bluuebunny/crossref_metadata_2025 huggingface dataset:
ATTENUATION OF PETHIDINE‐INDUCED ANTINOCICEPTION BY ZIMELIDINE, AN INHIBITOR OF 5‐HYDROXYTRYPTAMINE REUPTAKE
Authors: GEBHART G.F. , LORENS STANLEY A.
Published: July 2012

The effect of selective inhibition of 5‐hydroxytryptamine (5‐HT) re‐uptake by fluoxetine and zimelidine on morphine‐ and pethidine‐induced antinociception was studied in rats. The hot plate (55°C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception.

Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base).

Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine‐induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine‐induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine.

These and other results support (a) a role for 5‐HT in the expression of morphine‐induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5‐HT in pethidine‐induced antinociception remains unclear.
A MODEL OF REFLEX TRACHEAL CONSTRICTION IN THE DOG
Authors: ALLOTT C.P. , EVANS D.P. , LOVEDAY B.E. , MARSHALL P.W.
Published: July 2012

A tracheal pouch with its nerve and blood supply intact has been prepared in situ in dogs.

Mechanical stimulation of the upper airways in dogs anaesthetized with chloralose induced a consistent increase in pouch pressure which was abolished by bilateral vagal section.

The response of the pouch following mechanical stimulation of the airways was abolished by intravenous pentobarbitone, atropine, administered systemically or when present in the pouch, and tetracaine, applied to the stimulus area or when present in the pouch.

Salbutamol had no inhibitory effects on the response regardless of its route of administration.

These results suggest that the increase in pouch pressure following mechanical stimulation of the upper airways is mediated by a vagal reflex arc.

The technique may distinguish between drugs the site of action of which is at the afferent or efferent end of this reflex arc.
COMPARISON OF THE BINDING CHARACTERISTICS OF TRITIATED OPIATES AND OPIOID PEPTIDES
Authors: GILLAN MAUREEN G.C. , KOSTERLITZ H.W. , PATERSON S.J.
Published: July 2012

Binding assays on homogenates of guinea‐pig brain showed that the maximal number of binding sites was different for different tritiated ligands interacting with the opiate receptors.

At 25°C the binding capacity of morphine or dihydromorphine was only about 3 pmol/g fresh brain whereas etorphine and d‐Ala2‐l‐Leu5‐ and d‐Ala2‐l‐Met5‐enkephalin amide had capacities of 13 to 15 pmol/g brain. d‐Ala2‐d‐Leu5‐enkephalin had an intermediate capacity of about 6 pmol/g brain.

The binding capacities of the natural methionine‐ and leucine‐enkephalins measured at 0°C were 5 to 6 pmol/g brain. At this temperature, the binding capacity of dihydromorphine, d‐Ala2‐d‐Leu5‐enkephalin and of the two enkephalin amides was only slightly lower than at 25°C.

In assays in which unlabelled ligand competed with the same labelled ligand, the inhibition constants (K1) were equal to or not more than twice as large as the equilibrium dissociation constant (Kd) determined in saturation assays. In contrast, the K1 of unlabelled dihydromorphine against [3H]‐d‐Ala2‐d‐Leu5‐enkephalin or of unlabelled d‐Ala2‐d‐Leu5‐enkephalin against [3H]‐dihydromorphine were about 20 times higher than the respective Kd values.

When for a given compound the ratio of the K1 value against [3H]‐d‐Ala2‐d‐Leu5‐enkephalin to the K1 value against [3H]‐dihydromorphine (discrimination ratio) is calculated, a high value indicates selectivity in favour of the μ‐receptor and a low value selectivity in favour of the δ‐receptor. The most selective μ‐agonist known so far is normorphine with a discrimination ratio of 70 and the most selective δ‐agonist is d‐Ala2‐d‐Leu5‐enkephalin with a ratio of 0.11. The selectivity of the known antagonists is in favour of the μ‐receptor, since their discrimination ratios are larger than 1, varying between 10 for naloxone and 4 for Mr 2266.
DECREASED CONCENTRATION OF MYOCARDIAL α‐ADRENOCEPTORS WITH INCREASING AGE IN FOETAL LAMBS
Authors: CHENG JOHN B. , CORNETT LAWRENCE E. , GOLDFIEN ALAN , ROBERTS JAMES M.
Published: July 2012

Using [3H]‐dihydroergocryptine, we identified myocardial α‐adrenoceptor binding sites in foetal lambs and demonstrated that the concentration of receptors decreased with increasing foetal age. The presence of the receptor in the foetus correlated with the presence of myocardial α‐adrenergic responsiveness. However, we found neither the α‐receptor binding site nor responsiveness to α‐adrenoceptor stimulation in the myocardium of adult sheep.
FURTHER STUDIES ON THE INHIBITION OF MONOAMINE SYNTHESIS BY MONOFLUOROMETHYLDOPA
Authors: BEY PHILIPPE , JUNG MICHEL J. , KOCH‐WESER JAN , PALFREYMAN MICHAEL G. , SJOERDSMA ALBERT , WAGNER JOSEPH , ZRAÏKA MONIQUE
Published: July 2012

α‐Monofluoromethyldopa (MFMD, RMI 71963), a potent and selective enzyme‐activated irreversible inhibitor of aromatic l‐amino acid decarboxylase produces a substantial and long‐lasting decrease in the catecholamine content of mouse brain, heart and kidney.

Single doses of MFMD reduce the 5‐hydroxytryptamine concentration of mouse brain without altering the tryptophan concentration.

In animals treated with MFMD, peripheral but not brain noradrenaline is restored within 1 h to control levels by an intraperitoneal injection of dopamine.
EVIDENCE FOR TWO TYPES OF EXCITATORY RECEPTOR FOR 5‐HYDROXYTRYPTAMINE IN DOG ISOLATED VASCULATURE
Authors: APPERLEY EIRA , FENIUK W. , HUMPHREY P.P.A. , LEVY G.P.
Published: July 2012

As part of an investigation into the mode of action of anti‐migraine drugs, a study of the excitatory receptors for 5‐hydroxytryptamine (5‐HT) has been carried out in a range of isolated vascular preparations from the dog.

