bluuebunny/crossref_metadata_2025 huggingface dataset:
Resistance of noradrenaline in blood vessels to depletion by 6‐hydroxydopamine or immunosympathectomy
Authors: BERKOWITZ B. A. , SPECTOR S. , TARVER J. H.
Published: July 2012

The degree of the decrease in the noradrenaline concentrations caused by 6‐hydroxydopamine or immunosympathectomy was different in different areas of the cardiovascular system.

In rats or guinea‐pigs 6‐hydroxydopamine depleted the noradrenaline content of the heart by 90%, of the mesenteric vein by 80% and of the mesenteric artery and aorta by 30–60%. Immunosympathectomy elicited a 70% reduction in the cardiac noradrenaline but only a 50% reduction in the noradrenaline of the blood vessels of the rat.

The tyrosine hydroxylase activity of the heart, blood vessels, or adrenal glands was not significantly altered 2 weeks after 6‐hydroxydopamine. Nor was the monoamine oxidase activity in heart or blood vessels changed.

The inconsistent ability of both 6‐hydroxydopamine and immunosympathectomy to abolish experimental hypertension may be due to the partial persistence of noradrenaline and functional sympathetic nervous system activity in the blood vessels.
Effects of formyl tetrahydrofolic acid and noradrenaline on the oxygen consumption of rat brain synaptosome‐mitochondrial preparations
Authors: SPECTOR R. G.
Published: July 2012

The respiration of a mitochondrial and synaptasome fraction of rat cerebral cortex was measured using an oxygen electrode.

Little or no enhancement of oxygen uptake occurred on separately adding formyl tetrahydrofolate or noradrenaline.

When these substances were added together a marked increase in respiration was observed.

Both phenobarbitone and phenytoin inhibited the respiration of this preparation, but this was reversed on the addition of formyl tetrahydrofolate.

The possibility that some antiepileptic drugs may compete with formyl tetrahydrofolate in the brain is considered and structural similarities between folic acid and these drugs are indicated.
Studies on the effect of physostigmine on experimental cardiac arrhythmias in dogs
Authors: DAS P. K. , BHATTACHARYA S. K.
Published: July 2012

Experimental cardiac arrhythmias were produced in dogs anaesthetized with pentobarbitone. Ventricular arrhythmias were induced by strophanthin‐K, light petroleum plus adrenaline or coronary ligation procedures. Atrial flutter was induced by an injury‐stimulation technique. The acetylcholine and glycogen concentrations of the atria and ventricles were estimated.

Physostigmine pretreatment (0·1 mg/kg) significantly reduced the incidence of ventricular arrhythmias after myocardial ischaemia but had no effect on any of the other arrhythmias.

Physostigmine markedly increased the acetylcholine concentrations of atria and ventricles in control dogs, to nearly the same extent. Physostigmine had no effect on ventricular acetylcholine concentrations in dogs treated with strophanthin‐K and light petroleum plus adrenaline but in the coronary ligation group it caused a significant increase in the acetylcholine concentrations of both atria and ventricles, and of atrial acetylcholine only in the injury‐stimulation group.

All the arrhythmias produced marked glycogenolysis of both the atria and the ventricles, to nearly the same extent. Although physostigmine produced marked glycogenolysis in the control dogs it significantly inhibited cardiac glycogenolysis after light petroleum plus adrenaline, atrial glycogenolysis after strophanthin‐K‐induced arrhythmias and ventricular glycogenolysis after myocardial ischaemia.

There appears to be a possible correlation between the increase in the acetylcholine concentration of the ventricles and anti‐arrhythmic actions of physostigmine, but there is a less clear correlation between changes in the glycogen concentration of ventricles and the anti‐arrhythmic action.
Pharmacological studies on the hypogastric ganglion of the rat and guinea‐pig
Authors: BENTLEY G. A.
Published: July 2012

Preparations were developed whereby the hypogastric ganglion of the rat or guinea‐pig was perfused through its vasculature with saline solutions. Drugs were injected into the perfusion stream, and their effects were indicated by contractions of the vas deferens. The base of this organ could be ligated to prevent the drugs reaching the smooth muscle via the blood vessels. For comparison, experiments were also performed on fully isolated preparations of the rat and guinea‐pig hypogastric nerve‐vas deferens, where the vas deferens was held in an inner bath, so that drugs added to the outer bath could act only on the ganglion. Attempts were made to demonstrate non‐nicotinic receptors in these preparations.

It was shown that the perfused hypogastric ganglion of the guinea‐pig would respond repeatedly to several nicotinic stimulants, though autodesensitization eventually occurred. The fully isolated preparation behaved similarly, but desensitized much more rapidly. In contrast, the rat ganglion, either perfused or fully isolated, was remarkably insensitive to nicotinic stimulant drugs.

Neither species responded well to non‐nicotinic stimulants; that from the guinea‐pig gave small contractions to methacholine in about 33% of cases, but did not respond to (4‐m‐chlorophenyl‐carbamoyloxy)‐2‐butynyl trimethylammonium chloride (McN‐A‐343). With the rat, the situation was opposite.

The guinea‐pig ganglion did not become more sensitive to non‐nicotinic stimulants after some treatments known to sensitize the cat superior cervical ganglion. These include preganglionic tetanization, chronic decentralization, and removal of all potassium. Sensitization did occur, however, in the presence of physostigmine, after tachyphylaxis to dimethyl phenyl piperazinium iodide (DMPP) had developed, and when the preparation was perfused with a suspension of washed erythrocytes.

It is concluded that the responses of sympathetic ganglia vary from one species to another, and according to whether the organs are perfused or fully isolated.
Morphine hyperthermia in the rat: its attenuation by physostigmine
Authors: SHARKAWI M.
Published: July 2012

In rats, a subcutaneous injection of morphine (2·5 mg/kg) produced hyperthermia which was greatly attenuated by an intraperitoneal injection of physostigmine (0·1 mg/kg), but not of neostigmine (0·08 mg/kg) and promptly reversed by a subcutaneous injection of nalorphine.

