bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of vasopressin and isoprenaline infusions on the distribution of blood flow in the intestine; criteria for the validity of microsphere studies
Authors: GREENWAY C. V. , MURTHY V. S.
Published: July 2012

. The distribution of superior mesenteric arterial flow was investigated by radioactive microspheres. The small intestine received 83% of the flow ((85 ml/min)/100 g intestine) and flow was uniform along the length of the small intestine.

. The intestinal wall was separated into 3 layers—muscle, submucosa and mucosa. The muscle received (8 ml/min)/100 g intestine and the combined submucosa and mucosa (77 ml/min)/100 g intestine.

. The distribution of microspheres between the mucosa and submucosa depended on the size of the microspheres; the smaller the spheres, the more were found in the mucosa. It also depended on the state of the vascular bed; if microspheres were given during an infusion of vasopressin, a subsequent infusion of isoprenaline resulted in movement of some of the spheres from the submucosa into the mucosa.

. Histological studies after India ink injection showed few capillary‐sized vessels but many large vessels in the submucosa. Capillary‐sized vessels arose close to the junction with the mucosa and passed into the mucosa.

. These and other data suggest that the intestine consists of two parallel‐coupled sections, one to the muscle and the other through the submucosa to the mucosa. The vessels in the submucosa are in series with those in the mucosa and submucosal shunts do not exist. Redistributions of flow between mucosa and submucosa cannot therefore occur during stimulation of the sympathetic nerves or infusions of drugs such as noradrenaline or adrenaline.

. When microspheres are used in pharmacological investigations on distribution of blood flow in organs, controls to validate the method for the particular areas being studied are essential. If the vessels in the areas studied are in series rather than in parallel, the method is invalid.
The effects of dipyridamole on the myocardial vasodilator actions of noradrenaline, isoprenaline and adenosine
Authors: PARRATT J. R. , WADSWORTH R. M.
Published: July 2012

. In anaesthetized cats, intravenous adenosine infusions decreased resistance to blood flow in the myocardial vascular bed. This effect of adenosine was augmented during the 60 min following the intravenous injection of dipyridamole (1 mg/kg).

. In different experiments, intravenous infusions of noradrenaline caused either a slight increase or a slight decrease in myocardial vascular resistance. The dilator component of the action of noradrenaline was not augmented by dipyridamole.

. Isoprenaline infusions decreased the resistance of the myocardial bed. This effect was unaltered after dipyridamole.

. These results do not support the hypothesis that part of the effect of catecholamines on myocardial vascular resistance involves the release of adenosine from hypoxic myocardial cells.
The hyperglycaemic effect of morphine
Authors: FELDBERG W. , SHALIGRAM S. V.
Published: July 2012

. In the unanaesthetized cat, an injection of 0·75 mg of morphine into a lateral cerebral ventricle produced strong hyperglycaemia; on intravenous injection, 10 to 30 times larger doses were required. Other effects produced with both injections were shivering, pupillary dilatation, opening of the eyes, miaowing, periods of excitation, and analgesia. Between the periods of excitation the cat did not react to objects moving in front of its eyes and it had a vacant stare.

. Noradrenaline, adrenaline, and 5‐hydroxytryptamine (5‐HT) injected intraventricularly (250 μg, twice) depressed the hyperglycaemia due to intraventricular morphine, and noradrenaline also depressed the hyperglycaemia due to intravenous morphine. Adrenaline produced the strongest and 5‐HT the weakest depression. 5‐HT did not depress the other effects of morphine, but the catecholamines depressed most of them; only analgesia and the vacant stare appeared to be unaffected.

. Reserpine injected intraventricularly (0·5 mg, twice) greatly accentuated the hyperglycaemia as well as the other effects produced by intraventricular morphine, but pupillary dilatation and opening of the eyes no longer occurred; the protrusion of the nictitating membranes produced by the reserpine persisted.

. Pentobarbitone sodium injected intraperitoneally in an anaesthetizing dose practically abolished the morphine hyperglycaemia, but injected intraventricularly in a dose of a few milligrammes, it had a two fold effect: depression followed by enhancement of the morphine hyperglycaemia. The enhancement may be due to sensitization of the effect of the adrenaline released by morphine, since adrenaline hyperglycaemia was enhanced as well.

. Morphine did not seem to act on structures in the walls of either the lateral or third ventricle when producing its hyperglycaemic effect on intraventricular injection. The action may therefore be on more caudally situated parts of the neuro‐axis, on the central grey, on structures in the floor of the fourth ventricle or of the lateral recesses, or even on structures near the ventral surface of the brain stem.
The ring test: a quantitative method for assessing the ‘cataleptic’ effect of cannabis in mice
Authors: PERTWEE R. G.
Published: July 2012

. A bioassay for cannabis, called the ring test, has been developed in which the percentage of the total time spent on a horizontal wire ring during which a mouse remains completely immobile is recorded.

. The effect of cannabis on mobility is a dose‐related, graded response.

. Threshold doses of cannabis extract are 12·5 mg/kg when injected intravenously, and 100 mg/kg when injected intraperitoneally or subcutaneously.

. The method provides a measure of the ‘cataleptic’ effect of cannabis. Chlorpromazine in doses of 1 mg/kg upwards also produces the effect but barbitone does not.

. It is concluded that Δ1‐tetrahydrocannabinol (Δ1‐THC) is largely responsible for the effect of cannabis extract on mobility; the potency ratio of Δ1‐THC to cannabis extract is between 10 and 20. Δ1‐Tetrahydrocannabidivarol (Δ1‐THD) also affects mobility but is less active than Δ1‐THC. Cannabidiol has no effect when injected intraperitoneally in doses up to 100 mg/kg.
Changes in body temperature produced by cholinomimetic substances injected into the cerebral ventricles of unanaesthetized cats
Authors: HALL G. H.
Published: July 2012

The effects on body temperature of a number of substances injected into a lateral cerebral ventricle were examined in the unanaesthetized cat.