5‐HT contracted the dog isolated femoral artery and saphenous vein over the concentration‐range 1.0 × 10−8to 5.0 × 10−6mol/l.

In the femoral artery methysergide and cyproheptadine were potent, competitive and specific antagonists of the contractile responses to 5‐HT, with pA2 values of 8.52 and 8.55 respectively.

In the saphenous vein, methysergide was only a weak antagonist of 5‐HT. In addition, it was an agonist over the concentration‐range 5.0 × 10−8to 1.0 × 10−5mol/l. Cyproheptadine was a weak and unsurmountable antagonist of contractile responses to 5‐HT and methysergide.

Contractile responses to 5‐HT and methysergide in the saphenous vein were not antagonized by morphine (3.0 × 10−5mol/l), indomethacin (5.0 × 10−5mol/l), phentolamine (5.0 × 10−7mol/l), propranolol (1.0 × 10−6mol/l), atropine (1.0 × 10−6mol/l), mepyramine (1.0 × 10−6mol/l) or cimetidine (1.0 × 10−5mol/l).

In the external carotid and lingual arteries the pattern of activity obtained with methysergide and cyproheptadine was the same as that in the femoral artery, while in the auricular artery the pattern of activity was the same as that in the saphenous vein.

The results are consistent with the hypothesis that there are two types of receptor mediating 5‐HT‐induced vasoconstriction in dog vasculature. One type, characterized by the pattern of activity obtained in the femoral artery, is like the previously described ‘D‐receptor’. The other type, characterized by the pattern of activity obtained in the saphenous vein, has not been described before. The verification of this hypothesis requires the identification of a specific antagonist of 5‐HT and methysergide in the saphenous vein.
EFFECTS OF CHANGES IN THE STRUCTURE OF ENKEPHALINS AND OF NARCOTIC ANALGESIC DRUGS ON THEIR INTERACTIONS WITH μ‐ AND δ‐RECEPTORS
Authors: KOSTERLITZ H.W. , LORD J.A.H. , PATERSON S.J. , WATERFIELD ANGELA A.
Published: July 2012

The activity pattern of analogues of the enkephalins was determined in four parallel assays, the inhibition of the electrically evoked contraction of the guinea‐pig ileum and mouse vas deferens at 36°C and the inhibition of [3H]‐naltrexone and [3H]‐leucine‐enkephalin binding at 0 to 4°C in homogenates of guinea‐pig brain.

The activity pattern was best characterized by the ratio of the potency in the guinea‐pig ileum to that in the mouse vas deferens (G.p.i./M.v.d.) and the ratio of the potency in inhibiting [3H]‐naltrexone binding to that in inhibiting [3H]‐leucine‐enkephalin binding (Nal/Leu).

The enkephalins had low G.p.i./M.v.d. (0.02 to 0.09) and low Nal/Leu (0.05 to 0.18) ratios whereas the corresponding values for morphine were 7.0 and 7.5.

Analogues obtained by substituting d‐Ala for Gly2and d‐Met or d‐Leu for l‐Met5or l‐Leu5showed only minor changes in G.p.i./M.v.d. (0.01 to 0.11) and in Nal/Leu (0.06 to 0.13) ratios.

Analogues in which resistance to enzymatic degradation was brought about by amidation of the C‐terminal carboxylic group or methylation of the amino group of tyrosine or both modifications, had G.p.i./M.v.d. ratios of 1.2 to 5.5 and Nal/Leu ratios of 0.5 to 21. High values (2.1 and 3.4) were found for the potent antinociceptive analogue of Sandoz, Tyr‐d‐Ala‐Gly‐NCH3Phe‐Met(O)‐ol.

In the mouse vas deferens, some of the analogues with high G.p.i./M.v.d. and Nal/Leu ratios were tested for antagonism by naloxone and found to require less than the high concentration needed for the natural enkephalins. C57/BL mice, which have a lowered sensitivity to morphine but a normal response to peptides with low G.p.i./M.v.d. and Nal/Leu ratios, had a lowered sensitivity to analogues with high ratios.

In the alkaloid‐like series of narcotic analgesic drugs, ketobemidone, levorphanol, methadone, etorphine and the antagonist Mr 2266 had lower Nal/Leu ratios (1.0 to 2.8) than morphine, normorphine, naloxone and naltrexone (8 to 12).

It would appear that compounds with low G.p.i./M.v.d. and Nal/Leu ratios interact mainly with δ‐receptors in the brain and peripheral nervous system while compounds with high ratios interact mainly with μ‐receptors. For antinociceptive action μ‐receptors may be more important than δ‐receptors.
POTENTIATION BY DILAZEP OF THE NEGATIVE INOTROPIC EFFECT OF ADENOSINE ON GUINEA‐PIG ATRIA
Authors: FUJITA SHINJI , ISHIDA YUKIO , IZUMI KYOKO , MORITOKI HIDEKI , OHARA MASAYUKI , TAKEI MASAO
Published: July 2012

Dilazep, a coronary dilator, has been reported to potentiate the negative inotropic and negative chronotropic responses of guinea‐pig atria to adenosine. Studies were made on the mechanism of the potentiating action of dilazep with special reference to the degradation and uptake of adenosine.

The negative inotropic actions of adenosine and adenine nucleotides, such as ATP, ADP, AMP and cyclic AMP, on guinea‐pig atria were selectively and dose‐dependently augmented by dilazep at concentrations insufficient to produce any effect alone (0.01 to 1 μm).

Incubation of atrial tissue with 8.8 nm adenosine, containing 0.1 μCi of [3H]‐adenosine, resulted in accumulation of [3H]‐adenosine in the tissue; dilazep (0.01 to 1 μm) inhibited this accumulation.

Adenosine (10 μm to 10 mm) was degraded to inosine and hypoxanthine during incubation with atrial tissue; dilazep (0.1 to 10 μm) retarded the disappearance of adenosine and the formation of inosine and hypoxanthine.

