bluuebunny/crossref_metadata_2025 huggingface dataset:
The actions of dehydroemetine on isolated guinea‐pig atria. Influence of ouabain and calcium
Authors: SALAKO L. A.
Published: July 2012

. The mechanism of the inhibitory effect of dehydroemetine on the heart was investigated using (a) the spontaneously contracting isolated guinea‐pig atrial preparation and (b), the electrically driven left atrial preparation.

. Dehydroemetine decreased the rate and amplitude of contraction of spontaneously contracting atria.

. Increasing the calcium concentration of the bath fluid to 28·2 mm abolished the effect of dehydroemetine on amplitude of contraction while the effect on rate persisted.

. Pretreatment with dehydroemetine increased the capacity of ouabain to induce arrhythmias in spontaneously contracting atria. Similarly pretreatment with ouabain augmented the inhibitory effect of dehydroemetine on spontaneous atrial activity.

. In the electrically driven left atrial preparation, dehydroemetine caused a decrease in contractile strength which was opposed by ouabain and by increased calcium concentration of the bath fluid.

. The effect of dehydroemetine on spontaneously contracting and on electrically driven atria was mimicked by adding excess potassium to the bath fluid.

. It was concluded that the effects of dehydroemetine on rate and contractility are, to a large extent, independent of one another. The effect on spontaneous rate is consistent with alteration of the potassium permeability of the myocardial cell membrane while the effect on contractility appears to be due to a decrease in the uptake of calcium from the medium by the myocardial cell.
Respiratory responses to chemical pulses in the cerebrospinal fluid of cats
Authors: BORISON H. L. , HARANATH P. S. R. K. , McCARTHY L. E.
Published: July 2012

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.

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.

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 nonspecifically 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.

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.

It is concluded that the brain surfaces are insensitive to the substances tested and that the observed effects resulted from movement of the agents into the brain parenchyma.
Comparative study of six β‐adrenoceptive antagonists on airway resistance and heart rate in the guinea‐pig
Authors: ADVENIER C. , BOISSIER J. R. , GIUDICELLI J. F.
Published: July 2012

The effects of six β‐adrenoceptive antagonists [(±)‐propranolol, (+)‐propranolol, (±)‐sotalol, (±)‐practolol, (±)‐pindolol and (±)‐procinolol] were studied on airway resistance and heart rate in guinea‐pigs and dose‐response curves constructed.

All β‐adrenoceptive antagonists decreased heart rate and increased airway resistance. A significant correlation was found between the increase in airway resistance and the degree of bradycardia induced by all drugs except practolol. The orders of activity of the six drugs in inducing significant variations of the two parameters were respectively, for airway resistance: (±)‐procinolol>(±)‐pindolol>(±)‐propranolol>(±)‐sotalol>(±)‐propranolol>(±)‐practolol, and for heart rate: (±)‐pindolol>(±)‐procinolol>(±)‐propranolol>(±)‐sotalol>(±)‐propranolol>(±)‐practolol.

(±)‐Sotalol, (±)‐pindolol and (±)‐procinolol‐induced changes in airway resistance and heart rate reached plateau values, which were not modified by increasing the dose. Since sotalol and procinolol have only very weak partial agonist and cardiac depressant properties, it appears that these changes can mainly be accounted for by the suppression of sympathetic tone. It is probable that this is also the case with pindolol.

On the other hand, (±)‐propranolol and (±)‐propranolol induced dose‐related changes in airway resistance and heart rate. Thus, a direct and nonspecific effect of both drugs on the bronchial muscle, similar to that observed on the heart appears to be implicated, together with sympathetic tone suppression in these variations.

(±)‐Practolol‐induced effects on airway resistance and heart rate were different from those observed with the five other β‐adrenoceptive antagonists.
Action of some bisquaternary derivatives of phthalic acids and related substances on neuromuscular transmission
Authors: DANILOV A. F. , KVITKO I. J. , LAVRENTIEVA V. V. , MICHELSON M. J. , PORAI‐KOSHITS B. A. , ROZHKOVA E. K. , SHELKOVNIKOV S. A.
Published: July 2012

All the bisquaternary derivatives of terephthalic acid with three methyl groups on each nitrogen atom (PK‐107, PK‐95, PK‐97 and PK‐126) were depolarizing neuromuscular blocking agents. The most active was the compound PK‐97, in which the two quaternary groups are separated by sixteen atoms and are about 20 Å (2 nm) apart. Activity was reduced many fold either by decreasing the separation to twelve atoms or by increasing it to eighteen atoms. It was also reduced several hundred fold when one trimethylammonium group in PK‐97 was replaced by a hydrogen atom (as in PK‐119).

The presence and position of the ester groups in these compounds is important; depolarizing activity is in most cases greatest when the ester groups are the same distance from the quaternary nitrogen atoms as in acetylcholine, that is, in carbolonium, sebacoyldicholine and PK‐154. The monoquaternary analogues of carbolonium and sebacoyldicholine are appreciably active, having between about one‐tenth to one‐fifth of the activity of their bisquaternary analogues.

The relationships between the structure and activity of these compounds are discussed, particular consideration being given to the structure of the chain separating the quaternary groups and the arrangement of acetylcholine receptors on cells and of esterbinding groups within these receptors.
Renal excretion of metolazone, a new diuretic
Authors: BELAIR E. J. , COHEN A. I. , YELNOSKY J.
Published: July 2012

Metolazone, a new diuretic, was found to be excreted by glomerular filtration and renal tubular secretion.

