 5‐hydroxytryptamine than the rat. In both animal species, the content of 5‐hydroxytryptamine in the lung is elevated by administration of either 5‐hydroxytryptamine or 5‐hydroxytryptophan. In the rat, the administration of p‐chlorophenylalanine reduces the content of 5‐hydroxytryptamine in the brain but not in the lung.

. It is suggested that the 5‐hydroxytryptamine contained in the lung tissue is stored mainly in the platelets and in the mast cells.