Nicotine (50 and 100 μg) caused a fall in body temperature ranging from 0·95–2·1° C associated with skin vasodilatation, tachypnoea and panting. These responses were prevented by the intraventricular injection of hexamethonium or mecamylamine, but not of atropine or phentolamine.

Carbachol (5 μg) caused a rise in temperature associated with skin vasoconstriction, piloerection and severe shivering. These effects were prevented by the intraventricular injection of atropine, but not of hexamethonium or mecamylamine.

An acetylcholine/eserine mixture (10 μg of each) had no reproducible effect on body temperature. Because of the variability in the response, interaction studies with antagonist drugs were not performed.

Hexamethonium (100 μg) or mecamylamine (100 μg) caused a prolonged rise in temperature, together with skin vasoconstriction, piloerection and intense shivering. Atropine (200 μg) was without effect on body temperature.

Noradrenaline (100 μg) caused a fall in temperature with skin vasodilatation. The fall was converted to a rise with skin vasoconstriction, piloerection and vigorous shivering following an intraventricular injection of phentolamine (100 μg).

These observations suggest the existence of cholinergic heat loss and heat gain mechanisms in the hypothalamic thermoregulatory pathways of the cat and the interaction studies with hexamethonium, mecamylamine and atropine, support the involvement of ‘nicotinic’ and ‘muscarinic’ receptors within the cholinergic thermoregulatory system.
Origin of the after‐hyperpolarization that follows removal of depolarizing agents from the isolated superior cervical ganglion of the rat
Authors: BROWN D. A. , BROWNSTEIN M. J. , SCHOLFIELD C. N.
Published: July 2012

Potential changes in isolated rat superior cervical ganglia following addition and removal of depolarizing agents were recorded using a moving‐fluid extracellular electrode system.

Ganglionic negativity produced by carbachol was followed by a pronounced ganglionic positivity on washing. This after‐positivity was attributed to hyperpolarization of the ganglion cells since it was unaffected by crushing the postganglionic trunk.

The after‐hyperpolarization was selectively depressed by (a) cooling (Q10 2·3), (b) metabolic inhibitors (cyanide, azide, 2,4‐dinitrophenol), (c) reducing [K+]o or substituting Cs+ for K+, (d) ouabain, and (e) substituting Li+ for Na+. This suggested a close dependence on active Na+ transport.

When K+ was restored to K+‐free solution, or the preparation was warmed rapidly, or when metabolic inhibitors were washed away, the hyperpolarization was rapidly regenerated. The effect of restoring K+ indicated that the hyperpolarization was generated directly by the Na+ pump.

The hyperpolarization was not altered by replacing CI− with isethionate, indicating that the voltage change produced by the Na+ current was not modified by passive CI− movements.

Hexamethonium added to the washout fluid augmented the after‐hyperpolarization, suggesting that there was a high (cationic) leak current due to continued receptor‐activation on washing with normal Krebs solution.

The hyperpolarization was reduced by omission of Ca2+ and restored by addition of Mg2+. This was considered to result from changes in passive membrane permeability.

The time‐course of post‐carbachol hyperpolarization accorded with a Na+ extrusion process whose rate was directly proportional to [Na+]i with a rate constant of 0·38 ± 0·02 min−1 at 23–27° C.

With increasing concentrations of carbachol, the amplitude of the hyperpolarization increased in proportion to the preceding depolarization, but the rate constant of the hyperpolarization was unchanged.

The after‐hyperpolarization was reduced in proportion to the depolarization by hexamethonium, but was not affected by atropine, hyoscine or tetrodotoxin.

A hyperpolarization also followed depolarization by acetylcholine or by EDTA in Ca2+‐free solution.

Nicotine‐depolarization was not followed by a hyperpolarization unless hexamethonium was added to the washout fluid. This was attributed to prolonged receptor‐stimulation by nicotine.

It was concluded that the after‐hyperpolarization was due to the electrogenic extrusion of Na+ accumulated in the ganglion cells during the preceding depolarization, with no involvement of specific muscarinic receptors. The relationship of this process to post‐tetanic hyperpolarization and to other forms of drug‐induced ganglionic hyperpolarization is discussed.
Role of the α‐adrenoceptor in regulating noradrenaline overflow by nerve stimulation
Authors: ENERO MARÍA A. , LANGER S. Z. , ROTHLIN R. P. , STEFANO F. J. E.
Published: July 2012

A study of the actions of phenoxybenzamine on transmitter overflow, neuronal and extraneuronal uptake of noradrenaline and in causing α‐adrenoceptor blockade was carried out using the isolated cat nictitating membrane preparation.

Phenoxybenzamine increased transmitter overflow elicited by nerve‐stimulation at 10 Hz in a concentration dependent manner in the range 10−8 to 10−5 g/ml.

Neuronal uptake of [3H]‐noradrenaline was not inhibited by concentrations lower than 10−6 g/ml of phenoxybenzamine. With 10−7 g/ml of phenoxybenzamine a significant increase in transmitter overflow was obtained, although neuronal uptake of noradrenaline was not affected. Higher concentrations of phenoxybenzamine (10−6 and 10−5 g/ml) inhibited the neuronal uptake of noradrenaline and further increased transmitter overflow.

Extraneuronal uptake of [3H]‐noradrenaline was inhibited only with the highest concentration of phenoxybenzamine tested (10−5 g/ml) and therefore appears to be unrelated to the effects on transmitter overflow.