It is concluded that the hyperthermia is a specific response to morphine, central in origin, and the result of diminished acetylcholine (ACh) release from central cholinergic neurones.
Isolation and identification of pharmacologically active amino acids in skin and their structure‐activity relationship on the guinea‐pig ileum
Authors: LEWIS G. P. , McMARTIN C. , ROSENTHAL S. R. , YATES CATHERINE
Published: July 2012

. Aqueous extracts of stratum corneum were found to cause histamine‐like contractions of the guinea‐pig ileum which were not antagonized by mepyramine, atropine or bromolysergic acid diethylamide.

. The compounds responsible for this contraction were isolated by chromatography and shown to be common amino acids, particularly l‐serine and l‐alanine which occur in abundance in the stratum corneum.

. Amino acid analogues were assayed on the guinea‐pig ileum against alanine as standard. With the exception of γ‐amino butyric acid and l‐alanine benzyl ester all analogues which had appreciable activity gave dose‐response curves parallel to l‐alanine.

. The response to l‐alanine benzyl ester was abolished by mepyramine and this analogue appears to be a partial agonist on the histamine receptor.

. The effects of substitution on the equipotent molar ratios of amino acid analogues indicate that all four chemical groups attached to the α‐carbon of l‐alanine interact with the receptor.

. Our results suggest that the guinea‐pig ileum contains an l‐α‐amino acid receptor.
Dissociation of the behavioural and endocrine effects of lysine vasopressin by tryptic digestion
Authors: De WIED D. , GREVEN H. M. , LANDE S. , WITTER A.
Published: July 2012

. Lysine vasopressin induces resistance to extinction of active avoidance behaviour (De Wied, 1971).

. Digestion of lysine vasopressin with trypsin almost completely destroys the pressor‐, antidiuretic‐, oxytocic‐ and corticotrophin‐releasing factor activities of lysine vasopressin, but does not materially influence its effect on the maintenance of an avoidance response.
Characterization of angiotensin receptors in vascular and intestinal smooth muscles
Authors: PARK W. K. , REGOLI D. , RIOUX F.
Published: July 2012

. A series of analogues of angiotensin II (ATII) has been used in the present experiments to characterize receptors for ATII in intestinal (rat stomach strip, rat colon) and vascular (rabbit aorta) smooth muscles. Two types of compounds have been chosen: (a) agonists with reduced potency, in which 4‐Tyr, 6‐His or 7‐Pro had been substituted with l‐Ala or with Gly and 1‐aminocyclopentane carboxylic acid (Acpc) and (b) competitive antagonists (8‐Gly‐ATII, 8‐Leu‐ATII).

. Replacement of 4‐Tyr, 6‐His and 7‐Pro with l‐Ala decreases the potency, but does not influence the maximum effect of the analogue, while substitution of the same residue with Gly and Acpc reduces both potency and maximum effect.

. Compounds showing full size maximum responses were chosen to establish the following order of potency on the three preparations: ATII>4‐Phe‐ATII> 7‐Ala‐ATII>6‐Ala‐ATII>4‐Ala‐ATII.

. The four derivatives of ATII were completely inactive on tissues desensitized with ATII. The responses to 5‐hydroxytryptamine, acetylcholine and noradrenaline were not significantly modified, except for the rat colon.

. pA2 values for the two competitive antagonists against ATII and 4‐Phe‐ATII were estimated in the three preparations by the use of the cascade superfusion technique. For comparison, pA2 values were also estimated in rat stomach strips and rabbit aortas suspended in a normal organ bath, according to the method of Schild (1947). The similarities of the pA2 values obtained in two series of experiments indicate that (a) the cascade superfusion technique is suitable for this type of study and (b) the receptor for ATII in the three tissues may be the same.

. It is suggested that receptors for ATII in intestinal and vascular smooth muscles may be the same, because (a) the order of potency of various agonists follows the same pattern, (b) the agonists are inactive on tissues desensitized with ATII, (c) pA2 values for competitive antagonists are similar in the three preparations.
On the mechanism of l‐DOPA‐induced postural hypotension in the cat
Authors: DHASMANA K. M. , SPILKER B. A.
Published: July 2012

The effects of l‐DOPA on postural hypotension and carotid occlusion pressor effect were studied, mainly in cats the recovery of the blood pressure upon tilting was used as a measure of postural hypotension.

l‐DOPA (30 mg/kg) partially depressed the carotid occlusion pressor effect and caused some degree of postural hypotension, l‐DOPA (100 mg/kg) had more marked effects the responses returned to control after 90 to 150 minutes. l‐DOPA itself caused a pressor response in all cats.

The dopa decarboxylase inhibitor N1‐(dl‐seryl)‐N2‐(2,3,4‐trihydroxybenzyl) hydrazine (RO4‐4602, 50 and 10 mg/kg) had no effect itself on the tilt response but completely prevented the effects of l‐DOPA on the carotid occlusion pressor effect and postural hypotension.

After RO4‐4602 (3 and 1 mg/kg), l‐DOPA (100 mg/kg) caused a brief rise of blood pressure followed by a longer lasting fall in horizontally‐orientated cats (i.e. ‘supine’ hypotension). No postural hypotension was observed after l‐DOPA under these conditions.

Noradrenaline elicited only small and transient effects on postural hypotension, but dopamine's effects were more marked and longer lasting. Pressor dose‐response relationships for noradrenaline were the same before and after l‐DOPA, as well as in cats pretreated with l‐DOPA for 4 days.

In cats with kidneys and intestines removed, the tilt reflex was still present. Dose‐response curves to l‐DOPA were the same as in normal animals. RO4‐4602 (3 mg/kg) prevented postural hypotension and block of the carotid occlusion pressor effect; supine hypotension was also observed after l‐DOPA.