These results suggest that dilazep potentiates the negative inotropic effect of adenosine on guinea‐pig atria by preventing both its accumulation by atrial tissue and degradation by deaminase.
LYSOPHOSPHATIDYLSERINE‐INDUCED RELEASE OF INTRACELLULAR AMINES IN MICE
Authors: BIGON E. , BRUNI A. , MIETTO L. , TOFFANO G.
Published: July 2012

In the presence of mouse plasma, lysophosphatidyl‐serine stimulates histamine secretion from isolated mast cells. The extensive modification of carbohydrate metabolism produced by lysophosphatidylserine in mice was largely prevented by the antihistaminic drug, pyrilamine. However, to prevent completely the change in carbohydrate metabolism induced by lysosphosphatidylserine the administration of an antihistamine and an adrenoceptor antagonist was required. It is concluded that the effect of lysophosphatidylserine in mice is due to release of intracellular amines. Histamine and catecholamines are involved.
INCREASES IN AGGREGATION BY AND UPTAKE OF 5‐HYDROXYTRYPTAMINE WITH PLATELETS FROM RABBITS TREATED WITH CHLORPROMAZINE
Authors: CI M. BALDAC , BALDACCI MARA , BERGEL T.D. , BORN G.V.R. , HICKMAN MARGARET
Published: July 2012

Citrated platelet‐rich plasma was prepared from New Zealand white rabbits before, during and after administration of chlorpromazine (2 mg/kg) intramuscularly once daily for 3 to 4 weeks.

In these plasmas, the velocity of platelet aggregation by 5‐hydroxytryptamine (5‐HT) added at 1, 3 and 10 μm increased greatly, beginning 3 to 4 days after the start of chlorpromazine injections and lasting for a similar period after they were terminated The increase had two maxima, the first after 6 to 10 days and the second after 17 to 24 days. Chlorpromazine treatment did not affect aggregation by adenosine diphosphate (ADP).

The uptake of 5‐HT by rabbit platelets was very fast and linear for less than 10 s. In platelets from untreated rabbits the uptake had a Km of 0.35 ± 0.08 μm and a Vmax of 39.8 ± 6.1 pmol 10−8 platelets 10−1 (n = 5).

In platelets from rabbits injected with chlorpromazine (see (2) above) both kinetic constants increased significantly, the Km to 0.88 ± 0.08 μm and the Vmax to 67.8 ± 5.5 pmol. 10−8 platelets. 10−1 s (n = 9).
PRESYNAPTIC AND POSTSYNAPTIC DEPRESSANT EFFECTS OF PHENYTOIN SODIUM AT THE NEUROMUSCULAR JUNCTION
Authors: GAGE P.W. , LONERGAN M. , TORDA T.A.
Published: July 2012

Phenytoin sodium, 10μg/ml (3.6 × 10−5 m), reduces the amplitude of endplate potentials in mouse sternomastoid neuromuscular junctions.

The reduction in amplitude is due to a reduction both in the quantal content of endplate potentials and in the amplitude of the voltage response to quanta of acetylcholine.

The reduction caused by phenytoin in the amplitude of spontaneous miniature end plate potentials was due to a reduction in the time constant of decay of miniature endplate currents.

It is concluded that phenytoin depresses neuromuscular transmission by reducing both the amount of acetylcholine secreted in response to an action potential and by reducing the lifetime of postsynaptic channels activated by acetylcholine.
THE DISTRIBUTION OF ADRENOCEPTORS AND OTHER DRUG RECEPTORS BETWEEN THE TWO ENDS OF THE RAT VAS DEFERENS AS REVEALED BY SELECTIVE AGONISTS AND ANTAGONISTS
Authors: MacDONALD A. , McGRATH J.C.
Published: July 2012

The effects of adrenoceptor agonists and other agonists on the contractile responses of the prostatic and epididymal portions of the rat isolated vas deferens to single pulse field stimulation were investigated.

α‐Adrenoceptor agonists produced prejunctional α2‐mediated inhibition and post‐junctional α1‐mediated potentiation of the nerve‐induced responses. Guanabenz and xylazine produced mainly inhibitory effects, xylazine being 10 times less potent. Clonidine and oxymetazoline produced inhibition with similar potency to guanabenz but at higher concentrations excitatory effects were present, particularly in the epididymal portion. Phenylephrine produced only potentiation of the nerve‐induced response in both portions. Potentiation of nerve‐induced responses was a more sensitive and quantitative index of excitation than was direct contraction of the tissue.

Isoprenaline and salbutamol both gave β2‐mediated inhibition of the nerve‐induced responses in both portions of tissue. At least part of the effect was post‐junctional since phenylephrine contractions were inhibited. Isoprenaline also produced a post‐junctional α1‐mediated excitation.

Noradrenaline produced effects qualitatively similar to those of the other α‐adrenoceptor agonists, inhibition and excitation predominating in the prostatic and epididymal ends respectively.

Morphine produced inhibition in the mouse but not in the rat vas deferens. In rat vas, however, enkephalin analogues produced pre‐junctional inhibition of responses in both portions which could be partly reversed by naloxone; restoration of the adrenergic component was more complete. Rat anococcygeus showed no equivalent effect.

Adenosine 5′‐triphosphate (ATP) inhibited nerve‐induced responses in each portion with a greater effect on the prostatic portion.
EFFECT OF INDOMETHACIN ON HYDRALAZINE‐INDUCED RENIN AND CATECHOLAMINE RELEASE IN THE CONSCIOUS RABBIT
Authors: CAMPBELL WILLIAM B. , GRAHAM ROBERT M. , JACKSON EDWIN K. , LOISEL DANIEL P. , PETTINGER WILLIAM A.
Published: July 2012

The effects of hydralazine on mean arterial pressure (MAP) heart rate (HR), plasma renin activity (PRA) and plasma catecholamines were examined in conscious rabbits before and after prostaglandin synthesis inhibition with indomethacin.

Hydralazine (3 mg/kg, i.v.) produced a 12% decrease in MAP and significant increases in HR, PRA and plasma noradrenaline and adrenaline.

Indomethacin (5 mg/kg, s.c.) failed to alter significantly the control MAP, HR, PRA or plasma catecholamines but inhibited renal venous prostaglandin E2 by 56% (P < 0.02).

Indomethacin inhibited the hydralazine‐induced tachycardia by 24% and augmented its hypotensive effects by 6%.