There was a significant correlation between the degree of α‐adrenoceptor block produced by phenoxybenzamine and the increase in transmitter overflow obtained by nerve stimulation.

These results indicate that phenoxybenzamine, in addition to increasing overflow by preventing reuptake of noradrenaline, may increase transmitter release.

The possibility that phenoxybenzamine acts on α‐adrenoceptors in the adrenergic nerve terminal is discussed. These receptors would be involved in a negative feedback mechanism regulating transmitter release.
Modification by prostaglandin E2 (PGE2) of the response of guinea‐pig isolated vasa deferentia and atria to adrenergic stimuli
Authors: BHAGAT B. , DHALLA N. S. , GINN DONNA , La MONTAGNE A. E. , MONTIER A. D.
Published: July 2012

Prostaglandin E2 (PGE2) exerted positive cardiostimulant effects on isolated guinea‐pig atria. The response was not altered by treatment of the animal with reserpine or by addition of propranolol to the organ bath. These results suggest that the cardiostimulatory actions of PGE2 are not mediated through the release of catecholamines or stimulation of adrenoceptors.

On the electrically driven atria, PGE2 consistently exerted a cardiostimulant action which was not appreciably altered by changes in calcium ion in the bathing medium. PGE2 showed no effect on the transport of calcium by the fragments of heart sarcoplasmic reticulum.

PGE2 reduced the responses to both noradrenaline and tyramine in the isolated atria. The shifted dose‐response curve was not parallel to the original.

PGE2 increased the contractor response of the isolated vas deferens to nerve stimulation or to direct electrical stimulation.

PGE2 antagonized the increase caused by noradrenaline in contractor response of isolated vas deferens to direct electrical stimulation, whereas it affected the potentiation by noradrenaline differently when the vas deferens was contracting in response to nerve stimulation. In low concentration it inhibited and in large concentrations, it slightly enhanced the potentiation by catecholamine.

It is concluded that PGE2 has actions on multiple sites. It has postjunctional as well as pre‐junctional effects on adrenergic neurones.
Morphine‐induced kinetic alterations of choline acetyltransferase of the rat caudate nucleus
Authors: DATTA K. , WAJDA I. J.
Published: July 2012

In order to explain the decrease of choline acetyltransferase (2.3.1.6.) activity observed in the caudate nucleus of morphine‐treated rats, partially purified preparations of the enzyme were used in kinetic studies, with choline as substrate.

The apparent Michaelis constant for the enzyme obtained from normal rats was found to be 0·9 mm choline; this value doubled when the animals were killed one hour after a single injection of morphine (30 mg/kg). When the rats were injected daily for 4 or 15 days, and killed one hour after the last injection, the apparent Km value was 2·1 mm in each case. Prolonged daily treatment with morphine, followed by 48 h withdrawal, or by administration of 4 mg/kg of naloxone (given half an hour after the last injection of morphine) resulted in apparent Km values of 1·3–1·5 mm of choline, suggesting a gradual return to the lower, normal substrate requirement. Vmax changes were insignificant.

The effect of morphine added in vitro to different enzyme preparations was also studied. The Km values of 0·9 mm, in the enzyme isolated from normal rats, increased to 2·0 after incubation in vitro with 12·5 mm morphine. Similar increases were found in enzymes obtained from rats 48 h after the withdrawal of morphine or from rats injected with naloxone after prolonged morphine treatment. The high apparent Km values, found in enzyme obtained from animals killed one hour after the last dose of morphine, did not change upon incubation with 12·5 mm morphine. A similar pattern of Km changes was noticed after incubation with 25 mm acetylcholine.

An increase of 32% in acetylcholine (ACh) level was found in the caudate nucleus one hour after subcutaneous injection of 30 mg/kg of morphine. Return to normal values was observed when morphine was administered daily. After two to three weeks of daily treatment and subsequent withdrawal from morphine for 48 h, the levels of ACh were normal. If the daily treated rats were given naloxone within half an hour of the last injection of morphine, and killed 30 min later, the levels of ACh remained normal.

Fifty per cent inhibition of enzyme activity was observed upon in vitro incubation with 75 mm acetylcholine, or with 25 mm morphine. The same degree of inhibition was noticed when the enzyme was obtained from normal or from morphine‐treated rats.
Effects of amphetamine on the turnover rate of brain catecholamines and motor activity
Authors: COSTA E. , GROPPETTI A. , NAIMZADA M. K.
Published: July 2012

Rats receiving (+)‐amphetamine (either 0·3 or 0·2 mg/kg, i.v.) are anorexic. Only the former dose increases their motor activity. Both doses fail to change dopamine (DM) and noradrenaline (NA) concentrations in striatum and teldiencephalon. The turnover rate of striatal DM is increased only by 0·3 mg/kg of (+)‐amphetamine; neither dose changes NA turnover rate in teldiencephalon.

(—)‐Amphetamine (1 mg/kg, i.v.) causes anorexia and hyperthermia in rats but it changes neither the steady‐state concentration nor the turnover rate of striatal DM and tel‐diencephalic NA. Motor activity is not increased by this dose of (—)‐amphetamine.

Cocaine (3 mg/kg, i.v.) increases motor activity and accelerates the turnover rate of striatal DM. This drug neither accelerates turnover rate of tel‐diencephalic NA nor causes anorexia.