The recovery response to tilting in spinal cats was markedly depressed or absent unless the blood pressure was elevated by angiotensin, in which experiments l‐DOPA depressed the recovery upon tilting (i.e. induced postural hypotension).

Blood pressure responses to tyramine were increased after 10 mg/kg of l‐DOPA, but depressed after 100 mg/kg. The response to tyramine was not depressed, however, when RO4‐4602 was given to block the dopa‐dopamine conversion.

The response to sympathetic stimulation in pithed rats was depressed after l‐DOPA and dopamine, but not after α‐methyldopa.

α‐Methyldopa (300 mg/kg) given acutely caused a moderate degree of postural hypotension and a more marked postural hypotension if given for two days.

It is concluded that it is possible to differentiate between the supine and postural hypotension caused by l‐DOPA and that supine hypotension is due to a central effect and postural hypotension to an extracerebral effect. Postural hypotension is discussed in relation to six hypotheses presented to explain its effect. Postural hypotension after l‐DOPA is probably not due to α‐adrenoceptor blockade, a central effect or any effect on the kidney. The most likely hypothesis is that l‐DOPA forms dopamine which acts as a false transmitter in the peripheral sympathetic nervous system.
Effect of inhibitors of γ‐aminobutyrate aminotransferase on the accumulation of H‐γ‐aminobutyric acid by the retina
Authors: NEAL M. J. , STARR M. S.
Published: July 2012

Rat retinae pre‐incubated and incubated at 37° C in media containing amino‐oxyacetic acid (AOAA) (0·1 μm to 1 mm) accumulated more 3H‐γ‐aminobutyric acid (3H‐GABA) than control retinae incubated in the absence of AOAA. This increased accumulation of 3H‐GABA by tissue exposed to AOAA was not apparent at short incubation times (0–20 min), but became significant after incubations of 30 min, and maximal after incubation for 60 minutes.

At a concentration of 10 μm, AOAA did not alter the apparent Km for 3H‐GABA uptake or Vmax for either the low or the high affinity GABA uptake systems present in retina.

The potentiation of 3H‐GABA accumulation produced by AOAA appeared to parallel the inhibitory effect of this compound on 2‐oxoglutarate‐4‐aminobutyrate aminotransferase (GABA‐T). Similarly, hydrazinopropionic acid inhibited retinal GABA‐T and potentiated the accumulation of 3H‐GABA, but hydroxylamine and thiosemicarbazide which did not affect GABA‐T, were also without effect on the retinal accumulation of 3H‐GABA.

In vitro incubation with AOAA did not increase the endogenous levels of GABA or other amino acids in the retina.

AOAA did not significantly increase the retinal accumulation of radioactive l‐glutamate, l‐glutamine, taurine, glycine, α‐aminoisobutyrate or dopamine: the accumulation of l‐aspartate was increased by approximately 30%.

The inhibition of retinal GABA‐T by AOAA was time‐dependent and was not reversed by pyridoxal‐5′‐phosphate or by repeated washing of the tissue with fresh medium.

AOAA also inhibited glutamate decarboxylase (GAD) in retinae incubated in vitro. This inhibitory effect was partially reversed by pyridoxal‐5′‐phosphate.

Efflux of radioactivity from the retina was strikingly reduced in the presence of AOAA at concentrations sufficient to inhibit GABA‐T by 100%.

These findings suggest that AOAA potentiates the accumulation of 3H‐GABA by isolated retina, not by increasing the exchange of 3H‐GABA with the endogenous GABA pools, but by reducing the metabolism of the amino acid and hence reducing the loss of radioactivity from the tissue in the form of tritiated metabolites.
The distribution of lithium and its effects on the distribution and excretion of other ions in the rat
Authors: BIRCH N. J. , JENNER F. A.
Published: July 2012

In rats, lithium (ca 1 mEquiv/kg body weight) decreased brain sodium and magnesium, bone sodium and calcium and increased muscle calcium, plasma magnesium, urinary calcium and urine volume.

Lithium was particularly concentrated in bone.
Effect of probenecid on the excretion of ampicillin in human bile
Authors: KAMPMANN J. , LINDAHL F. , HANSEN J. MØLHOLM , SIERSBÆK‐NIELSEN K.
Published: July 2012

Ampicillin concentrations were determined in serum and bile after intravenous injection into patients with T‐tube bile drainage of 1 gram ampicillin before and during probenecid medication. The concentrations were followed up to fifteen hours after injection.

Probenecid increased the half‐life of ampicillin in serum from 74 minutes to 137 minutes.

Ampicillin concentrations in bile were higher following probenecid medication and a concentration over 5 μg/ml was obtained for 3 h longer than before probenecid.

The ampicillin concentrations in bile were approximately the same as those in serum both before and during probenecid medication suggesting passive transport of ampicillin from blood to bile.

A combined treatment of ampicillin and probenecid might be of clinical value in the therapy of cholangitis and typhoid carriers.
Rapid recovery of vascular adrenergic nerves in the rat after chemical sympathectomy with 6‐hydroxydopamine
Authors: FINCH L. , HAEUSLER G. , KUHN H. , THOENEN H.
Published: July 2012

Twenty‐four hours after the last of 4 intravenous doses of 6‐hydroxydopamine (2×50 mg/kg on day 1 and 2×100 mg/kg on day 7) a complete impairment of adrenergic nerve function was observed in various organs of the rat.

A complete recovery of adrenergic nerve function in vascular smooth muscle was observed 7 days after the last dose of 6‐hydroxydopamine whilst in non‐vascular smooth muscle recovery took between 14 and 21 days.

On day 8, noradrenaline depletion produced by 6‐hydroxydopamine was not as great in vascular tissues, such as the mesentery and renal artery, as in other tissues, such as the heart and salivary glands. Noradrenaline concentrations recovered much more rapidly in vascular than in other tissues.

Electron microscope studies of small mesenteric arteries showed a complete destruction of adrenergic nerve terminals 24 h after 6‐hydroxydopamine (2×100 mg/kg). However, there was a reappearance of growing terminals within 7 days and after 28 days the regrowth of adrenergic nerve terminals seemed complete.