The hydralazine‐stimulated increase in PRA was also inhibited 75% (P < 0.001) by indomethacin whereas noradrenaline and adrenaline concentrations were not significantly reduced.

Indomethacin inhibits hydralazine‐induced renin release in the presence of elevated concentrations of plasma catecholamines; these findings suggest that renal prostaglandins function as important mediators of sympathetically‐induced renin release.
EFFECT OF LOW‐DOSE LITHIUM ADMINISTRATION AND SUBSEQUENT WITHDRAWAL ON BIOGENIC AMINES IN RAT BRAIN
Authors: AHLUWALIA P. , SINGHAL R.L.
Published: July 2012

The effects of low‐dose lithium administration (2 mEq/kg, daily) and its subsequent withdrawal have been examined with reference to changes in biogenic amine systems in several discrete regions of rat brain.

Increased levels of striatal tyrosine and midbrain tryptophan were found following lithium administration together with slight decreases in striatal tyrosine hydroxylase and midbrain tryptophan hydroxylase activities. Withdrawal resulted in a decrease in tyrosine content with increased tyrosine hydroxylase activity, whilst tryptophan levels and tryptophan hydroxylase activity were increased.

Lithium treatment and withdrawal resulted in altered levels of noradrenaline and dopamine, these changes being regionally variable. 3‐Methoxy‐4‐hydroxyphenylglycol content was depressed in both treated and withdrawal rats as were 3,4‐dihydroxyphenylacetic acid levels. Homovanillic acid decreased as a result of lithium treatment, but was greatly elevated in the withdrawal group.

5‐Hydroxytryptamine content decreased in some brain regions following lithium treatment with return towards control values in withdrawal rats. 5‐Hydroxyindoleacetic acid levels also displayed a regional variation as a result of lithium treatment and withdrawal.

The implications of these observations in elucidating the pharmacological effect of lithium treatment and its subsequent withdrawal are discussed.
INHIBITION BY NICOTINE OF THE FORMATION OF PROSTACYCLIN‐LIKE ACTIVITY IN RABBIT AND HUMAN VASCULAR TISSUE
Authors: SONNENFELD T. , WENNMALM Å.
Published: July 2012

Rings of vascular tissue (from rabbit aorta or human peripheral vein) were incubated at room temperature in Tyrode solution in the absence or presence of nicotine or indomethacin.

Addition of portions of the incubates to human platelet‐rich plasma (HPRP) elicited a decrease in adenosine 5′‐diphosphate (ADP)‐induced platelet aggregation in this plasma. Authentic prostacyclin (PGI2) also induced such a decrease. The decreased aggregation amplitudes that followed the addition of the vascular tissue incubates and of PGI2 were equally potentiated by theophylline (10−4 m).

Both nicotine and indomethacin counteracted the formation of platelet anti‐aggregatory activity in the vascular tissue incubates. The IC50s of nicotine and of indomethacin on the formation of platelet antiaggregatory activity were 2 times 10−5 m and 6 times 10−6 m, respectively.

Nicotine failed to affect the platelet anti‐aggregatory effect induced by authentic PGI2 in HPRP.

It is concluded that nicotine counteracts the formation of platelet anti‐aggregatory activity in rabbit aorta and human peripheral vein by eliciting an inhibitory effect on the bioformation of prostacyclin in these types of vascular tissue.
EVALUATION OF ANTAGONISM OF ACONITINE‐INDUCED DYSRHYTHMIAS IN MICE AS A METHOD OF DETECTING AND ASSESSING ANTIDYSRHYTHMIC ACTIVITY
Authors: WINSLOW EILEEN
Published: July 2012

Antagonism of aconitine‐induced dysrhythmias in mice as a method of detecting and assessing antidysrhythmic activity was evaluated.

Aconitine‐induced dysrhythmias in mice appear to be selectively sensitive to antidysrhythmic agents (administered intraperitoneally) which reduce the inward sodium current in cardiac cells.

Antidysrhythmic agents whose mechanism of action is thought to depend on β‐adrenoceptor blockade, prolongation of cardiac monophasic action potentials or calcium antagonism are ineffective in delaying the onset of aconitine‐induced dysrhythmias in mice. The inactive drugs were practolol, sotalol, bretylium, amiodarone and verapamil.

Comparisons of anti‐dysrhythmic activities of test drugs should be based on more than one ED value and should take account of efficacy as well as potency.

The mouse aconitine test is a useful and rapid method of evaluating oral antidysrhythmic activity in terms of potency, efficacy and duration of action.

With respect to potency, efficacy, oral activity, duration of action and safety, 3α‐amino‐5α‐androstan‐2β‐ol‐17‐one hydrochloride (Org 6001) offered the most satisfactory overall profile of the active drugs tested (Org 6001, aprindine, quinidine, disopyramide, lignocaine, mexiletine, procainamide and propranolol).
LUTEINIZING HORMONE‐RELEASING FACTOR AND MUSCARINIC AGONISTS ACT ON THE SAME VOLTAGE‐SENSITIVE K+ ‐CURRENT IN BULLFROG SYMPATHETIC NEURONES
Authors: ADAMS P.R. , BROWN D.A.
Published: July 2012

The effect of bath‐applied luteinizing hormone‐releasing factor (LHRF) was recorded in voltage‐clamped bullfrog lumbar sympathetic neurones. At a holding potential of −30 mV, LHRF induced a steady inward (depolarizing) current and reduced membrane conductance; at −60 mV LHRF produced negligible inward current and much less conductance change. The effects of LHRF were accompanied by a reduced amplitude of the slow current relaxations following hyperpolarizing and depolarizing commands, without prominent change in their time‐course. This suggests a selective depression of the voltage‐sensitive outward K+ ‐current which is suppressed by muscarinic agonists.
ANTAGONISM BY FENAMATES OF PROSTAGLANDIN ACTION IN GUINEA‐PIG AND HUMAN ALIMENTARY MUSCLE
Authors: BENNETT A. , PRATT D. , SANGER G.J.
Published: July 2012

Low concentrations of meclofenamate, flufenamate or mefenamate had little effect on contractions in response to acetylcholine in any tissue studied.

