bluuebunny/crossref_metadata_2025 huggingface dataset:
C‐FRAGMENT OF LIPOTROPIN—AN ENDOGENOUS POTENT ANALGESIC PEPTIDE
Authors: FELDBERG W. , SMYTH D.G.
Published: July 2012

1 A series of peptides derived from porcine lipotropin was examined for analgesic and other morphine‐like properties on infusion into the cannulated third ventricle of cats.

2 Lipotropin (LPH 1‐91) itself produced no analgesia or other morphine‐like effects when infused in a dose of 150 μg.

3 C‐fragment (LPH 61‐91) produced strong long‐lasting analgesia when infused in a dose of 10 or 20 μg; on a molar basis the potency was between 90 and 180 times that of morphine. The following morphine‐like effects were also produced: shivering leading to fever, vasodilatation of the pinnae, mydriasis, opening of the palpebral fissures, tachypnoea with bouts of panting, vocalization, hyperexcitability, restlessness and catalepsy. All the effects, including analgesia, were abolished by an intraperitoneal injection of naloxone (1 mg/kg).

4 Hyperglycaemia, another central effect produced by morphine, was obtained with C‐fragment infused in a dose of 60 μg.

5 On intravenous injection, C‐fragment produced analgesia with a dose of about 200 μg/kg. Administered by this route, C‐fragment was again more potent than morphine.

6 C'‐fragment (LPH 61‐87), LPH 61‐78 and LPH 61‐69, either had no analgesic effect or produced weak short‐lasting analgesia when infused in doses up to 100 μg.

7 Methionine enkephalin (LPH 61‐65) either produced very weak short‐lasting analgesia or had no analgesic effect when infused in doses of between 30 and 400 μg.

8 N‐methyl methionine enkephalin amide in which both termini of methionine enkephalin were protected against degradation by exopeptidases produced long‐lasting analgesia when infused in doses of 150 to 180 μg; its analgesic potency was approximately 100 times less than that of C‐fragment. Blocking only one terminus of methionine enkephalin did not appear to endow the peptide with analgesic properties. The N‐methyl pentapeptide amide produced other morphine‐like effects of which the most striking was catalepsy. All the effects were abolished by intraperitoneal naloxone (1 mg/kg).
MECHANISMS UNDERLYING GASTRIC MUCOSAL DAMAGE INDUCED BY INDOMETHACIN AND BILE‐SALTS, AND THE ACTIONS OF PROSTAGLANDINS
Authors: WHITTLE B.J.R.
Published: July 2012

1 The mechanisms by which the bile salt, sodium taurocholate, potentiates the formation of gastric mucosal erosions induced by indomethacin has been investigated in the rat.

2 Systemic administration of indomethacin lowered resting mucosal blood flow but had no effect on the acid back‐diffusion across the mucosa.

3 Gastric perfusion of taurocholate in acid solution increased acid back‐diffusion and lowered the potential difference. This was accompanied by an increase in mucosal blood flow, which may represent a protective mechanism in the mucosa.

4 Administration of indomethacin during acid‐taurocholate perfusion reduced this elevated mucosal blood flow without any further change in acid back‐diffusion.

5 The results suggest that although a decrease in mucosal blood flow or an increase in acid back‐diffusion can lead to a low incidence of erosions, a combination of both produces extensive mucosal damage.

6 The (15S)‐methyl analogue of prostaglandin E2 reduced erosion formation induced by indomethacin and acid‐taurocholate administration.

7 It is suggested that this protective action of the prostaglandin analogue may be linked to changes in gastric mucosal permeability and in mucosal blood flow.
FLUVOXAMINE, A SPECIFIC 5‐HYDROXYTRYPTAMINE UPTAKE INHIBITOR
Authors: CLAASSEN V. , DAVIES J.E. , HERTTING G. , PLACHETA P.
Published: July 2012

1On the basis of both in vitro and in vivo experiments fluvoxamine has been characterized as a potential anti‐depressant drug with almost exclusively 5‐hydroxytryptamine (5‐HT) uptake inhibiting properties.

2 Fluvoxamine is effective in inhibiting 5‐HT uptake by blood platelets and brain synaptosomes. Due to inhibition of the membrane pump the compound prevents 5‐HT depletion by the tyramine‐derivatives H 75/12 and H 77/77. As a result of the interference with the neuronal re‐uptake mechanism for 5‐HT, fluvoxamine produces a decreased 5‐HT turnover in the brain. Effects of 5‐hydroxytryptophan (5‐HTP) are potentiated in mice and in combination with pargyline, fluvoxamine induces 5‐HT‐like behavioural effects.

3 In contrast to tricyclic antidepressants, noradrenaline uptake processes are either unaffected or only slightly inhibited by fluvoxamine. The noradrenaline depleting effects of tyramine derivatives are not influenced by fluvoxamine. Reserpine effects, such as ptosis are affected only at very high doses of the test compound. The antagonism by fluvoxamine of the reserpine‐induced lowering of the pentamethylenetetrazole convulsive threshold can be regarded as due to an effect upon 5‐HT uptake. In contrast to the effects of desmethylimipramine and imipramine, no stimulatory effects are found in rats when rapidly acting reserpine‐like compounds are given following a dose of fluvoxamine.
TAMOXIFEN INHIBITION OF AN in vitro OESTRADIOL‐INDUCED SURFACE COAT CHANGE ON MOUSE BLASTOCYSTS
Authors: BLOXHAM P.A. , PUGH D.M.
Published: July 2012

1 Eighty‐nine hour post‐coitus mouse blastocysts cultured in the presence of oestradiol‐17β underwent a histochemically detectable surface coat change.

2 Tamoxifen was found to inhibit this in vitro ‐induced change. The role of Tamoxifen as an inhibitor of implantation is discussed.
THE ANIMAL PHARMACOLOGY OF BUPRENORPHINE, AN ORIPAVINE ANALGESIC AGENT
Authors: COWAN A. , DOXEY J.C. , HARRY E.J.R.
Published: July 2012

1 The general pharmacology of buprenorphine, a potent analgesic agent derived from oripavine, is described.

2 After acute administration of buprenorphine, the spontaneous locomotor activity of mice was increased; rats displayed stereotyped licking and biting movements; behavioural depresssion was marked in guinea‐pigs but mild in rhesus monkeys. The behaviour of cats was unchanged.