The secretory mechanism was antagonized by probenecid but this did not affect the diuretic action of metolazone.
Effects of McN‐A‐343 and DMPP on the uptake and release of 3H‐noradrenaline by guinea‐pig atria
Authors: ALLEN G. S. , RAND M. J. , STORY D. F.
Published: July 2012

McN‐A‐343 4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammoniuin chloride and DMPP (N,N‐dimethyl‐N'‐phenylpiperazinium iodide) inhibit the uptake of (±)‐3H‐noradrenaline by guinea‐pig atria, being approximately as potent as cocaine in this respect.

The inhibition of uptake produced by McN‐A‐343 or DMPP was not affected by atropine or hexamethonium in concentrations which antagonized actions on muscarinic and nicotinic receptors respectively.

McN‐A‐343 in the presence of atropine had a positive inotropic action on atria, but this was not accompanied by efflux of radioactivity from atria previously incubated with (—)‐3H‐noradrenaline.

In the presence of McN‐A‐343, responses of atria to noradrenaline were increased and those to tyramine were decreased.

DMPP had positive inotropic and chronotropic actions on atria, and these effects were accompanied by an increase in efflux of radioactivity from atria previously incubated with (—)‐3H‐noradrenaline.
A quantitative study of the anticholinergic action of several tricyclic antidepressants on the rat isolated fundal strip
Authors: ATKINSON J. , LADINSKY H.
Published: July 2012

Investigations were carried out on the antagonism of the action of carbamylcholine chloride on the isolated fundus of the rat stomach by several tricyclic antidepressants.

The anticholinergic potency of the compounds was in the order: GP 45437>amitriptyline>protriptyline>desmethylimipramine>opipramol. All of the antagonists were less effective than atropine.

Statistical analysis was carried out to determine whether the theory of competitive antagonism would fit the data obtained.
The effects of cigarette smoking on the response to stress in a driving simulator
Authors: ASHTON HEATHER , SAVAGE R. D. , TELFORD ROSEMARY , THOMPSON J. W. , WATSON D. W.
Published: July 2012

Some behavioural and physiological responses of cigarette smokers and non‐smokers exposed to varying degrees of stress in a driving simulator were compared.

When the smokers were smoking a cigarette, some of their reaction times to light signals differed significantly from those of non‐smokers, some being longer and some shorter. These differences disappeared when the smokers were not smoking.

Of the physiological measurements, only heart rate differed significantly between smokers and non‐smokers, being higher at all levels of stress in the smokers. There were no significant differences in blood pressure, calf blood flow and respiration rate between smokers and non‐smokers.

The results of the Cattell Sixteen Personality Factor Questionnaire showed that the smokers were significantly more extroverted and self‐reliant than the non‐smokers.

The results are discussed in relation to the pharmacology of cigarette smoking. It is concluded that the differences in reaction times and heart rates between smokers and non‐smokers were a consequence of cigarette smoking.
Actions of the sympathomimetic bronchodilator, rimiterol (R798), on the cardiovascular, respiratory and skeletal muscle systems of the anaesthetized cat
Authors: BOWMAN W. C. , RODGER L W.
Published: July 2012

The actions of rimiterol [erythro(3,4‐dihydroxyphenyl, 2‐piperidyl methanol hydrobromide)], a new sympathomimetic bronchodilator, have been compared with those of salbutamol and laevoisoprenaline on the heart and lungs, and on contractions of the soleus muscle of cats under chloralose anaesthesia.

Rimiterol and salbutamol injected intravenously were about equipotent in all tests, and were about 8 times less potent than laevoisoprenaline both in opposing the bronchoconstrictor action of 5‐hydroxytryptamine, and in decreasing the tension and degree of fusion of incomplete tetanic contractions of the cat soleus muscle. They were about 19 times less potent than laevoisoprenaline in increasing heart rate.

The effect on the soleus muscle is considered to be analogous to the muscle tremor that often occurs in man, and the results therefore suggest that systemic administration of bronchodilator doses of rimiterol, like salbutamol, may produce muscle tremor as an unwanted side‐effect.

When equipotent doses to oppose 5‐hydroxytryptamine‐induced bronchospasm were compared, rimiterol and salbutamol produced less tachycardia than did laevoisoprenaline. In order to match the tachycardia produced by laevoisoprenaline, the doses of rimiterol or salbutamol had to be increased about two and a half times. This safety margin for salbutamol in the cat is considerably less than that reported by others for different species, which suggests that β1‐ and β2‐adrenoceptors may be less clearly differentiated in the cat than they are in other laboratory animals.
The effect of cold storage on the inhibitory action of isoprenaline, phenylephrine and nicotine on the mechanical and membranal activities of guinea‐pig taenia caecum
Authors: FUKUDA HIROYUKI , SHIBATA SHOJI
Published: July 2012

The effects of prolonged cold storage on the mechanical and membranal responses to stimulation of α‐ and β‐adrenoceptors by phenylephrine and isoprenaline, respectively, were studied on the guinea‐pig taenia caecum.

Cold storage invariably caused a decrease in the resting membrane potential, and this effect was enhanced as the duration of treatment was prolonged.