These observations suggest that the acceleration of striatal DM turnover rate elicited by (+)‐amphetamine and cocaine may be associated with an effect on motor activity. In contrast, the increase of motor activity seems unrelated to the effects of these drugs on noradrenergic tracts of the teldiencephalon.
Role of cardiotoxin and phospholipase A in the blockade of nerve conduction and depolarization of skeletal muscle induced by cobra venom
Authors: CHANG C. C. , CHUANG SING‐TAI , LEE C. Y. , WEI J. W.
Published: July 2012

The effects of phospholipase A (PhA), cardiotoxin (CTX) and neurotoxin (cobrotoxin) isolated from Formosan cobra (Naja naja atra) venom on conduction of the rat phrenic nerve and membrane potential of the rat diaphragm were studied.

Phospholipase A, lysolecithin and cobrotoxin were without effect on the axonal conduction. Cardiotoxin was the only active agent in cobra venom, but it was less potent than the crude venom.

The blocking action of cardiotoxin was markedly accelerated by the simultaneous administration of phospholipase A. However, the minimum effective concentration of cardiotoxin (100 μg/ml), was not decreased by phospholipase A. Pretreatment of the nerve with phospholipase A, followed by washout, did not alter the activity of cardiotoxin.

Cardiotoxin (3 μg/ml) completely depolarized the membrane of superficial muscle fibres within 60 min, being 3 times more potent than the crude venom. Phospholipase A, on the other hand, needed a dose 30 times higher and a prolonged period of incubation to induce depolarization of similar extent. Cobrotoxin was without effect on membrane potentials.

CaCl2 (10 mm) effectively antagonized the nerve blocking as well as the depolarizing effect of the crude venom, cardiotoxin or cardiotoxin plus phospholipase A. By contrast, the slow depolarizing effect of phospholipase A was enhanced by high concentrations of calcium.

Cardiotoxic fractions of Indian cobra venom affected both nerve conduction and diaphragm membrane potential in exactly the same way as cardiotoxin. Toxin A of the same venom was without effect.

It is concluded that the active agent in cobra venoms either on axonal conduction or on muscle membrane is cardiotoxin. The synergistic effect of phospholipase A on cardiotoxin appears to be due to acceleration rather than potentiation of its action. The mechanism of action of cardiotoxin and its synergism by phospholipase A are discussed.
The central action of clonidine and its antagonism
Authors: KATIC FRANCES , LAVERY HELEN , LOWE R. D.
Published: July 2012

We have examined the central actions of clonidine (2‐(2–6‐dichlorphenylamine)‐2‐imidazoline hydrochloride). It has been confirmed that when infused into the vertebral artery at 2 μg/min, it caused a decrease in blood pressure and a slight increase in heart rate. The same dose given intravenously or into the carotid artery had no effect.

Intravertebral clonidine also greatly reduced the reflex response to carotid occlusion and the effects of an intravertebral infusion of angiotensin (1 ng/kg)/min.

This central action of clonidine was antagonized by the adrenergic neurone blocking drug bethanidine (4–5 mg/kg intravenously) even after the cervical cord had been transected at C4–C6 suggesting that bethanidine also has central actions.

Other drugs which also antagonized the central effects of clonidine were guanethidine (4–5 mg/kg intravenously), bretylium (10 mg/kg intravenously) and phentolamine (0·2 mg/kg intravenously).

It is suggested that there are central adrenergic neurones which inhibit cardiovascular autonomic reflexes and that the central autonomic effects of clonidine are due to stimulation of inhibitory adrenoceptors. The antagonism by adrenergic neurone blocking drugs of the effect of clonidine could therefore be due to blockade of these inhibitory pathways.

The central action of clonidine could only be demonstrated when a high concentration was infused into the vertebral artery and could not be shown with oral doses of (20 μg/kg)/day for seven days. It is concluded that the hypotensive action of therapeutic doses is unlikely to be due to the central action of clonidine.
The action of bombesin on the systemic arterial blood pressure of some experimental animals
Authors: ERSPAMER V. , MELCHIORRI P. , SOPRANZI N.
Published: July 2012

The changes in blood pressure in response to parenteral administration of bombesin, the active tetradecapeptide of the skin of the European discoglossid frogs Bombina bombina and Bombina variegata variegata have been investigated in some experimental animals.

In most species, the polypeptide elicited hypertension which was usually gradual in onset and slow to disappear. Blood pressure increases rarely exceeded 40–50 mmHg. At the beginning of an experiment some dose‐response relationship could often be observed, but later tachyphylaxis developed. During an intravenous infusion of bombesin the rise in blood pressure could sometimes be maintained at a steady level as long as the infusion was continued, but at other times, the rise of pressure slowly subsided with continued administration of the polypeptide. In the rat and the chicken hypertension elicited by high doses of bombesin was often followed by secondary hypotension.

Bombesin‐induced hypertension was apparently not affected by pretreatment with either α‐ or β‐adrenergic blocking agents. Similarly secondary hypotension was not abolished by atropine. Thus, the effect of bombesin on vascular smooth muscle seems to be predominantly a direct one.

Angiotensin was usually more potent than bombesin, and its effect on blood pressure was more rapid and of shorter duration. Tachyphylaxis to angiotensin was lacking or moderate.

In sharp contrast to the other species, the monkey responded to bombesin with frank hypotension, which was usually proportional to the dose. In the monkey the hypotensive effect of bombesin was equal to, or greater than that of eledoisin or physalaemin and bombesin‐induced hypotension was of longer duration than that of the other polypeptides. Tachyphylaxis was moderate for low and adequately spaced doses of the polypeptide, but prompt and intense for high doses. Long‐lasting hypotension was obtained by intravenous infusion of bombesin, but repeated infusions caused tachyphylaxis. Bombesin‐induced hypotension was not affected by pretreatment with atropine.