3 In general, buprenorphine reduced heart rate but had no significant effect on arterial blood pressure in conscious rats and dogs.

4 In anaesthetized, open‐chest cats buprenorphine (0.10 and 1.0 mg/kg, i.v.) caused no major haemodynamic changes.

5 Buprenorphine (0.01‐10 mg/kg, i.a.) and morphine (0.30‐30 mg/kg, i.a.) increased arterial Pco2 values and reduced Po2 values in conscious rats. With doses of buprenorphine greater than 0.10 mg/kg (a) the duration of respiratory depression became less, (b) ceiling effects occurred such that the maximum effects produced were less than those obtained with morphine.

6 Buprenorphine was a potent and long‐lasting antagonist of citric acid‐induced coughing in guinea‐pigs.

7 At a dose level 20 times greater than the ED50 for antinociception (tail pressure), morphine suppressed urine output to a greater extent than the corresponding dose of buprenorphine in rats.

8 Over the range 0.01‐1.0 mg/kg (s.c.), buprenorphine slowed the passage of a charcoal meal along the gastrointestinal tract in rats. After doses in excess of 1 mg/kg, the meal travelled increasingly further such that the distances measured after 10 and 30 mg/kg did not differ significantly from control values. In contrast, the morphine dose‐response relationship was linear.
LIGATED RENAL PEDICLES AND DURATION OF ACTION OF NEOSTIGMINE AND PYRIDOSTIGMINE
Authors: MILLER R.D. , RODERICK LAURA
Published: July 2012

1 The duration of neostigmine or pyridostigmine antagonism of a (+)‐tubocurarine (Tc) neuromuscular blockade was determined in the cat anterior tibialis‐peroneal nerve preparation with and without ligated renal pedicles.

2 The infusion rate of Tc required to maintain a 90% depression of twitch tension was reduced from 8.8 ± 1.4 (s.e.) to 3.4 ± 0.6 μg kg−1 min−1 by renal pedicle ligation.

3 Renal pedicle ligation resulted in an increased duration of antagonism of Tc by both neostigmine and pyridostigmine.
EFFECTS OF Δ9‐TETRAHYDROCANNABINOL ON THE RATES OF OXYGEN CONSUMPTION OF MICE
Authors: PERTWEE R.G. , TAVENDALE R.
Published: July 2012

1 Experiments with untreated mice confirmed that at ambient temperatures below 30°C, the oxygen consumption rate of mice normally kept at about 23°C varies inversely with ambient temperature.

2 At given ambient temperatures in the range 20 to 31°C the oxygen consumption rate was 32 to 43% greater for restrained than for unrestrained mice.

3 Hypothermia induced in restrained mice by Δ9‐tetrahydrocannabinol (Δ9‐THC) (1.0 to 4.0 mg/kg i.v.) was accompanied by marked falls in the rate of oxygen consumption. The size of these falls parallelled the degree of hypothermia and increased both with increases in dose and with decreases in the ambient temperature. The oxygen consumption rates of unrestrained mice were also lowered by hypothermic doses (10 to 40 mg/kg i.p.) of Δ9‐THC.

4 The maximum falls in oxygen consumption rate occurred at earlier times after drug administration than the maximum falls in rectal temperature.

5 At none of the ambient temperatures studied did the oxygen consumption rates of Δ9‐THC‐treated mice fall significantly below the basal levels (59 ± 3 ml 25 g−1 h−1) of unrestrained, resting mice at 30°C.

6 The hypothesis that reduced rates of heat production contribute significantly towards the hypothermia induced by Δ9‐THC in our experiments is discussed. The possibility that biological processes responsible for increased heat production in response to cold are more sensitive to Δ9‐THC than those processes governing basal rates of heat production at thermally neutral environmental temperature is also raised.
THE EFFECTS OF ETHER STRESS AND BETAMETHASONE TREATMENT ON THE CONCENTRATIONS OF NORADRENALINE AND DOPAMINE IN VARIOUS REGIONS OF THE RAT BRAIN
Authors: VELLUCCI SANDRA V.
Published: July 2012

1 The effects of ether stress on noradrenaline (NA) and dopamine levels in different regions of the rat brain were studied.

2 Exposure to ether vapour (90 s) caused a significant decrease in the concentration of hypothalamic NA but had no effect on catecholamine (CA) concentrations in the other regions studied.

3 Treatment with betamethasone alone (20 μg/ml) given in the drinking water for 24 h, had no effect on CA levels in the cerebral cortex, midbrain or hypothalamus. However, pretreatment with this dose of steroid prevented the decreases in hypothalamic NA which were normally seen after ether stress and also induced significant increases in the concentration of midbrain NA.

4 The data provide further support for the involvement of NA in the regulation of stress‐induced corticotropin (ACTH) release and indicate that centres other than the hypothalamus may be involved in mediating the inhibitory action of betamethasone on the response to ether stress.
CARDIOVASCULAR EFFECTS OF Δ9‐TETRAHYDROCANNABINOL IN CONSCIOUS AND ANAESTHETIZED DOGS
Authors: FRIEDMAN E. , GERSHON S. , HINE B. , TORRELIO MARINA , MOSS IMMANUELA RAVE
Published: July 2012

Temporal effects of Δ9‐tetrahydrocannabinol (THC) on heart rate and blood pressure in conscious dogs were compared to those in anaesthetized dogs.

In conscious dogs, THC in doses of 0.25 and 0.1 mg/kg resulted in maximal heart rate reductions of 48 and 41%, respectively, and in no significant change in blood pressure.

In anaesthetized animals THC in doses of 0.5 and 0.25 mg/kg caused a peak reduction in heart rate of 38 and 34%, and of blood pressure of 24 and 8%, respectively.

The results demonstrate that the bradycardia in response to THC in dogs is independent of the concomitant anaesthesia.