Sodium meclofenamate potently antagonized contractions of guinea‐pig ileum longitudinal muscle to prostaglandin E2 (PGE2), PGF2α or PGD2.

In guinea‐pig colonic longitudinal muscle, contractions to PGE2 were reduced by sodium meclofenamate, but contractions of the longitudinal or circular muscle to PGF2α or PGD2 were less effectively inhibited.

In human gastrointestinal longitudinal muscle, sodium meclofenamate or flufenamate potently inhibited contractions to PGF2α, but not to PGE2.

Sodium mefenamate or mefenamic acid, even in high concentrations, had little effect on contractions to PGF2α, but tended to inhibit PGE2‐induced contractions of human gastrointestinal longitudinal muscle.

The therapeutic advantages of prostaglandin synthesis inhibitors which also antagonize responses to certain prostaglandins are discussed.
THE EFFECT OF SODIUM SALICYLATE ON CEREBRAL BLOOD FLOW AND METABOLISM
Authors: PICKARD J.D. , ROSE J.E. , SHAW M.D.M. , STRATHDEE ANN
Published: July 2012

The effect of intravenous sodium salicylate on cerebral oxygen consumption and cerebral blood flow and its response to hypercapnia was measured by the 133Xenon intracarotid injection technique in ten baboons.

After an initial peak, the plasma salicylate level maintained a stable value for 2 h of 1 mmol/l with 50 mg/kg sodium salicylate and 2.5 mmol/l with 200 mg/kg sodium salicylate.

Sodium salicylate (50 mg/kg) produced no change in baseline cerebral blood flow (CBF) or cerebral oxygen consumption (CMRO2) but the CBF response to hypercapnia was reduced by 41% during the first hour. During the second hour after salicylate administration, CMRO2 increased by 26%, CBF at normocapnia increased by 31% and the CBF response to hypercapnia was 67% of the baseline value.

Sodium salicylate (200 mg/kg) increased CMRO2 by 65%. There was no significant change in CBF at normocapnia or hypercapnia.

These results confirm that inhibitors of prostaglandin synthesis, which can cross the blood brain barrier in sufficient quantity, reduce the response of the cerebral circulation to hypercapnia. The difficulties in interpreting changes in the CBF CO2 response in the presence of increases in CMRO2 are discussed. It is suggested that the respiratory stimulation seen in salicylate intoxication is the result of a central metabolic stimulation.
SUBACUTE CANNABINOID TREATMENT: ANTICONVULSANT ACTIVITY AND WITHDRAWAL EXCITABILITY IN MICE
Authors: KARLER RALPH , TURKANIS STUART A.
Published: July 2012

The effects of subacute treatment with cannabidiol, Δ9‐tetrahydrocannabinol (Δ9‐THC), phenytoin and phenobarbitone on anticonvulsant activity and on withdrawal excitability in mice were compared in three electrically induced seizure‐threshold tests.

In the maximal electroshock‐threshold test, subacute treatment did not alter the anticonvulsant activity of cannabidiol, phenytoin or phenobarbitone, but tolerance developed to Δ9‐THC.

In the 60 Hz electroshock‐threshold test, the activity of Δ9‐THC and cannabidiol did not change, but tolerance developed to phenobarbitone, and there was an increase in sensitivity to phenytoin.

In the 6 Hz electroshock‐threshold test, there was an increase in sensitivity to both Δ9‐THC and cannabidiol, there was tolerance to phenobarbitone, while the activity of phenytoin did not change.

Although tolerance developed in some of the seizure‐threshold tests to Δ9‐THC and phenobarbitone, tolerance to cannabidiol and phenytoin did not develop in any of the tests.

Hyperexcitability followed withdrawal from only Δ9‐THC (6 Hz and 60 Hz electroshock‐threshold tests) and phenobarbitone (maximal electroshock‐threshold and 60 Hz electroshock‐threshold tests).

The Δ9‐THC withdrawal hyperexcitability suggests that the use of marihauana may jeopardize the control of seizures in epileptics.
THE BINDING OF SOME ANTIDEPRESSANT DRUGS TO BRAIN MUSCARINIC ACETYLCHOLINE RECEPTORS
Authors: GOLDS P.R. , PRZYSLO F.R. , STRANGE P.G.
Published: July 2012

The binding of some antidepressant drugs, including some new drugs of atypical structure (flupenthixol, iprindole, maprotiline, mianserin, nomifensine, tofenacine and viloxazine) to muscarinic acetylcholine receptors in the brain has been studied by displacement of [3H]‐atropine.

Many of the drugs are potent muscarinic antagonists.

Some correlation can be made between the affinity for binding to the muscarinic acetylcholine receptor and the incidence of anticholinergic side effects in clinical usage.
MORPHINE‐THEOPHYLLINE INTERACTION: ANTAGONISM OR FACILITATION?
Authors: BRAILOWSKY SIMÓN , GUERRERO‐MUN̆OZ FEDERICO , LUJÁN MIGUEL , SHKUROVICH MARIO
Published: July 2012

Morphine‐theophylline interactions were investigated in both acute and narcotic‐dependent preparations, in vitro and in vivo, using four different experimental models: LD50 doses of morphine and naloxone in the mouse; naloxone‐induced contractions in the electrically‐stimulated and opiate‐dependent isolated ileum of the guinea‐pig; naloxone‐induced jumps in the mouse; and calcium uptake in synaptosomal preparations.

The LD50 of morphine was significantly increased by theophylline.

The lethal effect of theophylline was potentiated by pretreatment of the animals with naloxone.

Theophylline displayed protective effects in the inhibitory response to morphine and antagonism to the withdrawal response induced by naloxone in the electrically‐stimulated isolated ileum of the guinea‐pig.

The number of jumps induced by naloxone in morphine‐dependent mice was significantly diminished by theophylline.

The inhibitory effect of morphine on the synaptosomal uptake of calcium was decreased by theophylline.