Bombesin may be easily distinguished from all other known peptides active on vascular and extravascular smooth muscle by its effects on blood pressure. This does not apply to bombesin‐like peptides, such as alytesin and ranatensin.
Acetylcholine inhibition in the intact and chronically isolated cerebral cortex
Authors: JORDAN L. M. , PHILLIS J. W.
Published: July 2012

Some spontaneously firing cells in the cerebral cortex of cats can be depressed by iontophoretically applied acetylcholine or acetyl‐β‐methylcholine, and this depression is antagonized by atropine. Thirteen per cent of 101 spontaneously active neurones tested were depressed by cholinergic agents and 64% were excited.

Single stimuli applied to the adjacent cortical surface excited 132 neurones orthodromically. Acetylcholine or acetyl‐β‐methylcholine depressed this synaptic firing in 18% of the cells. The depression was blocked by atropine.

The population of neurones in which cholinergic agents depressed spontaneous or synaptic firing was located within the superficial half of the cortex.

Glutamate‐induced firing was depressed by cholinergic agents in 41% of 211 cells tested; atropine and strychnine strongly antagonized this depressant action, while dihydro‐β‐erythroidine was a weaker antagonist.

Long duration inhibition of glutamate‐induced firing evoked by repetitive stimulation of the cortical surface could be blocked by atropine or strychnine in both the intact and chronically isolated cortex. This provides strong evidence for a system of intracortical cholinergic neurones which make direct inhibitory contacts with neurones in the superficial layers of the cortex.
Drug‐metabolizing capacity in states of drug dependence and withdrawal
Authors: BALLINGER B. , BROWNING M. , O'MALLEY K. , STEVENSON I. H.
Published: July 2012

Drug‐metabolizing capacity was assessed in 8 barbiturate‐dependent and in 3 Mandrax‐dependent patients using, as indices, plasma antipyrine half‐life and in some cases urinary output of 6β‐hydroxycortisol. For comparison, antipyrine half‐life was also measured in volunteers before and after a period of taking hypnotic doses of these agents.

Both indices indicated a very high drug‐metabolizing capacity in the dependent subjects on admission, the antipyrine half‐life value in the barbiturate patients being the shortest reported to date for any drug‐exposed group. The urinary output of 6β‐hydroxycortisol was approximately three times that in a control population.

This induction of drug‐metabolizing capacity presumably contributed to the marked drug tolerance observed in the dependent patients.

It appeared that drug‐metabolizing capacity eventually returned to normal levels after withdrawal of the barbiturate.

It is concluded that the abnormal drug‐metabolizing capacity of dependent patients must be taken into account in assessing dose requirements for other drugs.
Species and ionic influences on the accumulation of digitalis glycosides by isolated perfused hearts
Authors: DUTTA S. , MARKS B. H.
Published: July 2012

The ability of isolated perfused guinea‐pig (digitalis‐sensitive species) and rat (digitalis‐resistant species) hearts to accumulate radio‐labelled digitalis glycosides was studied in relation to the ionic composition of the perfusion medium.

It was observed that in both species much less digoxin was accumulated than was digitoxin or proscillaridin.

The accumulation of digoxin was markedly inhibited in a low sodium or in high potassium medium. These effects were similar, but relatively less marked, with digitoxin and proscillaridin. Calcium and magnesium removal had relatively smaller effects on the accumulation of both polar and non‐polar glycosides.

The low accumulation of all digitaloids by the rat heart in comparison to the guinea‐pig heart may be due to the formation of unstable complexes between the cellular membranes in the rat heart and the various digitaloids used in this study. Although digitaloids have a reduced affinity for rat hearts and rat heart membranes in comparison to guinea‐pigs, the order of the accumulation of different glycosides in both species is the same, i.e. much less with polar glycosides than with non‐polar glycosides.

It was concluded that non‐polar glycosides such as digitoxin and proscillaridin demonstrate the same ion‐dependent accumulation mechanism as do the more polar glycosides such as digoxin and ouabain. In addition, the non‐polar glycosides possess high capacity for ion‐independent binding presumably due to lipophilic interactions with membranes.
The role of 5‐hydroxytryptamine and noradrenaline in the hyperthermic reaction induced by pethidine in rabbits pretreated with pargyline
Authors: FAHIM I. , ISMAIL M. , OSMAN O. H.
Published: July 2012

Inhibition of 5‐hydroxytryptamine (5‐HT) synthesis by p‐chlorphenylalanine protected rabbits pretreated with pargyline from the fatal hyperthermic reaction which occurs on the intravenous injection of pethidine.

The development of tolerance to morphine did not protect against the fatal pargyline‐pethidine hyperpyrexia. Moreover, the injection of nalorphine before or after pethidine conferred no protection.

Pethidine evoked a hyperpyrexia in rabbits pretreated with lithium sulphate or yohimbine.

Sodium diethyldithiocarbamate caused a fatal hyperpyrexia in rabbits pretreated with pargyline.

It is concluded that the pargyline‐pethidine hyperthermic interaction might involve the relative concentrations of 5‐HT and noradrenaline in the hypothalamus.
Metabolism of isoprenaline in dog and man
Authors: CONOLLY M. E. , DAVIES D. S. , DOLLERY C. T. , MORGAN C. D. , PATERSON J. W. , SANDLER M.
Published: July 2012

The metabolism of isoprenaline has been studied in man and dog following intravenous and oral or intra‐duodenal administration.

Intravenous isoprenaline was excreted largely unchanged in urine in both species. Only one‐third of the radioactivity in urine was in the form of the O‐methyl metabolite.

After oral doses in man or intraduodenal doses in dogs, plasma radioactivity was almost entirely as conjugated isoprenaline and this metabolite accounted for more than 80% of radioactivity in urine.