We conclude that the discrepancy between heart rate response to THC in dogs and in man is due to a species difference.
PROFILE OF β‐ADRENOCEPTORS IN FEMORAL, SUPERIOR MESENTERIC AND RENAL VASCULAR BEDS OF DOGS
Authors: TAIRA N. , YABUUCHI Y. , YAMASHITA S.
Published: July 2012

The homogeneity of β‐adrenoceptors in femoral, superior mesenteric and renal vascular beds was investigated by the use of the regional perfusion technique in dogs.

Isoprenaline and salbutamol produced dose‐related increases in femoral and superior mesenteric blood flow. The dose‐response curves for the two agonists were parallel, but salbutamol was approximately 1/15 as potent as isoprenaline on a weight basis.

Isoprenaline and salbutamol increased renal blood flow in a dose‐related manner. However, salbutamol was approximately 1/240 as potent as isoprenaline on a weight basis, and the slope of the dose‐response curve for salbutamol was less steep than that for isoprenaline.

The dose‐response curves to isoprenaline for increase in femoral and superior mesenteric blood flow were shifted to the right by intravenous pindolol but not by intravenous or intra‐arterial practolol.

The dose‐response curves to isoprenaline for increase in renal bood flow were shifted to the right more markedly by intravenous pindolol than by intravenous or intra‐arterial practolol.

The results indicate that β‐adrenoceptors of the renal vascular bed consist of β1‐type and β2‐type whereas the femoral and superior mesenteric vascular beds contain only β2‐adrenoceptors.
EFFECTS OF Δ9‐TETRAHYDROCANNABINOL AND CANNABIDIOL ON A Mg2+‐ATPase OF SYNAPTIC VESICLES PREPARED FROM RAT CEREBRAL CORTEX
Authors: GILBERT J.C. , PERTWEE R.G. , WYLLIE M.G.
Published: July 2012

Δ9‐Tetrahydrocannabinol and cannabidiol both exhibited a concentration‐related inhibition of Mg2+‐ATPase of vesicles prepared from synaptosomes isolated from rat cerebral cortex. Cannabidiol was about 3 times more potent than tetrahydrocannabinol.

These results were similar to those obtained previously using drugs with well established anticonvulsant activity.

Tetrahydrocannabinol at a sub‐inhibitory concentration (1 μM) increased the activity of the Mg2+‐ATPase relative to values obtained with vehicle controls.
THE EFFECTS OF LABETALOL (AH 5158) ON ADRENERGIC TRANSMISSION IN THE CAT SPLEEN
Authors: BLAKELEY A.G.H. , SUMMERS R.J.
Published: July 2012

The competitive α‐ and β‐adrenoceptor blocking agent labetalol, in concentrations up to 10−4 M, produced dose‐dependent increases in transmitter overflow from the isolated blood perfused spleen of the cat following nerve stimulation at 10 and 30 Hz.

At concentrations above 10−4 M labetalol produced a pronounced decrease in transmitter overflow.

Labetalol (1.5 × 10−4M) increased the recovery of 3H label in the venous blood following the close‐arterial infusion of [3H]‐(‐)‐noradrenaline indicating that the drug inhibits uptake of the amine.

Both labetalol (3.8 × 10−5 M) and piperoxan (7.4 × 10−6 M) produced parallel shifts to the right of the dose‐response curves to noradrenaline and oxymetazoline in isolated strips of cat splenic capsule. In this preparation both drugs acted as competitive postsynaptic α‐adrenoceptor blocking agents.

Labetalol (3.3 × 10−5M) increased the transmitter overflow following stimulation of the splenic nerves with 200 impulses at 10 Hz. The overflow could be further increased by subsequent addition of piperoxan (7.2 × 10−6M). Piperoxan (5.7 × 10−6M) alone produced a marked increase in transmitter overflow which could be further increased by subsequent addition of desmethylimipramine (DMI; 3.2 × 10−5M). Cocaine (1.5 × 10−5M) or DMI (5.4 × 10−5M) produced a small increase in transmitter overflow which was not further increased by addition of labetalol (2.8 × 10−5 M).

Labetalol produced a biphasic effect on the responses of the isolated blood perfused spleen of the cat to nerve stimulation. With low doses (up to 10−4M) vascular responses were potentiated and with high doses (greater than 10−4M) inhibited. The potentiation was related to uptake blockade and the inhibition to decreased transmitter overflow and postsynaptic α‐adrenoceptor blockade.

Labetalol appears to act as a postsynaptic α‐adrenoceptor antagonist in the isolated blood perfused spleen of the cat with little effect on presynaptic α‐adrenoceptors. The moderate elevation of transmitter overflow by the drug is related to the inhibitory effect of the drug on neuronal uptake rather than on presynaptic α‐adrenoceptors.
TISSUE BLOOD FLOW AND DISTRIBUTION OF CARDIAC OUTPUT IN CATS: CHANGES CAUSED BY INTRAVENOUS INFUSIONS OF HISTAMINE AND HISTAMINE RECEPTOR AGONISTS
Authors: JOHNSTON BARBARA M. , OWEN D.A.A.
Published: July 2012

The effects of infusions of histamine on blood pressure, cardiac output, heart rate, total peripheral resistance, stroke volume and tissue blood flow have been determined in anaesthetized cats using radio‐active microspheres to measure cardiac output and tissue blood flow.

Histamine caused dose‐dependent falls in blood pressure and total peripheral resistance over the dose‐range 1 × 10−8 to 3.3 × 10−7 mol kg−1 min−1. Histamine had no effect on cardiac output, heart rate or stroke volume.

Histamine caused vasodilatation in the heart and stomach, with increased blood flow through these organs, and in the small and large intestine where blood flow was maintained despite the falls in arterial blood pressure. Blood flow to the brain, kidneys, liver, adrenal glands, skeletal muscle, spleen and skin was reduced when arterial blood pressure fell. Vascular resistance increased in the skin and spleen, presumably due to reflex vasoconstriction when blood pressure fell.

The selective H1‐receptor agonist 2‐(2‐aminoethyl)pyridine lowered blood pressure and decreased total peripheral resistance but did not change cardiac output, heart rate or stroke volume. 2‐(2‐Aminoethyl)pyridine caused vasodilatation in the heart, small and large intestine and kidneys. Vascular resistance was increased in the spleen and skin.