After cold storage (18 days) the tissue potassium ion content (89·7 ± 1·7 mmol/kg wet wt.) was decreased to 30·5 ± 1·9 mmol/kg wet wt. whereas that for sodium (69·2 ± 1·4 mmol/kg wet wt.) increased to 134·0 ± 2·3 mmol/kg wet wt.

In the fresh preparations, phenylephrine (1 and 2 μm) caused a cessation of spontaneous action potentials, accompanied by hyperpolarization of the membrane and relaxation of the muscle. These effects were markedly diminished after 18 days of cold storage. Isoprenaline (1 and 2 μm) also blocked the action potentials and caused a concomitant muscle relaxation, but in most cases the hyperpolarization was not observed. After 14 days of cold storage these mechanical and membranal changes associated with isoprenaline treatment were not demonstrable in most preparations.

Nicotine (5 μm and 50 μm) produced a biphasic effect, cessation of the action potential, hyperpolarization and subsequent relaxation followed by a long lasting depolarization, an accelerated discharge of action potentials and an increase in muscle tension. After a few days of cold storage the hyperpolarization effect disappeared but the intensity of the long‐lasting depolarization as well as the contractile effects were increased. After cold storage for more than 7 days, nicotine did not affect mechanical or electrical activity.

Dibutyryl 3′5′ cyclic AMP (1 μm to 500 μm) failed to affect the mechanical and electrical activities of taenia caecum.

Phenylephrine and isoprenaline had no effect on the high potassium‐depolarized taenia.

These observations suggest that the electro‐mechanical effect of an α‐adrenoceptor stimulant on the guinea‐pig taenia caecum is more resistant to cold treatment than that of a β‐adrenoceptor stimulant. This inhibitory system of stimulation of both α‐ and β‐receptors of guinea‐pig taenia caecum may react by different mechanisms. The results also demonstrate that cold storage itself changes the membrane permeability to ions and the tissue ion content (Na+ and K+) of smooth muscle of guinea‐pig taenia caecum.
Effects of enzyme inhibitors of catecholamine metabolism and of haloperidol on the pancreatic secretion induced by l‐DOPA and by dopamine in dogs
Authors: FURUTA Y. , HASHIMOTO K. , IWATSUKI K. , TAKEUCHI O.
Published: July 2012

Effects of inhibitors of DOPA decarboxylase, dopamine β‐hydroxylase and monoamine oxidase, and haloperidol on the secretion of pancreatic juice induced by l‐DOPA and dopamine were studied in preparations of the isolated blood‐perfused canine pancreas.

The increased secretion induced by the infusion of l‐DOPA (100 μg/min) was completely antagonized by Ro 4–4602 (300 μg), a DOPA decarboxylase inhibitor.

The secretogogue effect of dopamine (1–10 μg) intra‐arterially was not affected by Ro 4–4602, but was enhanced by the infusion of fusaric acid (100 μg/min), a dopamine β‐hydroxylase inhibitor.

The increase in the secretion induced by dopamine (1–10 μg) was enhanced by treatment with nialamide (100 mg/kg), a monoamine oxidase inhibitor, given intravenously.

Haloperidol (1 mg) intra‐arterially attenuated the dopamine‐induced pancreatic secretion.

It is concluded that l‐DOPA is converted to dopamine in the acinar cells which causes an increase in the secretion of pancreatic juice, thus the intracellular level of dopamine may be controlled by enzymatic equilibrium.
The prejunctional actions of some non‐depolarizing blocking drugs
Authors: BLABER L. C.
Published: July 2012

Trains of end‐plate potentials (e.p.p.s) have been recorded from the isolated tenuissimus of the cat. The muscle was paralyzed either by transversely cutting the muscle fibres or by non‐depolarizing blocking drugs.

The following parameters of transmitter synthesis, storage and release have been calculated: the quantal content of the first e.p.p. in the train, the size of the available store, fractional release, quantum size, and the rate of refilling of the available store.

Tubocurarine and benzoquinonium depressed the rate of refilling of the available store causing its depletion at high rates of stimulation. This was offset by an increase in fractional release, which in the case of tubocurarine was sufficient for the quantal content of the first e.p.p. to be unchanged.

Dimethyltubocurarine and pancuronium had a similar effect to tubocurarine on the rate of refilling of the store and depletion of the store at high rates of stimulation but did not increase fractional release. There was, therefore, a decrease in the quantal content of the first e.p.p.

Lignocaine depressed the rate of refilling of the store and depleted the store at high rates of stimulation. Fractional release was also depressed.

It is suggested that the non‐depolarizing drugs have a weak local anaesthetic action retarding the influx of sodium into the nerve terminal which slows the rate of refilling of the store. This effect is due to the quaternary ammonium head. The presence of a phenolic group increases fractional release due either to an increased influx of calcium into the nerve terminal or to a potentiation of the actions of calcium.
Influence of allopurinol on drug metabolism in man
Authors: RAWLINS M. D. , SMITH S. E.
Published: July 2012

Elimination rates of phenylbutazone and warfarin after single oral doses in human volunteers, and steady‐state plasma concentrations of these drugs in patients have been measured before, during and after administration of allopurinol.

Allopurinol, in usual clinical doses, had no significant influence on the elimination rate of either drug in the group of volunteers as a whole although in a few individuals an apparent inhibitory effect was observed.

No significant changes in the steady‐state plasma concentrations of either phenylbutazone or warfarin were observed in patients during the administration of allopurinol.