From the morphological and functional data it is concluded that 6‐hydroxydopamine does produce complete destruction of vascular adrenergic nerve terminals. However, these terminals regenerate more rapidly than those in other tissues. This could explain the failure of intravenously administered 6‐hydroxydopamine to prevent the development of experimental hypertension in the rat.
Effects of isoprenaline on contractions of directly stimulated fast and slow skeletal muscles of the guinea‐pig
Authors: TASHIRO N.
Published: July 2012

The actions of isoprenaline on the contraction and the resting potential of the isolated extensor digitorum longus (EDL), a fast contracting muscle, and the soleus, a slow contracting muscle, of the guinea‐pig were investigated. Twitch tension was elicited by direct supramaximal stimulation and recorded isometrically.

The twitch tension of EDL elicited by pulses of 0·5–10 ms duration was increased in the presence of isoprenaline (1 μg/ml). Isoprenaline increased the twitch tension of the soleus elicited by a pulse of more than 5 ms duration, but decreased it when elicited by a pulse of less than 1 millisecond. These effects were blocked by propranolol (1–3 μg/ml) but not by phentolamine (1–5 μg/ml).

In EDL, isoprenaline prolonged the time to peak tension and the half‐relaxation time. The twitch of the soleus was shortened by isoprenaline due to an acceleration of relaxation. These findings were independent of stimulus duration.

The potentiating effects of isoprenaline on the twitch tension of EDL and the soleus were not observed in K+‐free Krebs solution and were abolished by ouabain (1 μg/ml) and by reduction of the temperature from 33° to 18° C. The effects of isoprenaline on the relaxation process were not affected by these treatments.

In EDL, the resting potential increased from 77·3 mV to 78·5 mV after isoprenaline, whereas in the soleus it increased from 691 to 74·7 mV. These effects were blocked by propranolol, K+‐deficiency, ouabain, and cooling to 18° C. Hyperpolarization by isoprenaline was increased by substitution of isethionate for the external chloride.

There was a good correlation between the potentiation of the mechanical response and the hyperpolarization of the membrane by isoprenaline. The hyperpolarization seems to be due to activation of the Na+‐K+ pump.
The effects of bretylium on the subcellular distribution of noradrenaline and on adrenergic nerve function in rat heart
Authors: ABBS E. T. , PYCOCK C. J.
Published: July 2012

The effects of bretylium were investigated on the content and subcellular distribution of noradrenaline in the rat heart and on the response to stimulation of the sympathetic nerves supplying the heart.

In most experiments bretylium produced no change in the total noradrenaline content of the heart but significant changes were produced in the subcellular distribution of noradrenaline.

Treatment with amphetamine both prevented and antagonized the bretylium‐induced adrenergic neurone blockade and most of the accompanying changes in the subcellular distribution of noradrenaline.

There was a temporal correlation between the bretylium‐induced depletion of noradrenaline from the microsomal (P2) fraction and adrenergic neurone blockade.

The onset of adrenergic neurone blockade was also accompanied by an elevation of the noradrenaline content in the low‐speed coarse (P1A) fraction and in the mitochondrial (P1B) fraction; this elevation was prevented by pre‐treatment with α‐methyl‐p‐tyrosine.

It is concluded that although the elevation of the noradrenaline content of the P1a and P1B fractions and a depletion of amine from the P2 fraction are associated with the onset of adrenergic neurone blockade only the depletion from the P2 fraction is required for its maintenance. This conclusion supports the hypothesis that only a small portion of the noradrenaline content of an adrenergically‐innervated organ is associated with the release of transmitter, for when this small ‘store’ is depleted, by agents like bretylium, the nerves fail to function.
Assessment of selective β‐adrenoceptor blockade in man
Authors: BRIANT R. H. , DOLLERY C. T. , FENYVESI T. , GEORGE C. F.
Published: July 2012

Selective antagonism of the cardiac β1‐adrenoceptors has been studied in normal human volunteers.

Practolol and UK 6558 produced greater antagonism of the chronotropic and inotropic responses to i.v. isoprenaline than of the vasodilator response to either i.v. or intra‐arterial isoprenaline. A third drug, M&B 17,803A, produced non‐selective β‐adrenoceptor blockade in 2 of 3 subjects studied.

Practolol, UK 6558 and M&B 17,803A, produced an attenuation of the responses to Valsalva's manoeuvre.

A substantial reduction in blood pressure was seen in 3 of 4 normotensive subjects given UK 6558.
Cardiovascular responses to noradrenaline in the rat before and after administration of various anaesthetics
Authors: BREZENOFF H. E.
Published: July 2012

Cardiovascular responses to intravenously administered noradrenaline were monitored in the rat in the conscious state and again following anaesthesia. Injections and pressure recordings were made via permanently implanted venous and arterial catheters.

The pressor response to noradrenaline was inhibited by diethyl ether, urethane and deep pentobarbitone anaesthesia. It was unchanged by ketamine and was potentiated by chloralose and light pentobarbitone anaesthesia.

Reflex bradycardia was potentiated by chloralose, blocked by ketamine and reduced by pentobarbitone. It was either reduced or unchanged by ether or urethane.
The effect of cannabinoids on intestinal motility and their antinociceptive effect in mice
Authors: CHESHER G. B. , DAHL C. J. , EVERINGHAM M. , JACKSON D. M. , MARCHANT‐WILLIAMS H. , STARMER G. A.
Published: July 2012

After oral administration to mice, pethidine, Δ8‐tetrahydrocannabinol (THC), Δ9‐THC, a cannabis extract and cannabinol had a dose‐dependent antinociceptive effect when measured by the hot‐plate method. Cannabidiol was inactive at 30 mg/kg. Δ8‐THC, Δ9‐THC and pethidine did not differ significantly in potency, but Δ9‐THC was 6·5 times more active than cannabinol.