The selective H2‐receptor agonist 4‐methylhistamine also lowered blood pressure and decreased total peripheral resistance but did not change cardiac output, heart rate or stroke volume. 4‐Methylhistamine caused vasodilatation in the heart, stomach, small and large intestines and skeletal muscle. Vascular resistance was increased in the skin.
AN ELECTROPHYSIOLOGICAL STUDY OF THE ACTION OF CRUDE Enhydrina schistosa VENOM
Authors: FERRY C.B. , GEH SOO LIN
Published: July 2012

Electrophysiological studies on the rat diaphragm revealed that crude Enhydrina schistosa venom has a blocking action on postjunctional acetylcholine (ACh) receptors.

This venom in concentrations of 0.125‐1.0 μg/ml abolished the extracellular endplate potential (e.e.p.p.) without altering the presynaptic spike. When the phrenic nerve was stimulated at a frequency of 1 Hz the degree of depression of successive e.e.p.ps was approximately the same in records made before and after treatment with venom.

In concentrations of 0.25 and 0.5 μg/ml the venom reduced significantly the amplitude of miniature endplate potentials (m.e.p.ps). The frequency of m.e.p.ps did not increase but was decreased when the amplitude of the m.e.p.ps was much reduced.

The crude venom did not alter the resting membrane potential (RMP) of the muscle cell.

The venom inhibited the depolarization of the muscle membrane caused by carbachol.

It is concluded that an active component in the crude venom is responsible for a blocking action on postjunctional receptors.
CARDIAC ADRENOCEPTORS AT LOW TEMPERATURE AND THE ADRENOCEPTOR INTERCONVERSION HYPOTHESIS
Authors: BENFEY B.G.
Published: July 2012

The hypothesis that low temperature converts inotropic β‐adrenoceptors to α‐adrenoceptors has been tested in isolated heart preparations of the frog and rat.

The results do not support the adrenoceptor interconversion hypothesis. In the frog ventricle strip lowering the temperature from 24°C to 14°C did not significantly alter the inotropic potency of the sympathomimetic drugs isoprenaline, adrenaline and phenylephrine and did not reduce the potency of the β‐adrenoceptor blocking drug propranolol as an isoprenaline antagonist. In the isolated left atrium of the rat lowering the temperature from 31°C and 24°C to 17–19°C did not significantly alter the inotropic potency of isoprenaline, noradrenaline and phenylephrine, did not diminish the potency of the β‐adrenoceptor blocking drug propranolol and did not increase the potency of the α‐adrenoceptor blocking drug phentolamine.

Phenylephrine acted on α‐ and β‐adrenoceptors in rat left atrium at 31°C and 24°C, but only on β‐adrenoceptors at 17–19°C.
SPASMOGENIC AND POTENTIATING ACTIONS OF SOME AMINO ACIDS ON THE GUINEA‐PIG MYOMETRIUM
Authors: BEDWANI J.R. , ISHIZAWA M. , PICKLES V.R. , SUWANKRUGHASN SURANG
Published: July 2012

Thirty‐three amino acids were applied separately in concentrations of 2 to 10 mM to guinea‐pig uterine horns in vitro at pH 7.4. About half the acids regularly produced contractions.

Glycine and the straight‐chain L‐α‐amino acids up to norleucine were active (longer ones not tested); D‐isomers were less potent or inactive in these concentrations. The ω‐amino acids γ‐aminobutyric acid (GABA) and δ‐aminovaleric, and the α,ω‐diamino acids L‐α, β‐diaminopropionic and L‐α,γ‐diaminobutyric were active, whereas others of similar chain‐length such as β‐alanine and lysine were not. The diacidic acids, glutamic and homocysteic, were more active than the amido‐amino acids, glutamine and asparagine. Histidine and phenylalanine showed little or no activity.

The use of appropriate blocking agents indicated that the responses to representative acids were not mediated by histamine, 5‐hydroxytryptamine, acetylcholine, noradrenaline or by prostaglandins. Attempts to block the actions of glycine and GABA with strychnine, thebaine, picrotoxin, bicuculline or tetramethylenedisulphotetramine (TETS) were unsuccessful.

When some of the acids that were spasmogenic at 2 to 10 mM were applied at sub‐spasmogenic doses, they transiently potentiated other spasmogens such as oxytocin or acetylcholine. This effect was also shown by a mixture of amino acids at approximately the normal plasma concentrations.

There is some similarity between the spasmogenic activities of different amino acids and their known abilities to depolarize neurones.
THE INHIBITION OF HISTAMINE RELEASE FROM RAT PERITONEAL MAST CELLS BY NON‐STEROID ANTI‐INFLAMMATORY DRUGS AND ITS REVERSAL BY CALCIUM
Authors: LEWIS G.P. , WHITTLE B.J.R.
Published: July 2012

The non‐steroid anti‐inflammatory drugs, indomethacin, flufenamate and meclofenamate, inhibited the release of histamine from rat peritoneal mast cells induced by pharmacological or immunological challenge in vitro.

Anti‐inflammatory steroids had little effect on histamine release from the mast cells.

Th inhibition of histamine release by the aspirin‐like drugs was not prevented by incubation with glucose, unlike the inhibition of 2,4,dinitrophenol or antimycin‐A. This suggests that the non‐steroid anti‐inflammatory compounds do not act by preventing the energy production from oxidative metabolism, required for histamine release.

The inhibition of the calcium ionophore A23187‐induced histamine release by the aspirin‐like drugs was reversed by an increase in the calcium concentration of the incubation medium.

The results suggest that the non‐steroid anti‐inflammatory compounds inhibit histamine release by actions on calcium influx into the mast cell, or on calcium mobilization or utilization within the mast cell.
THE EFFECTS OF SODIUM CROMOGLYCATE ON HISTAMINE AEROSOL‐INDUCED REFLEX BRONCHOCONSTRICTION IN THE ANAESTHETIZED DOG
Authors: JACKSON D.M. , RICHARDS I.M.
Published: July 2012

The effects have been studied of sodium cromoglycate (SCG), given by aerosol or intravenously, on reflex bronchoconstriction induced by histamine aerosol in the anaesthetized dog.