It is concluded that although allopurinol may have an apparent inhibitory effect on drug elimination in a few individuals, its administration to most patients on anticoagulant therapy is unlikely to alter dose requirements.
Influence of chloride ions on changes in membrane potential during prolonged application of carbachol to frog skeletal muscle
Authors: JENKINSON D. H. , TERRAR D. A.
Published: July 2012

Micro‐electrodes were used to follow changes in the membrane potential at the end‐plate region of single fibres in narrow strips of frog skeletal muscle exposed to carbachol applied in continuously flowing Ringer solution containing tetrodotoxin (200 nm) and neostigmine (3 μm).

The depolarizations elicited by carbachol (5–20 μm) usually developed in two phases, the first of which was generally complete within 30 s whereas several min were required for the second.

Repolarization after carbachol also occurred in two phases, the second of which outlasted the time needed to clear the bath, and varied with the magnitude and duration of the depolarization which carbachol had caused.

These findings could best be explained in terms of the consequences of net entry of chloride ions into the fibre during the depolarization caused by carbachol. This hypothesis is supported by three lines of evidence:

Replacement of the chloride content of the Ringer solution by the less permeant anion isethionate abolished the slow phases of the carbachol response.

Reduction of chloride permeability (by lowering pH) caused rapid repolarization during the recovery period after carbachol.

When the membrane potential was clamped at the resting level throughout the action of carbachol, so avoiding chloride redistribution, the clamping current records did not show the slow phases attributed to chloride movement.

Chloride redistribution contributes to the gradual spread of depolarization during prolonged applications of depolarizing agents to skeletal muscle. It also complicates the interpretation of the dose‐response relationship, and may make it more difficult to assess the extent to which the receptors become desensitized during the action of agonists applied in the bath.
On the pharmacology of the glycine receptors on the cuneo‐thalamic relay cells in the cat
Authors: KELLY J. S. , RENAUD L. P.
Published: July 2012

In cats either decerebrated or anaesthetized with sodium pentobarbitone, strychnine released by iontophoresis from electrodes containing a 5 mm solution in 165 mm of NaCl, abolished the action of glycine and β‐alanine on cuneo‐thalamic relay cells without disturbing their response to equally effective applications of γ‐aminobutyric acid (GABA) and β‐guanidino‐propionic acid.

The loss of glycine sensitivity appeared to increase as long as the strychnine release continued until even the largest currents tolerated by the electrode were unable to eject effective amounts of glycine. Parallel shifts of the glycine log‐current response curves, equivalent to an equipotent dose‐ratio of about 20 only occurred when the duration of the strychnine applications by current in excess of 28 nA was restricted to a few minutes.

Without modifying either the frequency of the spike discharge or the amplitude or shape of the action potential, currents larger than 28 nA occasionally caused a loss of GABA sensitivity.

Strychnine administered either intravenously (0·2 mg/kg) or applied topically to the surface of the cuneate (0·5 mm) blocked the response to glycine without any obvious effect on the response to GABA.

It was concluded that the discovery of a strychnine‐sensitive component of the inhibitory potentials recorded from the cuneate nucleus will reveal the physiological role of the glycine receptors on cuneo‐thalamic relay cells.
Acute systemic anaphylaxis in the horse
Authors: EYRE P. , LEWIS A. J.
Published: July 2012

Histamine in small doses caused systemic depressor responses in horses, whereas greater doses caused biphasic effects. All doses of 5‐hydroxytryptamine (5‐HT) were pressor and all doses of bradykinin depressor. All three active substances raised pulmonary artery pressure and lowered central venous pressure. 5‐HT reduced ventilation volume. Histamine caused brief apnoea followed by hyperpnoea only.

Acute anaphylaxis in the horse was accompanied by a severe systemic arterial depressor response, a pressor response in the pulmonary artery and vena cava, and alternating phases of apnoea and dyspnoea.

During anaphylaxis, profound haemoconcentration, leucopoenia, thrombo‐cytopoenia and hyperkalaemia were in evidence. Early during anaphylactic shock (2 to 4 min) there were profound increases in plasma histamine (five to six‐fold) and plasma kinin activity (four to five‐fold). Plasma 5‐HT concentrations were reduced initially but recovered. Later in anaphylaxis (10 to 20 min) whole blood histamine concentration fell significantly. This coincided with the most profound period of leucopoenia.

No significant differences were observed in histamine concentration in any of five tissues between six ponies subjected to anaphylaxis and six controls. Mast cell numbers were not reduced but mast cells were more metachromatic (pink) and there was spilling of mast cell granules.

Gross pathological changes were noted mainly in the lungs which were extensively oedematous and congested. Inflamed, congested and oedematous areas in the large colon and caecum were seen, and the kidneys, spleen and liver were engorged. Alveolar emphysema, peribroncheolar oedema (containing mononuclear cells and neutrophils) were recorded. Alveoli contained erythrocytes.
The action of bombesin on the kidney of the anaesthetized dog
Authors: ERSPAMER V. , MELCHIORRI P. , SOPRANZI N.
Published: July 2012

In the anaesthetized dog bombesin had a potent antidiuretic effect, and sometimes arrested urine flow completely. Threshold doses, by i.v. infusion, were of the order of 0·5–1 (ng/kg)/minute. Antidiuresis was the result of a reduction in glomerular filtration rate provoked by a fall in intraglomerular hydrostatic pressure. This, in its turn, was due to afferent vasoconstriction.