Catechol‐O‐methyl transferase may be less important than Uptake2 in limiting the pharmacological action of isoprenaline.

Pharmacological response (heart‐rate increase) was related to plasma concentration of isoprenaline only after rapid intravenous injections. In dogs, following prolonged infusion or intraduodenal doses, heart rate returned to base‐line values when plasma concentrations of isoprenaline were high.
Inhibition by metrifonate and dichlorvos of cholinesterases in schistosomes
Authors: BUEDING E. , LIU C. L. , ROGERS S. H.
Published: July 2012

No species differences between Schistosoma haematobium and Schistosoma mansoni were detected when the I50 of metrifonate for the acetylcholinesterases (AChE) and the cholinesterases (ChE) of these two trematodes were determined in isolated enzyme preparations or following exposure of the intact worms to this drug in vitro.

S. haematobium appeared to be more affected by AChE inhibition because, after administration of metrifonate to hamsters, a hepatic shift of the parasites was observed with a dose of metrifonate (150 mg (0·6 mmol) per kg) which produced no shift of S. mansoni, although AChE inhibition was comparable in both species.

Administration of a possible metabolite of metrifonate, dichlorvos, to hamsters resulted in a greater inhibition of AChE and ChE activities of S. haematobium than those of S. mansoni. Furthermore, when schistosomes were incubated with dichlorvos, inhibition of AChE activity of female S. haematobium was significantly greater (P<0·005) than that of both sexes of S. mansoni and of male S. haematobium.

The discrepancy between the lack of a significant chemotherapeutic effect of metrifonate in hamsters infected with S. haematobium and the clinical results obtained with this organophosphorus compound in human schistosomiasis haematobium is discussed, and the need to conduct similar studies in primates is pointed out.
Myocardial and circulatory effects of E. coli endotoxin; modification of responses to catecholamines
Authors: PARRATT J. R.
Published: July 2012

The predominant acute effect of E. coli endotoxin in anaesthetized, ventilated cats was pulmonary hypertension resulting from a 8–12 fold increase in pulmonary vascular resistance. This was followed by decreases in left ventricular (LV) and systemic arterial pressures and in LV dP/dt max. Recovery occurred within 2–4 min and was dependent upon increased sympathetic drive; recovery did not occur in cats treated with the β‐adrenoceptor blocking drug alprenolol.

The pulmonary vasoconstriction was reduced in cats given compound 48/80 and evidence is presented that it results primarily from histamine release.

Over the 2–3 h period following endotoxin injection, systemic arterial pressure tended to decrease and heart rate and myocardial metabolic heat production to increase. Myocardial blood flow and LV dP/dt remained fairly stable until the terminal stages of shock.

The predominant delayed effects of E. coli endotoxin in cats were a markedly reduced stroke volume, an increase in peripheral vascular resistance and a severe metabolic acidosis (arterial base excess—20 mEq/litre). Arterial pO2 and pCO2 were not significantly affected. It is concluded that myocardial contractility is maintained at this time through the release of catecholamines and that endotoxin itself depresses contractility.

The effects of adrenaline and noradrenaline infusions on systolic and diastolic blood pressures, heart rate, cardiac output, myocardial blood flow and LV dP/dt max were markedly reduced in the period 2–3 h after endotoxin. In a few animals some recovery of the response to noradrenaline occurred and was associated with a general circulatory improvement and a reduced metabolic acidosis.
Pharmacological properties of centrally‐administered agents which interfere with neurotransmitter function: a comparison with the central depressant effects of ouabain
Authors: DOGGETT N. S. , SPENCER P. S. J.
Published: July 2012

Centrally administered sodium diethyldithiocarbamate (DDC) produced hypothermia, central nervous depression and potentiation of the antinociceptive effect of morphine. These effects resemble those seen with centrally administered ouabain. Furthermore, the interactions of (+)‐amphetamine, desmethylimipramine and nialamide with DDC and ouabain were similar.

6‐Hydroxydopamine by the same route also produced central nervous depressant effects including hypothermia, decreased locomotor activity and catalepsy but not ptosis.

Both ouabain and chlorpromazine produced similar effects on behaviour and body temperature including selective abolition of a conditioned avoidance response.

Although centrally administered tetrabenazine produced ptosis, decreased locomotor activity and catalepsy, it had no significant effect on body temperature. However, the hypothermia produced by peripherally administered reserpine was reversed by centrally administered dibutyryl cyclic 3′,5′‐adenosine monophosphate.

Centrally administered cocaine and desmethylimipramine produced no depressant effects but an increased excitability and responsiveness were apparent in both cases.

Although the observed behavioural depression and hypothermia can occur independently both seem to involve an interference with dopaminergic systems.
Effect of 2‐diethylaminoethyl‐2,2‐diphenylvalerate hydrochloride (SKF 525‐A) on sulphacetamide distribution and excretion in rats
Authors: MARCHAND C. , NADEAU D.
Published: July 2012

Administration of 2‐diethylaminoethyl‐2,2‐diphenylvalerate hydrochloride (SKF 525‐A), 40 mg/kg, i.p., simultaneously or 40 min before sulphacetamide sodium, 100 mg/kg, i.p., was associated with a three‐fold increase in sulphacetamide plasma concentration of rats. This effect was no longer evident after 30 minutes.

The augmentation in sulphacetamide plasma concentration was associated with parallel increases in the muscle, kidney and brain tissue. The stomach was the only organ that contained less sulphacetamide.

When sulphacetamide was administered i.v., a similar phenomenon was observed but the differences were less marked.

Pretreatment with SKF 525‐A was associated with decreased excretion of sulphacetamide by the kidney.