Four breaths of an aerosol generated from a 2% solution of SCG significantly inhibited the vagally mediated increase in total lung resistance (RL) produced by histamine.

SCG given intravenously as bolus injections (5–500 μg/kg) produced a dose‐dependent reversal of a sustained reflex bronchoconstriction induced by histamine aerosol. Propranolol (500 μg/kg) did not prevent this reversal.

SCG did not inhibit the increase in RL produced by supramaximal electrical stimulation of a vagus nerve.

The possibility is discussed that SCG may reduce the activity of lung irritant receptors in the anaesthetized dog.
POSSIBLE MECHANISM OF ADVERSE REACTION FOLLOWING LEVODOPA PLUS BENSERAZIDE TREATMENT
Authors: MESSIHA F.S.
Published: July 2012

Rats treated for seven days with seryl‐trihydroxybenzylhydrazine (benserazide), an inhibitor of peripheral aromatic l‐amino acid decarboxylase (500 mg/kg, daily, i.p.) alone or in combination with l‐DOPA methylester (500 mg/kg, daily, i.p.) for seven days showed a moderate but significant decrease of liver aldehyde dehydrogenase (ALDH), without accompanying change in alcohol dehydrogenase (ADH) activity, compared with saline‐treated controls.

Administration of l‐DOPA methylester (500 mg/kg, daily, i.p.) alone for seven days had little effect on liver ADH or ALDH.

The combined treatment might be conducive to the in vivo formation of l‐DOPA‐derived tetrahydroisoquinoline derivatives which might be implicated in l‐DOPA produced adverse effects.
METABOLIC BASIS FOR THE SUPRA‐ADDITIVE EFFECT OF THE ETHANOL‐DIAZEPAM COMBINATION IN MICE
Authors: PAUL C.J. , WHITEHOUSE L.W.
Published: July 2012

The comination of ethanol and diazepam elicits additive or supra‐additive pharmacological effects in animals and humans. Since the mouse appeared to be a reasonably good animal model for man, this species was examined to determine if a biochemical basis for these effects could be established.

The effect of ethanol (3 g/kg, orally), administered 0.5 h before [14C]‐diazepam (5 mg/kg, orally), on the pharmacokinetics of diazepam in male Swiss Webster mice was examined.

At 4, 6, 8 and 12 h after dosing, blood levels of 14C were higher in ethanol pretreated mice than in vehicle pretreated controls. A tissue distribution study indicated that ethanol had similar effects on levels of 14C in most tissues at 2, 6 and 12 hours.

Both pretreated and control mice eliminated approximately 25% of the dose of isotope in the urine and 50% in the faeces by 48 hours.

Biliary excretion was the major route of clearance in mice in which the bile ducts had been cannulated and ethanol reduced excretion at all time periods examined up to 12 hours.

Oxazepam (the glucuronide in bile) and desmethyl diazepam were the major metabolites identified in bile, plasma and brain. Ethanol reduced oxazepam levels but increased desmethyl diazepam levels, suggesting that 3‐hydroxylation of desmethyl diazepam was inhibited by ethanol.

The accumulation of the pharmacologically active desmethyl diazepam in the brains of ethanol pretreated mice offers an explanation for the supra‐additive effect of the ethanol‐diazepam combination on motor coordination.
RESPONSES OF THE CARDIOVASCULAR SYSTEM OF THE RAT TO α‐ AND β‐ADRENOCEPTOR AGONISTS
Authors: IMMS F.J. , NEAME R.L.B. , POWIS D.A.
Published: July 2012

The effects of intravenously infused phenylephrine and isoprenaline upon the cardiovascular system of the rat anaesthetized with pentobarbitone, have been investigated.

Phenylephrine produces a dose‐dependent rise in mean arterial blood pressure (MABP) that is due mainly to an increase in total peripheral vascular resistance (TPR), though at all doses tested cardiac output was invariably raised.

The increase in cardiac output was due in each instance to an increase in stroke volume, heart rate being unchanged. This increase in cardiac output is probably brought about by effects of phenylephrine on the capacitance vessels rather than by an effect on the heart.

Evidence is presented to show that the effects of phenylephrine are mediated largely by α‐adrenoceptors, but that β‐adrenoceptors which affect TPR are also stimulated by the amine.

Isoprenaline produces a dose‐dependent fall in MABP that is due entirely to a fall in TPR since the cardiac output increases.

Unlike phenylephrine, the increase in cardiac output obtained with isoprenaline was achieved by an increase in heart rate while stroke volume remained close to control values. It is contended that the augmented venous return required for the elevated cardiac output results in this case mainly from the isoprenaline‐induced fall in TPR which enhances transfer of blood from arteries to the veins.

Evidence is presented to show that the effects of isoprenaline are mediated mainly by β‐adrenoceptors.

Under the present experimental conditions the adrenoceptor‐mediated cardiovascular changes are little modified reflexly by the arterial baroreceptors.
THE NATURE OF POTASSIUM CHLORIDE‐INDUCED RELAXATIONS OF THE RAT ANOCOCCYGEUS MUSCLE
Authors: GIBSON A. , JAMES T.A.
Published: July 2012

The nature of KCl‐induced relaxations of the rat anococcygeus muscle was investigated.

The relaxations were mimicked by other K+ salts, but not by NaCl.

The muscle was more susceptible to the relaxant effects of KCl than the contractile effects.

Addition of ouabain (100 μm) had no effect on the relaxations.

The relaxations were abolished by tetrodotoxin (5 μg/ml), procaine (500 μm), and by section of the inhibitory nerves.

The results suggest that KCl‐induced relaxations are due to stimulation of the inhibitory nerves by K+.
COMPARATIVE EFFECTS OF GLYCERYL TRINITRATE ON VENOUS AND ARTERIAL SMOOTH MUSCLE in vitro; RELEVANCE TO ANTIANGINAL ACTIVITY
Authors: MACKENZIE J.E. , PARRATT J.R.
Published: July 2012

A quantitative in vitro study has been made of the actions of glyceryl trinitrate and sodium nitrite on vascular smooth muscle (dog femoral artery and saphenous vein; rat portal vein); these have been compared with the actions of papaverine, isoprenaline, salbutamol, pentaerythritol tetranitrate and trimetazidine.