The effects of both morphine and theophylline on the cyclic nucleotides and the possible role of calcium in these actions are discussed.
EFFECTS OF CYCLIC AMP‐ AND CYCLIC GMP‐PHOSPHODIESTERASE INHIBITORS ON IMMUNOLOGICAL RELEASE OF HISTAMINE AND ON LUNG CONTRACTION
Authors: FROSSARD N. , LANDRY Y. , PAULI G. , RUCKSTUHL M.
Published: July 2012

Cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP)‐ and cyclic guanosine 3′, 5′‐monophosphate (cyclic GMP)‐phosphodiesterase activities from rat lung were selectively inhibited by ZK 62711 and M & B 22948, respectively. Theophylline and papaverine inhibited both activities.

Rat lung strips contracted by carbachol were relaxed by 4‐(3‐cyclopentyloxy‐4‐methoxyphenyl)‐2‐pyrrolidone (ZK 62711, EC25 = 7 × 10−8m) and 2‐O‐propoxyphenyl‐8‐azapurin‐6‐one (M&B 22948, EC25 = 5 × 10−7m) indicating relaxant properties of both cyclic AMP and cyclic GMP.

The antigen‐induced histamine release from human basophils was inhibited by ZK 62711 (IC25 = 8 × 10−7m), whereas M&B 22948 had no effect. On the contrary, the release from rat mast cells was inhibited by M&B 22948 (IC25 = 10_6m), while ZK 62711 had no effect.

These data show an inhibitory effect of cyclic AMP on histamine release to be involved with basophils, whereas cyclic GMP is predominantly involved with mast cells. It is suggested that the antianaphylactic properties of cyclic nucleotide phosphodiesterase inhibitors are mainly linked to the increase of cyclic GMP.
NON‐ADRENERGIC, NON‐CHOLINERGIC INNERVATION IN MONKEY AND HUMAN CEREBRAL ARTERIES
Authors: TODA NOBORU
Published: July 2012

Transmural electrical stimulation (0.5 to 20 Hz) and nicotine (10−4 m) produced relaxations of helically‐cut strips of monkey and human cerebral arteries, contracted with prostaglandin F2α.

The relaxation induced by electrical stimulation was suppressed or abolished by tetrodotoxin, while the nicotine‐induced relaxation was abolished by hexamethonium but was unaffected by tetrodotoxin. Both relaxations were not attenuated by β‐adrenoceptor antagonists and atropine.

These findings may indicate that large cerebral arteries of the monkey and man are innervated by non‐adrenergic, non‐cholinergic nerves, excitation of which liberates unknown vasodilator substance(s).
ACTIONS OF VARIOUS MUSCARINIC AGONISTS ON MEMBRANE POTENTIAL, POTASSIUM EFFLUX, AND CONTRACTION OF LONGITUDINAL MUSCLE OF GUINEA‐PIG INTESTINE
Authors: BOLTON T.B. , CLARK J.R
Published: July 2012

Depolarizations were recorded intracellularly in smooth muscle from the taenia of the guinea‐pig caecum in response to the iontophoretic application of acetylcholine, carbachol, oxotremorine‐M, methylfurmethide, hexyl trimethylammonium and tetramethylammonium (TMA).

No differences between the iontophoretic responses to agonists stable to cholinesterase were detected.

The latency and time to peak of acetylcholine‐induced depolarizations were less than those to stable agonists, and the response was briefer and less complex in shape. These differences were reduced, or disappeared, upon inhibition of cholinesterase.

The rate of loss of 42K and changes in length were measured in superfused strips weighing about 10 mg of separated longitudinal muscle of guinea‐pig ileum.

Acetylcholine, carbachol, methylfurmethide, butyltrimethylammonium and TMA contracted the muscle and increased the rate of loss of 42K.

Contrary to previous reports, no evidence of a selective action of any of these agonists on 42K loss was detected. TMA appeared to be a partial agonist in evoking 42K loss, although it produced a maximum contraction.

The maximum 42K efflux produced by acetylcholine was about 40% of the maximum evoked by application of carbachol or methylfurmethide. If cholinesterase was inhibited, the 42K efflux evoked by maximally effective concentrations of acetylcholine was comparable to that evoked by a stable agonist.

These results are consistent with the idea that the muscarinic agonists used interact in an essentially similar way with muscarinic receptors to produce their effects on membrane potential, permeability, and tension.
ACTIONS OF THE CRUDE VENOM OF THE SYDNEY FUNNEL‐WEB SPIDER, Atrax robustus ON AUTONOMIC NEUROMUSCULAR TRANSMISSION
Authors: HARRIS J.B. , SUTHERLAND S. , ZAR M.A.
Published: July 2012

The effects on mammalian autonomic neuromuscular transmission of the crude venom of the female Sydney funnel‐web spider Atrax robustus, have been investigated.

At doses of 10 μg/ml or lower the indirectly elicited twitch‐like responses of the rat anococcygeus preparation were inhibited. At doses greater than 10 μg/ml there was an initial reduction in the twitch‐like response followed by a sustained contracture of the tissue.

The long‐lasting contracture caused by the venom was abolished by the application of phentolamine. It was virtually non‐existent in muscle preparations isolated from reserpine‐treated rats.

In the presence of tetrodotoxin the contracture was smaller and less well maintained than in its absence.

The venom caused a small reduction in the amplitude of the indirectly elicited twitch‐like response of the longitudinal muscle of the guinea‐pig ileum, followed by an increase in the tone of the preparation. The increase in tone was maintained for several minutes and was rapidly abolished by the application of atropine. The presence of venom did not affect control responses to either histamine or acetylcholine.

Inhibitory transmission in the rat anococcygeus preparation was unaffected by the venom.

The neurally‐mediated twitch‐like responses of both guinea‐pig and rat vas deferens were inhibited by the venom at doses below 10 μg/ml. At higher doses the inhibition was accompanied by spontaneous contractions, and at doses in excess of 100 μg/ml the inhibition of twitch‐like responses was transient and was followed by a potentiation of the motor response and extensive spontaneous activity. The preparation became quiescent 20 min after the application of venom and the evoked response was abolished after 60 min.

The venom had qualitatively similar effects on motor transmission in the human vas deferens as on the rat and guinea‐pig preparations. However, the human preparations were 50 to 100 times more sensitive to the effects of the venom.
SELECTIVE DEPRESSION OF SYNAPTIC EXCITATION IN CAT SPINAL NEURONES BY BACLOFEN: AN IONTOPHORETIC STUDY
Authors: DAVIES JOHN
Published: July 2012

The effects of baclofen have been examined on responses of neurones in the spinal cord of the anaesthetized cat to stimulation of appropriate synaptic pathways, acetylcholine and a range of amino acid excitants. Baclofen and excitant substances were administered by standard microiontophoretic techniques.