The spasmogenic effect of bombesin on the smooth muscle of the afferent arterioles was directly demonstrated by the radioactive microspheres technique and indirectly by the 85Kr washout method and by [3H]‐p‐aminohippurate clearance. The vascular compartment most sensitive to bombesin was that of the outer cortical zone, especially in its external half.

Filtration fraction decreased under the influence of bombesin, indicating that the effect of the polypeptide on postglomerular arterioles was, if present, only of minor importance.

At high infusion rates (above 6 (ng/kg)/min), bombesin produced a decrease in [3H]‐p‐aminohippurate extraction. The effect of the polypeptide on fractional distal delivery of sodium varied with the dose: at moderate infusion rates it decreased, at high infusion rates it increased. The total glucose appearing in urine following a glucose load was sharply reduced by bombesin. However, the glomerular filtration rate/maximum tubular glucose transport ratio did not show any appreciable change.

Afferent vasoconstriction produced by bombesin was accompanied by an intense activation of the renin‐angiotensin system, as shown by a conspicuous increase in renin secretion, followed by increases in renin activity and angiotensin II concentration in arterial blood. When bombesin was infused into one renal artery only the infused kidney showed afferent vasoconstriction and increased renin secretion. The time‐course of renin secretion produced by bombesin depended upon the rate of infusion of the polypeptide. At low rates an increased renin secretion was observed throughout the infusion period, at high rates two peaks of renin secretion could be seen, one at the beginning of the infusion, the other soon after the infusion had finished.

The mechanism of action of bombesin is discussed and the interest of the polypeptide as a possible hormonal regulator of the circulation and function of the kidney is pointed out.
A study of compounds which initiate and block nerve impulses in the perfused rabbit liver
Authors: ANDREWS W. H. H. , ORBACH J.
Published: July 2012

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.

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.

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.

Three methods for using the preparation for the assessment of local anaesthetic action are described.

Lobeline, potassium cyanide and 2,4‐dinitrophenol stimulated nerve bundles which were not stimulated by anoxia or hypoxia.
The time courses of the changes in contractile force and in transmembrane potentials induced by cardiac glycosides in guinea‐pig papillary muscle
Authors: LÜLLMANN H. , RAVENS URSULA
Published: July 2012

The effects of ouabain, digoxin, digoxigenin monodigitoxoside, digoxigenin bisdigitoxoside and digitoxigenin bisdigitoxoside on the force of contraction and on the transmembrane action potential were compared in isolated papillary muscles of guinea‐pigs.

All cardiac glycosides studied had a dose‐dependent positive inotropic effect and simultaneously shortened the duration of the action potential at all levels of repolarization from the start of drug action.

In every instance, the reduction of the action potential duration developed more slowly than the increment in contractile force. However, the ratios between the two rates were independent of the concentrations used and seemed to be characteristic for the individual cardiac glycosides.

All cardiac glycosides had a biphasic effect on the time‐to‐peak tension. An initial increase was followed by a dose‐dependent decrease.

The results are discussed with respect to the possible sites of action. Taking into account the different rates as well as the different ratios, it is proposed that more than one site of action is involved in producing the different effects of cardiac glycosides on heart muscle.
Uptake, disposition and metabolism of histamine in isolated heart preparations
Authors: MANNAIONI P. F. , MORONI F.
Published: July 2012

The uptake and metabolism of histamine by the guinea‐pig heart and by the isolated electrically driven guinea‐pig left atria was studied with both labelled and unlabelled histamine.

Histamine uptake took place against a concentration gradient and, at low concentrations, this was blocked by hypoxia plus glucose deprivation or by a toxic dose of ouabain.

The histamine taken up was retained by cardiac tissues and mainly metabolized into methyl‐histamine and other metabolites. The uptake and metabolism of histamine was higher in atria than in ventricles thus reflecting the regional distribution of endogenous histamine and mast cell numbers.

The uptake and metabolism of histamine were greatly reduced in hearts which had been depleted of mast cells, by combining cardiac anaphylaxis and (+)‐tubocurarine (1 mg/ml), but pretreatment of guinea‐pigs with 6‐hydroxydopamine failed to affect uptake of total radioactivity in the isolated left atria.

In the guinea‐pig heart histamine appears to be taken up, stored and metabolized in at least two pools, one of which is linked to the mast cells.
The number of muscarinic receptors in chick amnion muscle
Authors: CUTHBERT A. W. , YOUNG J. M.
Published: July 2012

[3H]‐Propyl benzilylcholine mustard ([3H]‐PrBCM) an irreversible specific antagonist of muscarinic acetylcholine receptors, has been used to label the muscarinic receptors in the aneuronal muscle of isolated 11 day amniotic membranes of chick embryos.

This muscle was found to have about 9 fmol/mg dry weight of receptor material. This is only 1–2% of the amount found in intestinal muscle.

Pharmacological studies with isolated amniotic membranes using PrBCM show that labelling is to functional receptors and that the receptor reserve is small.

The significance of the difference in receptor reserve in innervated and aneuronal plain muscle is discussed.
The β‐adrenoceptor blocking properties of the α‐methyl analogues of propranolol and practolol in the anaesthetized dog
Authors: LEVY B.
Published: July 2012

The β‐adrenoceptor blocking properties of α‐methyl propranolol and α‐methyl practolol were determined in anaesthetized dogs according to their abilities to modify the isoprenaline‐induced effects on diastolic pressure, heart rate, myocardial contractile force, femoral arterial blood flow and pulmonary airway resistance.