Glyceryl trinitrate was more active on the saphenous vein than on the femoral artery in inhibiting noradrenaline and potassium‐induced tone.

Unlike glyceryl trinitrate, sodium nitrite and isoprenaline, papaverine and diazoxide inhibited noradrenaline‐induced contractions of venous and arterial smooth muscle to the same extent.

The selective dilator effects of glyceryl trinitrate on venous smooth muscle may explain its action in alleviating the pain of angina pectoris. It is suggested that the use of these three vascular smooth muscle preparations (arterial, and veins with and without spontaneous myogenic activity) is a useful initial screening procedure for prospective antianginal drugs acting by venodilatation.
TIME COURSES OF THE ANTI‐ANAPHYLACTIC AND ANTI‐INFLAMMATORY EFFECTS OF DEXAMETHASONE IN THE RAT AND MOUSE
Authors: CHURCH M.K. , MILLER P.
Published: July 2012

The time course of the activity of dexamethasone has been studied in a variety of anaphylactic and inflammatory reactions in the rat and the mouse.

The times of peak activity of dexamethasone, expressed as time between oral dosage and induction of response, and the approximate ED50 values (mg/kg) found were: anaphylactic bronchoconstriction in rats, 12–24 h, ED50 1.8; passive cutaneous anaphylaxis in rats, 6 h, ED50 0.04; cutaneous reactions to histamine in rats, 4 h, ED50 0.01; carrageenin‐induced paw oedema in rats, 4 h, ED50 0.03; pinnal anaphylaxis in mice, 6 h, ED50 0.82; histamine‐induced pinnal reactions in mice, 6 h, ED50 0.05.

In rats, the characteristics of the inhibitory effects of dexamethasone indicate a differential activity against anaphylactic and inflammatory reactions and between different types of inflammatory reactions. Possible reasons for these differences are discussed.

In mice there was little difference between the inhibition by dexamethasone of cutaneous allergic and histamine‐induced reactions.

Pinnal anaphylaxis in mice was potentiated by dexamethasone given 1–2 h before challenge.
DIFFERENTIAL DEPLETION OF CYTOPLASMIC HIGH AFFINITY OESTROGEN RECEPTORS AFTER THE in vivo ADMINISTRATION OF THE ANTIOESTROGENS, CLOMIPHENE, MER‐25 AND TAMOXIFEN
Authors: KURL R.N. , MORRIS I.D.
Published: July 2012

The in vivo actions of the oestrogen antagonists clomiphene, MER‐25 and tamoxifen upon the cytosol oestrogen receptors prepared from amygdala, hypothalamus, pituitary and uterus of rats were studied 24 h after drug administration.

There was a dose‐related depletion of cytosol oestrogen receptors. However, the uterine and pituitary receptors were consistently affected at a lower dose than were those from the brain.

The ratios of the combined central ED50 to the combined peripheral ED50 were clomiphene 169 < MER‐25 19.2 > tamoxifen 2.13.

The receptor changes were not related to biological activity monitored by serum luteinizing hormone levels and uterotrophic response.

The possible role of these drug effects in the induction of ovulation and future developments are discussed.
INVESTIGATION OF THE ROLE OF HISTAMINE IN ANTIGEN‐INDUCED BRONCHOCONSTRICTION IN THE ASCARIS‐HYPERSENSITIVE DOG
Authors: KRELL ROBERT D.
Published: July 2012

Aerosol administration of ascaris antigen to the airways of ascaris‐hypersensitive dogs provoked increases in pulmonary resistance (Rp) and decreases in dynamic lung compliance (Cdyn). These changes in pulmonary mechanics were not inhibited by the histamine H1‐receptor antagonists, diphenhydramine or mepyramine.

Increases in Rp and decreases in Cdyn induced by a histamine aerosol were markedly or totally inhibited by comparable doses of these HI‐antihistamines.

Doses of antigen which produced pathophysiological pulmonary responses failed to produce a detectable histamine release from the cardiopulmonary system in vitio. Aerosol antigen provocation, equivalent to 5 to 9 times greater than that which produced substantial pathophysiological pulmonary responses, did cause histamine release in vivo.

The canine cardiopulmonary system showed only a modest ability to remove and/or degrade circulating histamine.

It is concluded that histamine may not play a major role in mediating the acute antigen‐induced bronchoconstriction in the ascaris‐hypersensitive dog.
CHARACTERIZATION OF RECEPTORS MEDIATING 5‐HYDROXYTRYPTAMINE‐ AND CATECHOLAMINE‐INDUCED PLATELET AGGREGATION, ASSESSED BY THE ACTIONS OF α‐ AND β‐BLOCKERS, BUTYROPHENONES, 5‐HT ANTAGONISTS AND CHLORPROMAZINE
Authors: BOULLIN DJ. , GLENTON PATRICIA A.M.
Published: July 2012

Blood platelets from normal human volunteers were isolated and aggregated in vitro with 5‐hydroxytryptamine (5‐HT), noradrenaline (NA), dopamine and N‐dimethyldopamine (DMDA).

The effects of 5‐HT antagonists, α‐ and β‐adrenoceptor blocking agents, butyrophenones and chlorpromazine upon aggregation induced by the four amines were investigated.

Only the 5‐HT antagonists, chlorpromazine and spiroperidol were potent inhibitors of 5‐HT‐induced aggregation, and only phentolamine was a potent inhibitor of the catecholamine‐induced aggregation.

Evidence was obtained for two populations of receptors, one for 5‐HT and one for the three catecholamines.
THE INFLUENCE OF AN EXTRANEURONAL COMPARTMENT ON THE RELAXATION OF THE CAT NICTITATING MEMBRANE in vivo
Authors: ECCLES R. , MACLEAN A.G.
Published: July 2012

Contractions of the cat nictitating membrane were elicited on stimulation of the internal carotid nerve, and the effects were studied of desipramine and two inhibitors of catechol‐O‐methyltransferase, U‐0521 and pyrogallol, on the subsequent relaxation of the muscle.