Small ejecting currents of baclofen (<10 na) depressed non‐cholinergic, excitatory, synaptic responses evoked by stimulation of dorsal roots or muscle or cutaneous afferents. Excitatory monosynaptic responses were particularly sensitive to the depressant action of baclofen.

Spontaneous firing in neurones was sometimes reduced in parallel with synaptic excitatory responses, but synaptically evoked inhibition was unaffected and ventral root evoked excitation of Renshaw cells was either unaffected or enhanced by baclofen.

Ejecting currents of baclofen which markedly depressed excitatory synaptic responses either had no effect or minimal depressant effects on responses induced by iontophoretically administered acetylcholine and excitant amino acids. However, relatively large currents of baclofen (e.g. 20 to 40 na) reduced excitatory responses to exogenously administered excitants.

It is suggested that baclofen depresses (a) synaptic response by an action on excitatory nerve terminals and (b) responses to exogenous excitants via a postsynaptic action.

Comparison of baclofen with a number of other substances indicates that the depression of noncholinergic, excitatory, synaptic responses is unlikely to involve an interaction of this agent with receptors for monoamines, 5‐hydroxytryptamine or the inhibitory amino acids, γ‐aminobutyric acid and glycine.
INSULIN‐INDUCED ENHANCEMENT OF UPTAKE OF NORADRENALINE IN ATRIAL STRIPS
Authors: BHAGAT B. , BURKE W.J. , DHALLA N.S.
Published: July 2012

Addition of insulin to the organ bath increased the force of contraction of guinea‐pig left atrial strips driven electrically at 1 Hz

The positive inotropic response to insulin remained unaltered in atria depleted of catecholamine or when β‐adrenoceptors were blocked by addition of propranolol to the organ bath

The response of isolated atria to noradrenaline was significantly reduced in the presence of insulin

Insulin affected neither the calcium accumulating abilities of the heart sarcolemma, mitochondria or microsomes, nor the cyclic adenosine 3′, 5′‐monophosphate (cyclic‐AMP)‐protein kinase‐induced stimulation of microsomal calcium uptake

Addition of insulin to the organ bath enhanced significantly the ability of the cardiac tissue to take up [3H]‐noradrenaline as well as [3H]‐metaraminol. The activities of monoamine oxidase and catechol‐O‐methyl transferase were not changed after addition of insulin to homogenates of the heart

The ability of insulin to facilitate uptake of noradrenaline would be expected to cause a decrease in the amount of the amine reaching the receptors, thus leading to a diminished response to this amine. This may explain, at least in part, insulin‐induced subsensitivity to noradrenaline

This view is supported by the observation that after blockade of amine uptake by destruction of nerve terminals, insulin failed to reduce the positive inotropic response to noradrenaline.
THE INFLAMMATORY EFFECTS OF HYDROPEROXY AND HYDROXY ACID PRODUCTS OF ARACHIDONATE LIPOXYGENASE IN RABBIT SKIN
Authors: HIGGS G.A. , SALMON J.A. , SPAYNE J.A.
Published: July 2012

The inflammatory effects of hydroperoxy (HPETE) and hydroxy (HETE) acids, synthesized by arachidonic acid lipoxygenases, have been investigated in rabbit skin

High doses (10–20 μg) of 5‐, 12‐ or 15‐HPETE or the 5, 12‐di‐hydroxy acid, leukotriene B4 (0.1‐1 μg), caused small but significant increases in plasma exudation following intra‐dermal injection

Leukotriene B4 was equipotent with prostaglandin E2 and prostacyclin in potentiating bradykinin‐induced plasma exudation, and was 100 times more active in this property than any other lipoxygenase product tested

Leukotriene B4‐induced plasma exudation was enhanced by prostaglandin E2

The mono‐HETEs were relatively inactive in causing or enhancing plasma exudation

Leukotriene B4 (0.1 μg) or prostaglandin E1 (1.0 μg) significantly elevated leukocyte accumulation in rabbit skin, whereas PGE2, 5‐HPETE, 5‐HETE, 12‐HPETE or 12‐HETE were inactive at doses up to 1 μg.
METABOLITES OF ARACHIDONIC ACID FORMED BY HUMAN GASTROINTESTINAL TISSUES AND THEIR ACTIONS ON THE MUSCLE LAYERS
Authors: BENNETT A. , HENSBY C.N. , SANGER G.J. , STAMFORD I.F.
Published: July 2012

Gas chromatography‐mass spectrometry demonstrated the presence of arachidonic acid (AA), 6‐keto‐prostaglandin F1α and thromboxane B2 (TxB2) in all extracts of homogenized muscle or mucosa from human stomach, terminal ileum or sigmoid colon. Prostaglandin D2 (PGD2), PGE2 or PGF2α were usually found more often in the mucosal extracts. The 12‐hydroxy‐derivative of AA (12‐HETE) was detected in all extracts of the colon but in only some of the other tissues

Most prostanoids tested contracted the longitudinal muscle, the order of potency being U‐46619 (an epoxymethano analogue of PGH2)>PGE2>PGF2α>PGD2; PGI2 usually caused relaxation, whereas its breakdown products or TxB2 had weak and variable effects

U‐46619 or, less potently, PGF2α contracted the circular muscle, whereas PGI2 and usually PGE2 caused relaxation. PGD2, 6‐keto‐PGF1α, 6, 15‐diketo‐PGF1α or TxB2 usually had little or no effect

PGI2 antagonized contractions to some excitatory prostanoids, without greatly affecting contractions to acetylcholine

For both muscle layers there was a gradient in sensitivity to prostanoids along the gastrointestinal tract. The sensitivities were stomach>distal ileum>sigmoid colon

The results are discussed in relation to gastrointestinal physiology and pathophysiology.
TWO TYPES OF γ‐AMINOBUTYRIC ACID RECEPTOR ON EMBRYONIC SENSORY NEURONES
Authors: DUNLAP KATHLEEN
Published: July 2012

Embryonic sensory neurones of the chick grown in dissociated cell culture respond to application of low concentrations of γ‐aminobutyric acid (GABA) with a change in resting membrane resistance (Rin) and/or a change in action potential duration (APD) (Dunlap & Fischbach, 1978; Choi & Fischbach, 1981). Intracellular microelectrode recording techniques were employed to determine if these two effects are mediated by the same, or different, GABA receptors.