After oral administration, three different cannabis extracts, Δ8‐THC, Δ9‐THC and morphine produced dose‐dependent depressions of the passage of a charcoal meal in mice. Δ8‐THC and Δ9‐THC were equipotent and were about five times less potent than morphine. Cannabidiol was inactive up to 30 mg/kg. The effect of the three cannabis extracts on intestinal motility could be accounted for by their Δ9‐THC content.

The antinociceptive effect of pethidine and the effect of morphine on intestinal motility were antagonized by nalorphine whilst the effects of the cannabis extracts and the pure cannabinoids were not.

From these results it is concluded that although cannabis and the narcotics share several common pharmacological properties, the mode of action of each is pharmacologically distinct.
VASCULAR REACTIVITY IN SPONTANEOUSLY HYPERTENSIVE NORMOTENSIVE AND HYPOTENSIVE RATS
Authors: DUPONT J. , SASSARD J.
Published: July 2012

Three strains of rats spontaneously hypertensive (HRS), normotensive (NS) and hypotensive (HOS), were selected by repeated inbreeding.

In order to explain the different blood pressure levels observed, we have studied their vascular reactivity to noradrenaline and angiotensin II. Experiments were performed in anaesthetized ganglion‐blocked, vagotomized rats.

The reactivity to noradrenaline was significantly higher in HRS than in NS and HOS rats.

The reactivity to angiotensin II appeared identical in the three strains used.
EFFECTS OF MARIHUANA IN LABORATORY ANIMALS AND IN MAN
Authors: CARLINI E.A. , KARNIOL I.G. , RENAULT P. F. , SCHUSTER C.R.
Published: July 2012

The pharmacological potencies of the resins from three different samples of Brazilian marihuana (A, B and C) were determined through corneal areflexia in rabbits, decrease of spontaneous motor activity and induction of catatonia in mice, and decrease of rope climbing performance of rats.

The Δ9‐tetrahydrocannabinol (Δ9 THC) content of the marihuanas, measured by gas chromatography, was 0.82, 2.02 and 0.52%, respectively, for samples A, B and C. Approximately 2% cannabinol was present in samples A and B whereas the content of cannabidiol was approximately 0.1%.

The petroleum ether extraction of the samples A, B and C yielded, respectively, 12.06, 14.56 and 4.26% of resin.

In all animal tests resin B was nearly twice as active as resin A, whereas C was the weakest.

The smoke of the marihuana samples was inhaled by 33 human subjects, under a double‐blind standardized procedure. Pulse rate, a time production task and an evaluation of psychological effects were recorded.

The smoke of 250 mg of sample B provoked disruption of the time production task, increased pulse rate, and induced strong psychological reactions in four of the six subjects who received it. Similar effects, although slightly smaller, were obtained with 500 mg of sample A. On the other hand, 500 mg of sample C did not differ from placebo.

It is suggested that it is possible by means of animal tests to predict the potency of a marihuana sample in man.

In parallel experiments, Δ9‐THC was administered to other human subjects and to laboratory animals in a manner similar to that in which the marihuana samples were administered.

Comparison of the results between the marihuanas and Δ9‐THC showed that in man and in the laboratory animals marihuanas A and B induced effects two to four times greater than expected from their Δ9‐THC content.

It is suggested that there may be potentiation of the effects of Δ9‐THC by other substances present in these marihuana samples.
THE INFLUENCE OF ANAESTHETICS ON THE INCREASE IN THE WATER PERMEABILITY OF THE TOAD BLADDER INDUCED BY VASOPRESSIN
Authors: GREY D. , ULLMANN ELISABETH
Published: July 2012

Single lobes of the bladder of Bufo marinus were isolated and filled with, and suspended in, oxygenated Ringer solution. The fluid in contact with the outside (serosa) of the lobes had a total osmolarity of 225 m‐osmol/litre, and that bathing the inside (mucosa) of 45 m‐osmol/litre.

Osmotic water flow from mucosa to serosa was measured by weighing the lobes every 30 minutes. It was negligible unless vasopressin was added to the serosal bath. Standard concentrations of either 1.25 or 6.25 mu/ml were used to render the bladder lobes permeable to water.

The presence in the serosal medium of pentobarbitone or thiopentone in concentrations ranging from 0.25 to 2.5 mm, or of chloralose in concentrations ranging from 0.65 to 6.5 mm, diminished the increase in water permeability induced by vasopressin.

The three anaesthetics exerted similar inhibitory effects on the action of vasopressin from the serosal and from the mucosal surface of the bladder.

In the presence of a constant high concentration of anaesthetic, increasing the concentration of vasopressin over three orders of magnitude led to stepwise increases of osmotic water flow out of the lobes, although at every dose level the effect of vasopressin was depressed by the anaesthetic. However, it was not completely abolished even if the concentration of vasopressin was close to threshold.

The increase in water permeability of the bladder induced by 3′,5′‐adenosine monophosphate (cyclic AMP) was also depressed by the three anaesthetics.

Possible explanations of the findings are discussed.
THE BINDING OF [3H]‐PROPYLBENZILYLCHOLINE MUSTARD BY LONGITUDINAL MUSCLE STRIPS FROM GUINEA‐PIG SMALL INTESTINE
Authors: BURGEN A.S.V. , HILEY C.R. , YOUNG J.M.
Published: July 2012

The synthesis of tritium labelled propylbenzilylcholine mustard ([3H]‐PrBCM; N‐2′‐chloroethyl‐N‐[2″, 3″‐3H2] propyl‐2‐aminoethyl benzilate) is described.

The uptake by muscle strips was measured and shown to be considerably increased by previous immersion of the muscle in distilled water.

A considerable part of the uptake is inhibited selectively by atropine, but not by nicotinic antagonists. A number of muscarinic agonists also inhibit uptake and their apparent affinity constants have been determined.