The relaxation of the nictitating membrane occurred in at least two phases. The late phase of relaxation was prolonged after increase in the period of nerve stimulation and the duration of this phase was further prolonged after treatment with pyrogallol.

After inhibition of neuronal uptake of noradrenaline with desipramine both the early and late phases of relaxation were increased in duration, and subsequent administration of pyrogallol or U‐0521 caused a further increase in the duration of the late phase of relaxation.

The results suggest that the late phase of relaxation of the nictitating membrane is influenced by efflux of noradrenaline from an extraneuronal pool.
EFFECTS OF PROPYLBENZILYLCHOLINE MUSTARD ON INJECTION INTO THE LIQUOR SPACE OF CATS
Authors: BERGMANN F. , FELDBERG W.
Published: July 2012

In unanaesthetized cats the effects were examined of propylbenzilylcholine mustard (PrBCM) on injection into the cannulated cerebral ventricles and cisterna magna. Extreme motor excitation, vocalization, shivering leading to fever, tachypnoea, panting, piloerection and salivation were produced on ventricular, vigorous scratching bouts on cisternal, injections. The sites of these actions are discussed. None of the effects was produced by atropine similarly injected. All effects were suppressed by anaesthetizing doses of pentobarbitone sodium injected intraperitoneally.
CENTRAL ADRENOCEPTORS AND CHOLINOCEPTORS IN CARDIOVASCULAR CONTROL
Authors: BHARGAVA K.P. , JAIN L.P. , SAXENA A.K. , SINHA J.N. , TANGRI K.K.
Published: July 2012

In cats anaesthetized with chloralose, adrenoceptor and cholinoceptor agonists and antagonists were localized to the posterior hypothalamus (PH), lateral medullary pressor area (LMPA) and spinal autonomic loci to delineate the role of central cholinoceptors and adrenoceptors in cardiovascular control.

All along the neuroaxis, the α‐adrenoceptors seem to subserve an inhibitory and the β‐adrenoceptors a facilitatory role in cardiovascular control. There appears to be a predominance of α‐adrenoceptors at the medullary level and β‐adrenoceptors at the hypothalamic level.

The nicotinic cholinoceptors at the hypothalamic, medullary and spinal levels were facilitatory, whereas muscarinic cholinoceptors were inhibitory for cardiovascular control. However, muscarinic receptors were undetectable at the posterior hypothalamus.

The central cardiovascular effects of nicotine are attributed to nicotinic receptor activation and release of central catecholamines.

There appears to be a relationship between central cholinergic and adrenergic mechanisms in cardiovascular control.
EFFECTS OF SPIPERONE ON SELF‐STIMULATION AND OTHER ACTIVITIES OF THE MONGOLIAN GERBIL
Authors: FRANCIS N. , MARLEY E. , STEPHENSON J. D.
Published: July 2012

Self‐stimulation to lever pressing and capacitance probe touching was obtained in Mongolian gerbils (Meriones unguiculatus) from electrode placements within the medial forebrain bundle.

Lever pressing was more sensitive to the decremental effects of a central depressant, pentobarbitone, than capacitance probe touching, suggesting its greater responsiveness to disturbances of motor function.

Spiperone (0.005 to 0.05 mg/kg) attenuated capacitance probe touching and lever pressing equally, a finding explained by action on either reward pathways or on the ability to initiate responding.

This same dose range of spiperone (0.005 to 0.05 mg/kg) attenuated locomotor activity, whether spontaneous or evoked by non‐contingent electrical stimulation, and produced catalepsy.

The spiperone‐induced attentuation of self‐stimulation was not necessarily a result of its action on dopaminergic reward pathways since the effects could equally well be explained by a failure to initiate responding.
INHIBITION BY MORPHINE OF PROSTAGLANDIN‐STIMULATED FLUID SECRETION IN RAT JEJUNUM
Authors: COUPAR I.M.
Published: July 2012

Anaesthetized rats (225 to 300 g) were used to study the inhibitory effect of morphine on fluid secreted by the small intestine.

Small intestinal fluid secretion was stimulated by infusion of prostaglandin E1 (PGE1) into the aortic arch, the jejunum being more sensitive than the ileum. Infusion of PGE1 2 μg/min caused maximal net fluid secretion in the jejunum but inhibited net fluid absorption in the ileum.

Morphine caused a dose‐related inhibition of maximal PGE1‐stimulated fluid secretion in the jejunum. At the higher doses of morphine used (5 to 20 mg/kg) the fluid transporting function of the jejunum was restored almost to normal net absorption.

The inhibitory effect of morphine on PGE1‐stimulated fluid secretion was antagonized by naloxone. Naloxone caused a parallel shift to the right of the dose‐response curve for morphine.

Two other narcotic analgesics were assayed relative to morphine and their descending order of potency was oxymorphone < morphine > pethidine.

It is suggested that the antisecretory effect of morphine in the small intestine may contribute to its efficacy as an anti‐diarrhoeal drug. Further studies on the rat jejunum may show it to be a useful model for predicting narcotic drug activity and as such, may give some insight into the mechanisms of action of these drugs.
PHARMACOLOGICAL AND ELECTROPHYSIOLOGICAL STUDIES OF MORPHINE AND ENKEPHALIN ON RAT SUPRASPINAL NEURONES AND CAT SPINAL NEURONES
Authors: DAVIES J. , DRAY A.
Published: July 2012

The actions of morphine, methionine and leucine enkephalin, administered electrophoretically, were studied on supraspinal neurones in the cortex and brainstem of the rat anaesthetized with urethane and on spinal Renshaw cells and dorsal horn interneurones in the cat anaesthetized with pentobarbitone.

The majority of Renshaw cells and cortical and brainstem neurones were excited by all three compounds although some supraspinal neurones were depressed.

Naloxone reversibly antagonized both excitatory and depressant actions of morphine and enkephalin. Acetylcholine‐induced excitation but not amino acid‐induced excitation was also antagonized by naloxone.

Neither morphine nor the enkephalins had any naloxone‐reversible action on dorsal horn neurones when ejected from conventional multibarrelled electrodes. However, morphine but not enkephalin, administered into the substantia gelatinosa region of the spinal cord selectively reduced responses to noxious stimuli of neurones in deeper laminae. Naloxone administered into the same region antagonized this action of morphine.