Cells responded, for the most part, with a change in either Rin or APD, but 10% of the cells exhibited both effects. In the latter cells the two responses were clearly distinguishable as discussed below.

The proportion of neurones exhibiting a GABA‐induced decrease in Rin declined during the first week in vitro while the proportion exhibiting a decrease in APD increased during that time.

The two effects were pharmacologically distinct. Muscimol, a GABA analogue, produced only the change in Rin (ED50 = 5.5 μm) while baclofen, another analogue of GABA, produced only the change in APD (ED50 = 1 μm). The analogues were approximately equipotent with GABA. Bicuculline, a GABA antagonist, blocked the muscimol‐induced change in Rin (but not the baclofen‐induced change in APD) in a dose‐dependent fashion with an ID50 = 0.7 μm.

The time courses of the two effects were different. The change in APD resulting from a brief application of GABA (or baclofen) was prolonged relative to the rapid return to control associated with the GABA‐ (or muscimol‐) induced change in Rin.

Desensitization of the two responses exhibited separate time courses. In the continual presence of the agonists, GABA‐ and muscimol‐induced decreases in Rin completely desensitized in ca. 10 s while GABA‐ and baclofen‐induced decreases in APD persisted undiminished throughout a prolonged (1 min) application of the drugs and returned to control only after cessation of application.

It is concluded that embryonic chick sensory neurones in culture exhibit two types of GABA receptor that differ in their functional and pharmacological properties. Implications of these results are discussed.
ACUTE EFFECTS OF PROPRANOLOL ON THE CIRCULATION AND ON OXYGEN UPTAKE IN CONSCIOUS RATS
Authors: LEDINGHAM JOHN M. , LEES DOUGLAS C.P.
Published: July 2012

The acute effect of orally administered propranolol (100 mg/kg) on blood pressure, heart rate, cardiac output, venous pressure, haemoglobin concentration and oxygen uptake was studied in conscious rats.

Oxygen uptake was measured in a closed circuit respirometer and cardiac output determined by the direct Fick method. Other variables were measured by means of chronically implanted cannulae.

Significant falls occurred in heart rate (8.9%), cardiac output (30.5%), derived stroke volume (21.3%) and oxygen uptake (12.2%).

There were significant rises in arterial blood pressure (12.9%), derived arterial resistance (69%), arterio‐venous oxygen difference (31.5%) and arterial haemoglobin concentration (6.3%).

A rise in venous pressure occurred in lightly anaesthetized rats but was only of borderline significance.

Correlations between the different variables revealed only one significant relationship, between heart rate and oxygen uptake.

It is concluded that only one primary site of action of propranolol has to be postulated to account for these findings, that of the well known negative inotropic and chronotropic effect on the heart.
THE CALCIUM ANTAGONISTIC EFFECTS OF CYPROHEPTADINE ON CONTRACTION, MEMBRANE ELECTRICAL EVENTS AND CALCIUM INFLUX IN THE GUINEA‐PIG TAENIA COLI
Authors: LOWE1 D.A. , MATTHEWS E.K. , RICHARDSON B.P.
Published: July 2012

The ability of cyproheptadine (Cph) to inhibit membrane translocation of calcium in smooth muscle was investigated by studying the drug's action on contraction, electrical activity and calcium influx in the guinea‐pig taenia coli.

Cph>10−6M reduced the amplitude of normal spontaneous contractions and concurrently decreased the number of action potentials occurring with each slow‐wave of depolarization (sucrose‐gap recordings). These inhibitory effects of Cph were antagonized by increasing the medium [Ca] three fold to 7.68 mM.

Intracellular recordings showed that Cph>2 × 10−6M decreased the amplitude and extended the duration of the action potential. These effects were only partially reversible in normal medium whereas large overshooting action potentials were again seen in 7.68 mM Ca medium.

High frequency mechanical activity was produced by inclusion of veratridine 5 × 10−6M in the perfusate. Low concentrations of Cph (> 10−7m) reduced the amplitude of such contractions at a faster rate than they did normal spontaneous contractions.

At concentrations between 10−7 and 10−6M, Cph fully reduced the tonic component of contractions elicited in 112 mM isotonic KC1 whilst having little or no effect on either (i) the initial phasic KC1 contraction or (ii) the ‘repolarization contracture’ normally produced on wash‐out of the KC1 or (iii) the spontaneous contractions before and after KC1 treatment. In contrast, at Cph 2 × 10−6M, the repolarization contracture, as well as the isotonic KC1 contraction, was totally blocked whereas spontaneous contractions were still unaffected. Progressively higher Cph concentrations inhibited all components of this contractile cycle.

Dose‐response curves for the rate of drug‐induced relaxation of tonic contractures produced in hypertonic 42.7 mM high‐potassium medium, showed the calcium antagonistic potency of Cph to be intermediate between that of chlorpromazine and D600. The minimum Cph concentration for effect lay between 1 and 5 × 10−7M, and the effects of Cph 2 × 10−6M (approximately the ID50) were totally antagonized by 12.8 mM Ca.

By means of a lanthanum wash procedure, Cph>2 × 10−6M was found to decrease the 45Ca uptake occurring into strips of taenia coli in normal medium, although the maximum effect (at Cph 10−5m) amounted to only 25 % inhibition of the uptake occurring into control strips (also found with D600). The increased uptake occurring in hypertonic 44.7 mM high‐potassium medium was inhibited in a dose‐dependent manner by Cph 1 × 10−7M.

The results are consistent with an action of Cph in reducing the flow of Ca2+ through voltage‐dependent Ca channels in the smooth muscle cell membrane. It is suggested that the interaction of Cph molecules with such sites is dependent upon membrane potential as well as drug concentration.