The uptake by atropine‐sensitive sites is temperature‐insensitive, whereas the other sites are temperature‐sensitive. Recovery is highly temperature‐sensitive and there is good agreement between recovery of sensitivity to agonists and loss of radioactivity from the muscle.
A NON‐ADRENERGIC INHIBITORY NERVOUS PATHWAY IN GUINEA‐PIG TRACHEA
Authors: COLEMAN R.A. , LEVY G.P.
Published: July 2012

Electrical stimulation of the guinea‐pig isolated tracheal tube causes a biphasic response, initially excitatory and then inhibitory. The excitatory response was abolished by atropine leaving the inhibitory response unaffected.

The inhibitory response was greatly reduced but not abolished by propranolol or guanethidine. A residual inhibitory response was still present in tracheas in which sympathetic nerve function had been abolished by pretreatment with syrosingopine or 6‐hydroxydopamine. These results show that the inhibitory response is predominantly adrenergic but that a small non‐adrenergic component is also present.

The non‐adrenergic inhibitory response was abolished by lignocaine and tetrodotoxin suggesting that it is nervous in origin.

Optimal stimulation parameters for the predominantly adrenergic inhibitory response were a pulse width of 0.7–2 ms, a stimulation period of 7 s and a frequency of 20 Hz. For the non‐adrenergic inhibitory response, optimal stimulation parameters were a pulse width of 2 ms, a stimulation period of 12 s and a frequency of 20 Hz.

Evidence obtained with pharmacological antagonists, enzyme inhibitors and activators suggested that the transmitter mediating the non‐adrenergic inhibitory nervous response is unlikely to be: acetylcholine, histamine, 5‐hydroxytryptamine, cyclic 3′,5′‐adenosine monophosphate or a prostaglandin.

The adenosine uptake blocking drugs dipyridamole, hexobendine and Dilazep potentiated the non‐adrenergic inhibitory nervous response and unmasked inhibitory responses to adenosine and adenosine 5′‐triphosphate.

It is concluded that electrical stimulation of the guinea‐pig trachea, in addition to activating cholinergic and adrenergic nervous pathways, may activate a separate and distinct inhibitory nervous pathway. This pathway has some features in common with the non‐adrenergic non‐cholinergic inhibitory pathways in gastro‐intestinal muscle.
GUANETHIDINE AND GUANACLINE ON THE RAT VAS DEFERENS
Authors: GERKENS J.F.
Published: July 2012

In acute experiments guanethidine was considerably more potent than guanacline in reducing contractile responses of the rat vas deferens to electrical stimulation of intramural nerves.

Chronic treatment of rats for 19 weeks with guanethidine (5mg/kg, daily) reduced responses to electrical stimulation to 25% of control, potentiated responses to exogenous noradrenaline and depleted endogenous noradrenaline.

After cessation of guanethidine treatment responses to electrical stimulation increased to 60% of control (in one week) but showed no further increase. There was no decrease in the potentiation of exogenous noradrenaline (after 14 weeks) nor any increase in endogenous noradrenaline levels (after 7 weeks).

Chronic treatment of rats for 19 weeks with guanacline (5mg/kg, daily) potentiated responses to exogenous noradrenaline and depleted endogenous noradrenaline as much as guanethidine treatment but did not reduce responses to electrical stimulation.

On cessation of guanacline treatment there was some increase in noradrenaline content (after 2 to 3 weeks) and some decrease of potentiated responses to exogenous noradrenaline (after 2 weeks).

The noradrenaline‐depleting action of these drugs is distinct from blockade of nerve‐mediated responses in the rat vas deferens and contractile function after guanethidine treatment can be partly restored despite persistence of noradrenaline depletion and supersensitivity.
EVIDENCE FOR INVOLVEMENT OF 5‐HYDROXYTRYPTAMINE IN THE ACTIONS OF AMPHETAMINE
Authors: BREESE G.R. , COOPER B.R. , MUELLER R.A.
Published: July 2012

Pargyline treatment, 1 h before (+)‐amphetamine (1 mg/kg), reduced amphetamine‐stimulated motor activity. This inhibition was reversed in animals pretreated with p‐chlorophenylalanine (PCPA).

Following treatment with PCPA or 5,6‐dihydroxytryptamine (5,6‐DHT), amphetamine‐induced locomotor activity was significantly potentiated. The increased response to amphetamine in PCPA‐treated rats was reversed in animals pretreated with 5‐hydroxytryptophan.

The inhibition of amphetamine‐stimulated locomotor activity by treatment with 6‐hydroxydopamine was not reversed by PCPA treatment.

Stereotypies produced by amphetamine were not found to be altered by depletion of 5‐hydroxytryptamine.

Induction of adrenal tyrosine hydroxylase activity produced by chronic amphetamine administration was significantly potentiated by PCPA, emphasizing the involvement of a 5‐hydroxytryptamine inhibitory system in more than one action of amphetamine.
CHANGES IN PLASMA KININOGEN LEVELS INDUCED BY CELLULOSE SULPHATE DURING PREGNANCY IN THE RAT
Authors: McCORMICK J.T. , SENIOR JUDITH , WHALLEY E.T.
Published: July 2012

Cellulose sulphate (1 mg/kg) produced a 30–40% depletion of plasma kininogen in rats.

The time course of repletion of kininogen in the plasma was compared in rats in the oestrous and dioestrous stages of the cycle and in 22 day pregnant animals. A partial repletion occurred, 3 h after the cellulose sulphate injection, which was followed by a secondary fall in plasma kininogen. Plasma kininogen values were back to control levels 10 h after the treatment in all groups.

Treatment of rats from days 19–22 of pregnancy with cellulose sulphate resulted in 40% depletion of plasma kininogen and in prolongation of pre‐parturition behaviour.