Intravenous morphine also antagonized responses of dorsal horn neurones to noxious stimuli and subsequent intravenous naloxone reversed this effect.

It was concluded that the excitatory and inhibitory effects of morphine and enkephalin on central neurones may be mediated by actions on different opiate receptors and that depression of noxious responses of dorsal horn neurones may be relevant to the analgesic action of morphine.
TACHYPHYLAXIS TO ETHACRYNIC ACID IN THE ISOLATED ATRIUM OF GUINEA‐PIG AND ITS RELATION TO NORADRENALINE STORES
Authors: KHOYI M.A. , POUSTI A. , POWIS G. , ZARRINDAST M.R.
Published: July 2012

The isolated electrically‐paced atrium of the guinea‐pig developed a dose‐dependent increase in the force of contraction in response to ethacrynic acid (12–100 μg/ml) which was blocked by pretreatment of the animals with reserpine but was unaffected by desipramine or colchicine added to the bathing medium.

There was a rapidly developing tachyphylaxis to repeated doses of ethacrynic acid which was not reversed by rest or incubation of the tissue with noradrenaline.

There was no cross tachyphylaxis between ethacrynic acid and tyramine, amphetamine or nicotine.

Ethacrynic acid (200 μg/ml) decreased the noradrenaline content of the atria by 32%.

It is concluded that ethacrynic acid exerts its effects indirectly through the release of endogenous noradrenaline and that the mechanism of release seems to be different from that of other known indirect sympathomimetic drugs.
RESPONSES OF RABBIT PORTAL VEIN TO HISTAMINE
Authors: COOK D.A. , MACLEOD K.M.
Published: July 2012

Histamine produced a dose‐dependent contraction of the isolated portal vein of the rabbit. This contraction was not antagonized by atropine, methysergide, indomethacin, cocaine or 6‐hydroxydopamine, nor by pretreatment of the rabbit with reserpine.

The response to histamine was blocked by H1‐receptor antagonists only when the blocking agent was used in very high concentrations, and was not antagonized by the H2‐receptor blocking agent, metiamide. H1‐receptor antagonists did not block the effects of 5‐hydroxytryptamine.

The contractions elicited by histamine, 5‐hydroxytryptamine and noradrenaline were blocked by phentolamine.

Desensitization to high doses of 5‐hydroxytryptamine caused a concomitant depression in the response to histamine but not to noradrenaline or acetylcholine.

The results suggest that the contractions of rabbit portal vein elicited by histamine are not mediated by receptors of the H1‐ or the H2‐type, but may involve an action of histamine at a receptor which is also involved in the action of 5‐hydroxytryptamine.
THE METABOLISM OF PROSTAGLANDINS BY THE GUINEA‐PIG UTERUS WITH PARTICULAR REFERENCE TO CORPUS LUTEAL MAINTENANCE IN EARLY PREGNANCY1
Authors: WALKER FELICITY M. MAULE , POYSER N.L.
Published: July 2012

Homogenized lung tissue from day 15, pregnant and non‐pregnant guinea‐pig metabolized exogenous prostaglandin E2 (PGE2) and prostaglandin F2α (PGF2α) almost completely when incubated in Tyrode solution containing β‐nicotinamide adenine dinucleotide (NAD+).

Metabolism of PGE2 and PGF2α by homogenates of day 15, pregnant or non‐pregnant, guinea‐pig uteri was relatively low (8 to 20%) when incubated in Tyrode solution containing NAD+.

Day 15, guinea‐pig conceptuses (placentae and embryos), homogenized and incubated in Tyrode solution containing NAD+, metabolized prostaglandins to a slightly greater extent (14 to 22%) than day 15, uterine tissue.

Addition of exogenous arachidonic acid to day 12 or day 15, pregnant, guinea‐pig uterine homogenates in Tyrode solution did not increase the yield of PGF2α following incubation.

It is concluded that neither an increase in metabolism of PGF2α by the uterus and conceptus nor lack of precursor is responsible for the lower secretion of PGF2α from the day 15, pregnant, guiena‐pig uterus when compared to the day 15, non‐pregnant uterus.
INITIAL INVESTIGATIONS INTO ADRENALINE ACCUMULATION AND ADRENERGIC RESPONSIVENESS IN CULTURED NEONATAL RAT HEART CELLS
Authors: WALKER M.J.A.
Published: July 2012

Accumulation of tritiated adrenaline (and/or its products) has been studied by a variety of techniques in viable, attached and free‐floating myoblasts cultured from neonatal rat heart cells.

Accumulation increased with the number of cells used, the culture age of cells, incubation time and the concentration of adrenaline in the incubation mixture.

Accumulation‐concentration data were not linearly correlated with dose‐response data.

Accumulation did not correlate well with β‐adrenoceptor responsiveness in a number of situations of varying responsiveness.

Accumulation was not blocked by a variety of uptake blocking agents or α‐ and β‐adrenoceptor antagonists.

A much smaller accumulation process was observed in fibroblasts which respond to adrenaline with reversible morphological changes.
EFFECT OF PARATHYROIDECTOMY ON CARDIOVASCULAR REACTIVITY IN RATS WITH MINERALOCORTICOID‐INDUCED HYPERTENSION
Authors: BERTHELOT A. , GAIRARD A.
Published: July 2012

Previous work has shown that parathyroidectomy protected Sprague‐Dawley rats against mineralocorticoid hypertension.

In order to explain this protection, we studied vascular reactivity to noradrenaline and angiotensin II in several groups of rats with and without their parathyroid and thyroid glands. Work was performed in vagotomized, anaesthetized rats after ganglionic blockade with pentolinium, and atropine sulphate.

The reactivity to noradrenaline was significantly lower in parathyroidectomized rats, especially at the beginning of mineralocorticoid treatment.

Autotransplantation of parathyroid glands in thyroparathyroidectomized rats re‐established normal cardiovascular reactivity and development of hypertension.

Cardiovascular reactivity to angiotensin II was not affected in parathyroidectomized rats and was lowered in thyroparathyroidectomized thyroxine‐treated rats.