It is concluded that SKF 525‐A may alter the distribution and excretion of drugs as well as inhibiting drug metabolizing enzymes.
Cellular and metabolic tolerance to an opioid narcotic in mouse brain
Authors: GOLDSTEIN A. , JUDSON BARBARA A. , SHEEHAN PATRICIA
Published: July 2012

Running activity and brain levorphanol concentration were measured in nontolerant and tolerant mice given various doses of 3H‐levorphanol.

The principal factor responsible for tolerance in the mouse is a loss of sensitivity to the narcotic drug at the cellular level in brain; despite adequate brain concentrations, the pharmacological effects are diminished or absent.

There is also metabolic tolerance; a given dose establishes a lower brain concentration in tolerant than in non‐tolerant animals.

The two kinds of tolerance are distinguished here and the contribution of each is assessed.
Kinetics and bioavailability of two formulations of amiloride in man
Authors: SMITH A. J. , SMITH R. N.
Published: July 2012

Two formulations of [14C]‐amiloride were compared in six oedema‐free subjects in single‐dose (20 mg) studies separated by a two‐week interval.

Calculation of the elimination rate constant (Ke), half‐life (T½) and apparent volume of distribution (Vd) from serum and urinary data showed no significant difference between the two formulations. The Vd values (350 to 380 litres) were greater than total body fluid volume suggesting extravascular sequestration of amiloride.

Serum and urinary amiloride levels were similar with both formulations. Pharmacokinetic parameters were similar to those of an earlier report based on one formulation.

The calculated amiloride concentration in the renal distal tubule (3 μm to 20 μm) was similar to, but higher than, reported in vitro concentrations of amiloride which reduced sodium transport in isolated membranes.
The effect of prolonged treatment with oxyfedrine on intracellular potentials and on other features of cardiac function in rabbits and guinea‐pigs
Authors: POLSTER P. , WILLIAMS E. M. VAUGHAN
Published: July 2012

Previous work in acute experiments has shown that the main pharmacological action of oxyfedrine is stimulation of β‐adrenoceptors, yet there have been clinical reports that the drug is beneficial in the treatment of angina pectoris.

In the present experiments rabbits and guinea‐pigs were treated for several weeks with daily i.p. injections of oxyfedrine.

A daily dosage of 15 mg/kg oxyfedrine had no effect on growth rate for 4 weeks, but thereafter the growth rate of treated animals fell below that of controls.

The heart weights of the treated animals, expressed as a percentage of body weight, were significantly lower than those of controls.

Measurement of intracellular potentials in hearts taken from treated rabbits showed that the main effects were a reduction in the maximum rate of depolarization and a prolongation of the plateau of the action potential.

Guinea‐pigs treated for 6 weeks with 15 mg/kg oxyfedrine daily i.p. were protected to some extent from the toxic effect of ouabain infused intravenously.
Further evidence for a central hypotensive action of α‐methyldopa in both the rat and cat
Authors: FINCH L. , HAEUSLER G.
Published: July 2012

α‐Methyldopa (300 mg/kg i.p.) produced a fall in blood pressure in conscious genetic hypertensive rats. Pretreatment with intraventricular 6‐hydroxydopamine prevented this hypotensive effect of α‐methyldopa, whilst intravenous 6‐hydroxydopamine reduced but did not prevent the hypotension.

The hypotensive effect of α‐methyldopa was prevented or reversed by intraventricular injection of phentolamine (200 μg/rat).

Pressor responses obtained by stimulation of the entire sympathetic outflow in the Gillespie & Muir preparation, were unaffected by pretreatment with α‐methyldopa (300 mg/kg i.p.).

Vasoconstrictor responses to periarterial nerve stimulation of the isolated renal artery preparation of the rat were markedly reduced by pretreatment with α‐methyldopa. Furthermore, α‐methylnoradrenaline was found to have one‐eighth the vasoconstrictor potency of noradrenaline in this particular artery preparation.

Pressor responses obtained by stimulation of the posterior hypothalamus or midbrain reticular formation in the rat anaesthetized with urethane were markedly reduced by pretreatment with α‐methyldopa. FLA‐63, a selective dopamine‐β‐hydroxylase inhibitor, prevented the reduction of the pressor responses to hypothalamic stimulation produced by α‐methyldopa.

Stimulation of the posterior hypothalamus in the anaesthetized cat caused both an increase in sympathetic nerve activity and a rise in blood pressure. These responses were markedly reduced 3–4 h after the injection of α‐methyldopa (100 mg/kg i.v.).

These results strongly suggest that the central actions of α‐methyldopa are important for its hypotensive effect, although a possible peripheral effect cannot be excluded.
Effect of centrally acting drugs on the uptake of γ‐aminobutyric acid (GABA) by slices of rat cerebral cortex
Authors: HARRIS M. , HOPKIN JUDY M. , NEAL M. J.
Published: July 2012

The effects of centrally acting drugs on the uptake of 3H‐γ‐aminobutyric acid (GABA) by slices of rat cerebral cortex have been studied.

Many centrally acting drugs at concentrations of 0·1–1·0 mm significantly inhibited the uptake of 3H‐GABA by cortical slices, but the only classes of drugs in which all members consistently produced inhibition of uptake were the phenothiazines, tricyclic antidepressants, and butyrophenones.

The receptor blocking drugs; phentolamine, propranolol, thymoxamine, mepyramine, and diphenhydramine at concentrations of 0–5–1 mm also significantly reduced the uptake of 3H‐GABA. However, atropine, hexamethonium and (+)‐tubocurarine had little effect on the uptake of 3H‐GABA by cortical slices.