α‐Methyl propranolol shifted the isoprenaline dose‐response curves for the fall in diastolic pressure and the positive inotropic and chronotropic responses to the right in a parallel manner yielding pA2 and slope values of 6·66 (0·92), 6·34 (0·77) and 6·59 (0·61) respectively. The slopes of the graphs for determining pA2 values for the cardiac β‐adrenoceptor blocking properties of α‐methyl propranolol were significantly less than 1 and indicated a mechanism other than simple, competitive, reversible antagonism.

α‐Methyl propranolol exerted a much weaker blockade of respiratory smooth muscle β‐adrenoceptors than has been reported for propranolol.

α‐Methyl practolol exerted a weaker blocking effect on myocardial β‐adrenoceptors than has been reported for practolol. No significant blockade of vascular or respiratory smooth muscle β‐adrenoceptors occurred after a total cumulative dose of 10 μg/kg of α‐methyl practolol.

α‐Methyl substitution of propranolol and practolol reduces the potency but increases the selectivity of their β‐adrenoceptor blocking properties.

The β‐adrenoceptors subserving cardiac stimulation, vasodilatation and bronchodilatation are representative of three different β‐adrenoceptor sub‐types in the dog.
ATROPINE‐RESISTANT EFFECTS OF THE MUSCARINIC AGONISTS McN‐A‐343 AND AHR 602 ON CARDIAC PERFORMANCE AND THE RELEASE OF NORADRENALINE FROM SYMPATHETIC NERVES OF THE PERFUSED RABBIT HEART
Authors: FOZARD J.R. , MUSCHOLL E.
Published: July 2012

The effects of 4‐(m‐chlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride (McN‐A‐343) and N‐benzyl‐3‐pyrrolidyl acetate methobromide (AHR 602) on cardiac performance and noradrenaline release from terminal sympathetic fibres were measured in isolated perfused hearts of rabbits.

In the presence of sufficient atropine to block muscarinic receptors, high concentrations of McN‐A‐343 and AHR 602 caused no cardiac stimulation and there was no increase in the resting output of noradrenaline into the perfusates.

McN‐A‐343 and AHR 602 increased both the mechanical responses and the transmitter overflow evoked by electrical stimulation of the sympathetic nerves (SNS) but inhibited both parameters during perfusion with 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP). The effects were atropine‐resistant and qualitatively similar to those seen with cocaine. Hexamethonium inhibited DMPP, but affected neither SNS per se nor the facilitatory effects of McN‐A‐343 and AHR 602 on SNS.

McN‐A‐343, cocaine and desipramine (but not AHR 602 or hexamethonium) blocked the net cardiac noradrenaline uptake and increased the positive chronotropic effect of noradrenaline.

Prior perfusion with concentrations of cocaine and desipramine sufficient to block uptake reduced or abolished the facilitatory effects of both McN‐A‐343 and AHR 602 on SNS.

Cocaine, McN‐A‐343 and AHR 602 displayed local anaesthetic properties on the guinea‐pig wheal and frog nerve plexus tests, and their relative potencies in this respect were similar to those for inhibition of DMPP‐evoked transmitter overflow. Hexamethonium did not produce local anaesthesia.

The results indicate that the facilitated release of noradrenaline after SNS and the inhibition of release after DMPP produced by McN‐A‐343 and AHR 602 are the result of their combined local anaesthetic action and inhibition of amine uptake.
DISSOCIATION OF 5‐HYDROXYTRYPTAMINE EFFECTS ON MYOCARDIAL CONTRACTILITY AND CYCLIC AMP ACCUMULATION
Authors: BENFEY B.G. , COHEN J. , KUNOS G. , VERMES‐KUNOS I.
Published: July 2012

5‐Hydroxytryptamine increased the contractility of the isolated rat atrium and produced a small rise in cyclic 3′,5′‐adenosine monophosphate (cyclic AMP) accumulation in rat heart slices. These effects were similar to those of tyramine.

Incubation with phenoxybenzamine prevented the inotropic effect of 5‐hydroxytryptamine but did not inhibit the rise in cyclic AMP accumulation.

A single injection of reserpine 24 h before the experiment did not inhibit the inotropic effect of 5‐hydroxytryptamine but prevented the rise in cyclic AMP accumulation.

It is concluded that in the rat 5‐hydroxytryptamine increases cardiac contractility chiefly by a direct effect which is blocked by phenoxybenzamine, whereas it increases myocardial cyclic AMP accumulation indirectly by releasing endogenous catecholamines. Cardiac contractility may thus be increased without a rise in cyclic AMP accumulation, and cyclic AMP accumulation may be increased without a rise in contractility.
THE MODIFICATION OF LUMBAR MOTONEURONE EXCITABILITY BY STIMULATION OF A PUTATIVE 5‐HYDROXYTRYPTAMINE PATHWAY
Authors: BARASI S. , ROBERTS M.H.T.
Published: July 2012

Changes in lumbar motoneurone excitability were monitored by recording spinal reflex activity from the ventral roots of rats anaesthetized with fluothane.