It is suggested that the increase which normally occurs in plasma kininogen levels towards the end of pregnancy in the rat may play a role in the process of parturition.
STUDIES ON THE KINETICS OF [3 H]‐OUABAIN UPTAKE AND EXCHANGE IN THE ISOLATED PAPILLARY MUSCLE OF THE GUINEA‐PIG
Authors: LÜLLMANN H. , PETERS T. , RAVENS URSULA
Published: July 2012

The uptake, wash‐out and exchange of [3 H]‐ouabain was studied in isolated, resting, and electrically stimulated papillary muscles of the guinea‐pig.

At the equilibrium level of uptake, a different tissue/medium ratio was obtained for each of the concentrations used, i.e. 3.4, 1.8 and 0.82 for 1 × 10−7 M, 7.7 × 10−7 M, and 5 × 10−6 M ouabain, respectively. Equilibrium was reached more rapidly at high concentrations of ouabain.

The maximum number of binding sites for ouabain was estimated to be 1 × 1015 binding sites/g wet weight.

No difference in [3 H]‐ouabain uptake could be detected between resting and electrically stimulated papillary muscles.

The kinetics of the ouabain uptake, wash‐out and exchange are discussed. The results suggest that there is a saturable compartment in papillary muscle which can best be demonstrated if low concentrations of ouabain are used. Because of its small size, the saturable compartment submerges in the process of the filling of the extracellular space at high concentrations (5 × 10−6 M).
INHIBITION OF 5‐HYDROXYTRYPTAMINE‐INDUCED HUMAN BLOOD PLATELET AGGREGATION BY CHLORPROMAZINE AND ITS METABOLITES
Authors: BOULLIN D.J. , GRAHAME‐SMITH D.G. , GRIMES R.P.J. , WOODS H.F.
Published: July 2012

Blood platelets from normal human subjects were isolated and aggregated in vitro with adenosine diphosphate (ADP) or 5‐hydroxytryptamine (5‐HT).

The effects of chlorpromazine and 7 major metabolites upon 5‐HT‐induced aggregation were investigated.

All the phenothiazines inhibited 5‐HT‐induced aggregation when added to platelet rich plasma 3 min prior to 5‐HT.

There were no qualitative differences in the inhibitory effects, but inhibitory potency varied over a wide range. The decreasing order of potency was monodesmethylchlorpromazine, chlorpromazine, 7‐hydroxychlorpromazine, didesmethylchlorpromazine, 3,7‐dimethoxychlorpromazine, didesmethylchlorpromazine sulphoxide, chlorpromazine sulphoxide, chlorpromazine nitroxide.
INVESTIGATION OF THE VASODILATOR AND ANTISECRETORY ROLE OF PROSTAGLANDINS IN THE RAT GASTRIC MUCOSA BY USE OF NON‐STEROIDAL ANTI‐INFLAMMATORY DRUGS
Authors: MAIN I.H.M. , WHITTLE B.J.R.
Published: July 2012

The effects of non‐steroidal anti‐inflammatory drugs on gastric acid secretion and mucosal blood flow were studied in the rat.

Indomethacin, in ulcerogenic doses, caused a dose‐dependent rise in pentagastrin‐stimulated acid secretion, but decreased mucosal blood flow per unit acid secretion.

During resting conditions, indomethacin had no significant effect on acid output, but reduced mucosal blood flow.

Pretreatment with indomethacin, phenylbutazone or meclofenamate potentiated the secretory response to dibutyryl cyclic adenosine 3′,5′‐monophosphate.

Indomethacin markedly reduced the mucosal prostaglandin‐like activity at a time when mucosal erosion formation had reached steady levels.

These results provide evidence that prostaglandins have a local role in the regulation of blood flow and acid secretion in the rat gastric mucosa, and suggest that non‐steroidal anti‐inflammatory drugs cause mucosal erosions by disrupting these processes.
LIVER AND BRAIN TRYPTOPHAN METABOLISM FOLLOWING HYDROCORTISONE ADMINISTRATION TO RATS AND GERBILS
Authors: GREEN A. R. , SOURKES T.L. , YOUNG S.N.
Published: July 2012

Liver tryptophan pyrrolase activity is low in the mongolian gerbil (Meriones unguiculatus) and is not induced by hydrocortisone (5 mg/kg). In contrast, there is measurable activity in the rat liver and this is induced by hydrocortisone. In vivo measurements confirmed the absence of induction in gerbils but suggested that they were able to metabolize tryptophan. However, no detectable pyrrolase activity was found in any other tissues either before or after hydrocortisone.

In agreement with previous observations hydrocortisone decreased rat brain 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) 6 h after administration. Brain tryptophan concentrations were also decreased at this time. In contrast, hydrocortisone did not alter gerbil brain 5‐HT, 5‐HIAA or tryptophan. α‐Methyltryptophan activated hepatic tryptophan pyrrolase and decreased brain 5‐HT and 5‐HIAA in both animals.

Results suggest that the decrease in rat brain 5‐HT and 5‐HIAA following hydrocortisone may be associated with the rise in liver tryptophan pyrrolase and that the brain amine changes are mediated through the decrease in brain tryptophan concentration.
KINETICS OF AGONIST CONDUCTANCE CHANGES DURING HYPERPOLARIZATION AT FROG ENDPLATES
Authors: ADAMS P.R.
Published: July 2012

The effect of rapid hyperpolarization on acetylcholine‐ or carbachol‐induced currents was studied at voltage clamped frog endplates. Following a hyperpolarizing step the agonist‐induced conductance increased approximately exponentially to a new level. The rate constant for this process was smaller during hyperpolarization or lowered temperature, and was also smaller for acetylcholine than for carbachol. The results are interpreted in terms of a potential‐ dependent conformational change of the receptor.
THE EFFECTS OF HYPERCHOLESTEROLAEMIC PLASMA ON VASCULAR SENSITIVITY TO NORADRENALINE
Authors: BLOOM D. , McCALDEN T.A. , ROSENDORFF C.
Published: July 2012

The pressor responses to injected noradrenaline (NA) of 42 isolated perfused femoral arteries of the rabbit were studied.