Centrally acting drugs, which did not significantly inhibit 3H‐GABA uptake, included barbiturates, local anaesthetics, hallucinogens, monoamine oxidase inhibitors, anticonvulsants, and convulsants (except picrotoxin).

Chlorpromazine, prochlorperazine, l‐2,4,diaminobutyric acid, desmethylimipramine, and iprindole inhibited the uptake of 3H‐GABA by 50% (IC50) at concentrations of 30–100 μm. The most potent inhibitor of 3H‐GABA uptake was p‐chloromercuriphenylsulphonate (IC50 = 18 μM).

With the exception of l‐2,4,diaminobutyric acid, an outstanding characteristic of these drugs was their complete lack of specificity. Thus at the IC50 for GABA, p‐chloromercuriphenylsulphonate, chlorpromazine, prochlorperazine, iprindole, desmethylimipramine, apomorphine and diphenylhydramine also inhibited the uptake of radioactive glycine, alanine, noradrenaline, and 5‐hydroxytryptamine. The uptake of the latter two compounds was often inhibited to a greater extent than GABA, glycine and alanine.

Kinetic analysis indicated that the inhibition of 3H‐GABA by p‐chloromercuriphenylsulphonate, chlorpromazine, and desmethylimipramine was non‐competitive. l‐2,4,Diaminobutyric acid reduced the uptake of 3H‐GABA by a ‘mixed’ type of inhibition.

The present results do not support the suggestion that some centrally acting drugs may produce their effects by reducing the uptake of GABA in the brain after its release from inhibitory nerve terminals. Conceivably, the design of compounds which interfere effectively with the mechanisms of GABA operated synapses may lead to the introduction of whole new groups of centrally acting drugs.
The effect of immunosympathectomy and of 6‐hydroxydopamine on the responses of the rat anococcygeus to nerve stimulation and to some drugs
Authors: GIBSON A. , GILLESPIE J. S.
Published: July 2012

The rat anococcygeus muscle possesses a dense motor adrenergic innervation and also a powerful inhibitory innervation whose transmitter is unknown. The possibility that the adrenergic nerves released both noradrenaline and the unknown inhibitory transmitter was investigated by destroying the adrenergic nerves either by immunosympathectomy or by 6‐hydroxydopamine.

Immunosympathectomy was only partially effective in destroying the adrenergic neurones to the anococcygeus. 6‐Hydroxydopamine destroyed the terminal adrenergic varicosities abolishing almost completely the motor response. Neither treatment affected the inhibitory response.

6‐Hydroxydopamine induced a specific hypersensitivity of the muscle to noradrenaline which was not shared with carbachol.

The maximum tension response of the anococcygeus muscle was greater in the male than in the female probably because the muscle is bigger.
Effects of salicylates on blood changes in mycoplasma arthritis in rats
Authors: EISEN V. , LOVEDAY C.
Published: July 2012

The polyarthritis produced in rats by i.v. inoculation with Mycoplasma arthritidis was made more severe by salicylates.

The infection increased the erythrocyte sedimentation rate (ESR), serum lysozyme, counts of total white blood corpuscles, polymorphonuclear cells and lymphocytes, haemolytic serum complement (CH 50) and its component C3. Salicylates enhanced the rise in ESR, CH 50 and C3, but suppressed the rise in lymphocytes and even induced a fall.

Salicylates did not interfere with the development and action of metabolic inhibition antibodies against M. arthritidis, and did not promote the growth of M. arthritidis.

Rats treated with salicylate during the first infection acquired the same immunity to reinfection as did infected controls.

Salicylates did not render rats susceptible to M. fermentans which is nonpathogenic to rats, but may be involved in human rheumatoid arthritis.
Inhibition of functional vasodilatation and prostaglandin formation in rabbit adipose tissue by indomethacin and aspirin
Authors: BOWERY BARBARA , LEWIS G. P.
Published: July 2012

The epigastric adipose depot of rabbits has been used to examine the effect of indomethacin, aspirin and nicotinic acid on the free fatty acid release and blood flow in fat tissue.

The prostaglandin formation which occurs in adipose tissue during lipolysis is prevented by indomethacin and aspirin. The corresponding functional vasodilatation which occurs after infusions of lipolytic substances is also abolished by these two anti‐inflammatory compounds.

This finding is consistent with the theory that prostaglandin E2 is the mediator of functional vasodilatation in adipose tissue.

Nicotinic acid sometimes inhibits the release of free fatty acids from adipose tissue by preventing activation of the tissue lipase. In those experiments in which this inhibition occurred, the vasodilatation was also prevented.

This finding is consistent with the view that the prostaglandin E2 which mediates the functional vasodilatation, originates in the triglycerides of the fat tissue.
The dependence of paracetamol absorption on the rate of gastric emptying
Authors: HEADING R. C. , NIMMO J. , PRESCOTT L. F. , TOTHILL P.
Published: July 2012

The rate of gastric emptying was measured directly in 14 convalescent hospital patients and paracetamol absorption was studied following an oral dose of 1·5 g.

Rapid gastric emptying was associated with the early appearance of high peak plasma paracetamol concentrations whereas peak concentrations were low and occurred late when gastric emptying was slow.

There was a significant correlation between the rate of gastric emptying and the 0·4 and 0·24 h urinary excretion of paracetamol and its metabolites.

In five patients with abnormally slow gastric emptying the mean maximum plasma concentration and 0·4 and 0·24 h urinary excretion of paracetamol were significantly lower than in seven patients with normal gastric emptying rates while the time taken to reach maximum plasma concentrations was longer.

Individual differences in the rate of gastric emptying may contribute to variable absorption of many drugs.