Electrical stimulation of nucleus raphes medianus increased the amplitude of the monosynaptic reflex via a pathway having a slow conduction velocity. Stimulation elsewhere in the lower brain stem was less effective. This increase in motoneurone excitability was potentiated by the intravenous injection of l‐tryptophan and reduced by intravenous injections of lysergic acid diethylamide (LSD), methysergide or Cinanserin.

Extracellular field potential responses to stimulation of dorsal or ventral roots were recorded with six barrelled microiontophoresis electrodes. Stimulation of nucleus raphes medianus and iontophoretic application of 5‐hydroxytryptamine (5‐HT) both increased the excitability of lumbar motoneurones as reflected by an increase in field potential amplitude.

Responses to both stimulation of raphe nuclei and iontophoretic application of 5‐HT were reduced by iontophoretic application of Cinanserin and methysergide.

The similarities of the responses of lumbar motoneurones to applied 5‐HT and activity within the raphe‐spinal pathway are discussed. It is suggested that activity within the raphe‐spinal pathway can increase lumbar motoneurone excitability via the release of 5‐HT in the ventral horn of the spinal cord.
BIOLOGICAL ACTIONS In vivo AND In vitro OF TWO γ‐AMINOBUTYRIC ACID (GABA) ANALOGUES: β‐CHLORO GABA AND β‐PHENYL GABA
Authors: BUU N.T. , VAN GELDER N.M.
Published: July 2012

The synthesis of two analogues of γ‐aminobutyric acid (GABA), β‐chloro GABA and β‐phenyl GABA is described.

The activity of brain GABA aminotransferase was inhibited by β‐chloro GABA (5.7 × 10−5 M) and β‐phenyl GABA (4.6 × 10−3 M) in a competitive manner with GABA.

β‐Chloro GABA exhibited 50% of the inhibitory activity of GABA in blocking the discharge of the crayfish stretch receptor neurone; β‐phenyl GABA had no detectable effect.

Injection of β‐phenyl GABA (200 mg/kg) into normal or epileptic cats (cobalt) caused the appearance of synchronized slow‐wave EEG activity.

Administration of β‐chloro GABA (200 mg/kg) to epileptic cats (cobalt) produced a temporary diminution or abolition of epileptic discharges while causing no alteration in normal EEG activity.

β‐Chloro GABA and β‐phenyl GABA had no effect on the concentrations of catecholamines or of amino acids in mouse brain.

The results suggest that both β‐chloro GABA and β‐phenyl GABA may pass the blood‐brain barrier.
A STUDY OF THE METABOLIC REQUIREMENTS FOR THE CONTRACTILE ACTION OF ANGIOTENSIN UPON GUINEA‐PIG ILEUM
Authors: CROCKER ANN D. , WILSON K.A.
Published: July 2012

Acetylcholine and angiotensin elicit a contraction of guinea‐pig ileum. The metabolic requirements for these actions have been investigated.

The angiotensin‐induced response was far more dependent upon the presence of glucose than was the response to acetylcholine.

Anoxia and oxidative enzyme inhibition preferentially reduced the angiotensin‐induced response.

The significance of these results is discussed. It is concluded that the response to angiotensin is dependent upon an ATP source distinct from that required by the contractile process. It is further shown that this energy‐dependent stage cannot be identified with the indirect, cholinergic component of the angiotensin response in this tissue.
CARDIOVASCULAR ACTIONS OF PROSTAGLANDIN C IN THE CAT AND DOG
Authors: JONES R.L. , KANE KATHLEEN A. , UNGAR A.
Published: July 2012

Prostaglandin C2 causes a prolonged fall in arterial blood pressure in the cat.

At constant heart rate this fall in arterial pressure is accompanied by falls in stroke volume, left ventricular end diastolic pressure, and left ventricular dP/dt max.

If mean aortic pressure and left ventricular end diastolic pressure are held constant as well as heart rate, prostaglandins C2 and E2 do not affect dP/dt max in the cat.

In the dog, under similarly controlled conditions, prostaglandins C2 and E2 raise dP/dt max.

We conclude that prostaglandins E2 and C2 have no direct inotropic action in the cat, but both have a direct positive inotropic action in the dog.
EFFECTS OF TIPRENOLOL, PRACTOLOL AND PROPRANOLOL ON EXPERIMENTAL VENTRICULAR TACHYARRHYTHMIAS
Authors: ALLEN J.D. , SHANKS R.G.
Published: July 2012

Low doses of tiprenolol (0.01–0.02 mg/kg) and propranolol (0.05 mg/kg) abolished the ventricular arrhythmias produced by the intravenous injection of adrenaline in anaesthetized dogs respired with halo thane.

Larger doses of tiprenolol (2.0–4.0 mg/kg) restored sinus rhythm in four of five dogs with ventricular tachycardia produced by toxic doses of ouabain. Propranolol (2.0–4.0 mg/kg) had the same effect in each of four dogs.

Both tiprenolol (4.0–8.0 mg/kg) and propranolol (4.0 mg/kg) increased the frequency of sinus beats and reduced the ventricular rate in dogs with ventricular tachycardia 20–44 h after ligation of a coronary artery.

Practolol (0.5–16.0 mg/kg) did not reduce the ventricular rate or increase the frequency of sinus beats in dogs with ventricular tachycardia after ligation of a coronary artery.