Potentiation of the responses was found when hypercholesterolaemic plasma was perfused through the arteries. No change was found with normal plasma.

Potentiation of the responses was found when isolated β‐lipoprotein in Krebs solution was perfused. No change was found with similar amounts of bovine albumen.

Pure cholesterol dissolved directly into normal plasma, and dissolved via propanol into Krebs solution or plasma caused no potentiation. Propanol alone in Krebs or plasma had no effect.

Potentiation was caused by a decreased equilibrium coefficient (Keq) for the NA‐adrenoceptor interaction and an increased maximal pressor response (Rmax).

It is concluded that cholesterol carried on its apoprotein is capable of potentiating the pressor effects of noradrenaline.
ELECTROCONVULSIVE SHOCK INCREASES THE BEHAVIOURAL RESPONSES OF RATS TO BRAIN 5‐HYDROXYTRYPTAMINE ACCUMULATION AND CENTRAL NERVOUS SYSTEM STIMULANT DRUGS
Authors: EVANS JANE P.M. , GRAHAME‐SMITH D.G. , GREEN A.R. , TORDOFF ANN F.C.
Published: July 2012

A single electroconvulsive shock (ECS) of 150 V for 1 s increased the concentration of rat brain 5‐hydroxyindoleacetic acid (5‐HIAA) but did not alter brain 5‐hydroxytryptamine (5‐HT) or tryptophan concentrations 3 h later.

A single ECS decreased 5‐HT synthesis 3 h and 6 h later. Synthesis was back to normal after 24 hours. The ECS‐treated rats did not show greater hyperactivity produced by the increased brain 5‐HT accumulation following administration of l‐tryptophan and tranylcypromine at any time up to 24 h later. This suggests that a single electroshock does not alter 5‐HT functional activity.

Twenty‐four hours after the final ECS of a series of 10 shocks given once daily, the rats were given tranylcypromine and l‐tryptophan. They displayed greater hyperactivity than control rats not treated with ECS, suggesting that ECS increased 5‐HT functional activity. Brain concentrations of 5‐HT, 5‐HIAA and tryptophan were then unchanged by ECS. 5‐HT synthesis and accumulation of 5‐HT following tranylcypromine and l‐tryptophan were not altered by ECS.

The hyperactivity following administration of the 5‐HT agonist 5‐methoxy N,N‐dimethyltryptamine was enhanced by repeated (10 day) ECS, suggesting altered post‐synaptic responses to 5‐HT receptor stimulation.

Repeated ECS enhanced locomotor activity following tranylcypromine and l‐DOPA. It did not alter brain noradrenaline or dopamine concentrations.

The latent period before a pentylenetetrazol‐induced convulsion was shortened by repeated ECS.

Following repeated ECS there appears to be increased neuronal sensitivity to certain stimuli producing centrally mediated behavioural stimulation. This is discussed in relation to the mechanism by which electroconvulsive therapy (ECT) produces its therapeutic effect.
INFLAMMATORY EFFECTS OF PROSTAGLANDIN D2 IN RAT AND HUMAN SKIN
Authors: FLOWER R.J. , HARVEY E.A. , KINGSTON W.P.
Published: July 2012

Intradermal injection of prostaglandin (PG) D1 and D2 in the human forearm produced a long‐lasting dose‐related erythema. When compared with prostaglandin E1 or E2 the order of potency for erythema production was PGE1 > PGE2 > PGD2 > PGD1.

In rat skin, prostaglandin D2 but not D1 caused an increase in vascular permeability as quantitated by the Evans blue method and the 125I‐albumin extravasation technique. Prostaglandin E2 was 3–5 times more potent than prostaglandin D2.

Prostaglandin D2 (10 ng) potentiated the increase in vascular permeability in rat skin produced by histamine, but not that produced by bradykinin.

Prostaglandin D2 (10, 20 and 50 ng) did not elicit oedema or hyperalgesia in the rat paw oedema test, but potentiated carrageenan‐induced oedema; hyperalgesia was potentiated by doses of 100 ng and above.
EMETINE MYOPATHY IN THE RAT
Authors: BRADLEY W.G. , FEWINGS J.D. , HARRIS J.B. , JOHNSON MARGARET A.
Published: July 2012

(–)‐Emetine (0.25‐2.0 mg/kg i.p.) was administered to rats for up to 220 days.

At doses of 1.0 mg/kg or less, the animals continued to gain weight but more slowly than the untreated control animals. The physiological changes in the muscles from these animals were minimal; there was a small reduction in both the resting membrane potential and in the maximum rate of rise of the action potential. There was no atrophy or loss of muscle fibres although in the occasional muscle, hyaline fibres, necrotic fibres and split fibres were observed. There was a focal loss of myofibrillar adenosine triphosphatase (ATPase) and nicotinamide adenine dinucleotide tetrazolium reductase (NADH‐TR) in Type II and Type III fibres, but no such loss in Type I fibres.

The animals receiving 2.0 mg/kg of (–)‐emetine gained weight slowly for up to 20 days but then rapidly lost weight and by 30 days they were weak and emaciated. The muscles from these animals were severely atrophied and the total muscle wet weight was reduced by almost 20%.

The strength of the muscles from these animals was measured in vitro using direct stimulation. They were weaker than normal both in absolute terms and when expressed in terms of tension developed/unit wet weight.

There was no evidence of either functional or structural denervation but surgically denervated muscles from animals in this group were indistinguishable from denervated muscles from normal rats.

Severe structural damage was obvious in the fibres of both extensor digitorum longus and soleus. Necrotic, hyaline and splitting fibres were common and the focal loss of myofibrillar ATPase and NADH‐TR activity was extensive and occurred in Type I fibres as well as in Type II and Type III fibres.

It is concluded that the muscular weakness induced by (–)‐emetine is due to a direct effect on the muscle fibres and that this occurs at a subcellular level. There is no evidence that functional or structural denervation plays any role in the aetiology of emetine myopathy in the rat.