In dogs with ouabain‐induced ventricular tachycardia mean arterial pressure was reduced after the administration of tiprenolol (0.5–8.0 mg/kg) or propranolol (4.0–8.0 mg/kg). Depression of sinus and atrioventricular nodal function, and of intraventricular conduction developed in some of the dogs given tiprenolol (4–8 mg/kg) or propranolol (8.0 mg/kg).

The administration of tiprenolol (1.0–8.0 mg/kg) or propranolol (4.0–8.0 mg/kg) depressed the arterial pressure and caused the deaths of some dogs in which a coronary artery had been ligated. Such deaths did not occur in the group which had been given toxic doses of ouabain.
THE PROPERTIES OF MUSCARINIC RECEPTORS IN MAMMALIAN CEREBRAL CORTEX
Authors: BURGEN A.S.V. , HILEY C.R. , YOUNG J.M.
Published: July 2012

The reaction of tritiated propylbenzilylcholine mustard ([3H]‐PrBCM; N‐2′‐chloroethyl‐N‐[2″,3″‐3H2]‐propyl‐2‐aminoethylbenzilate) with homogenates of mammalian brain has been studied.

The uptake can be divided into an atropine‐sensitive component of fixed capacity (380 pmol/g protein in the rat) and an atropine‐insensitive part.

The atropine‐sensitive portion is identified as muscarinic receptor by its insensitivity to nicotinic antagonists and anticholinesterases and its sensitivity to a range of muscarinic antagonists.

The uptake of [3H]‐PrBCM is also inhibited by muscarinic agonists and there is reasonable quantitative agreement between the affinities of agonists estimated in this way and in intact tissues by physiological responses.

The fraction of [3H]‐PrBCM uptake inhibited by muscarinic antagonists and agonists is the same.

The amount of receptor found in six mammalian species was inversely related to the size of the brain, but the rates of alkylation and the sensitivity to atropine were not dissimilar.
STRAIN DIFFERENCES IN THE INHIBITION BY HEMICHOLINIUM‐3 OF THE PRESSOR RESPONSE TO INTRAVENTRICULAR INJECTION OF NEOSTIGMINE IN RATS
Authors: BREZENOFF H.E. , RUSIN JUDITH
Published: July 2012

The pressor response to intracerebroventricular (i.c.v.) injections of neostigmine was examined in three groups of Sprague‐Dawley rats (MFS, CS and CFE) obtained from different breeders and in Long‐Evans rats (MLE) obtained from one of the same breeders. All rats responded with a rise in blood pressure to i.c.v. injection of neostigmine, although the CFE strain was 6‐fold less sensitive to the drug than were the other strains.

Prior i.c.v. injection of hemicholinium‐3 (HC‐3; 0.4 μg) reduced by more than 50% the pressor response in the two strains obtained from the same breeder (MFS and MLE) and caused an 11% reduction in the CS strain. In contrast, the pressor response in CFE rats was not affected by as much as 40 μg of HC‐3, although this dose decreased the response to neostigmine by 47–66% in the other three strains.
BIOGENIC AMINES AND HEAD TWITCHES IN MICE DURING ETHANOL WITHDRAWAL
Authors: COLLIER H.O.J. , HAMMOND M.D. , SCHNEIDER C.
Published: July 2012

After chronic administration of ethanol to mice by the intragastric route head twitches occur as part of the ethanol withdrawal syndrome. Treatments which reduce brain 5‐hydroxytryptamine or increase brain noradrenaline inhibited ethanol withdrawal head twitches, whereas treatments which increase brain 5‐hydroxytryptamine or reduce brain noradrenaline were capable of inducing head twitches in control animals.
THE CARDIOVASCULAR EFFECTS OF l‐DOPA IN THE PITHED RAT
Authors: EDEN E. , NASMYTH P.A.
Published: July 2012

l‐DOPA (1–2 mg i.v.) in the pithed rat reduced the arterial and increased the venous pressure responses to noradrenaline.

Infusions of dopamine (4–8 μg kg−1 min−1) and noradrenaline (500 ng kg−1 min−1) also reduced the pressor responses to noradrenaline. The pressor response did not recover after stopping dopamine infusions, but it usually did so after stopping noradrenaline infusions.

The effect of l‐DOPA on the response to noradrenaline was prevented by the prior injection of the dopa decarboxylase inhibitor NSD 1024.

The prior injection of the dopamine‐β‐hydroxylase inhibitor diethyldithiocarbamate, only partially prevented the effect of l‐DOPA on pressor responses to noradrenaline.

The perfusion of noradrenaline (400 ng kg−1 min−1) together with Krebs solution (10 ml/min) through an organ bath containing an isolated aortic strip, depressed the response of the strip to doses of noradrenaline after the infusion was stopped. Infusions of dopamine (0.5–8.0 μg kg−1 min−1) had a similar effect. Fifteen minutes after adding l‐DOPA (0.5 mg) to the bath and 10 min after washing it out, the response to noradrenaline was depressed in three out of four experiments.

Infusions of noradrenaline (1 μg kg−1 min−1) in an isolated heart perfused by Langendorf's method blocked the response to injected noradrenaline whilst perfusion was in progress. Infusions of dopamine (4–8 μg kg−1 min−1) or of l‐DOPA (200 μg kg−1 min−1) did not have this effect.

It is concluded that the effect of l‐DOPA on pressor responses to noradrenaline in the pithed rat are mediated by its conversion to dopamine and noradrenaline.