bluuebunny/crossref_metadata_2025 huggingface dataset:
GUANETHIDINE‐INDUCED VASODILATATION IN THE RABBIT, MEDIATED BY ENDOGENOUS HISTAMINE
Authors: ANGUS J.A. , BOBIK A. , KORNER P.I. , STONEHAM M.T.
Published: July 2012

The effects of guanethidine (0.5–4 mg/kg i.v.) on arterial pressure, hindlimb blood flow and hindlimb vascular resistance (HVR) were studied in unanaesthetized rabbits subjected to ‘total’ autonomic block.

Evidence that this response was mediated by histamine release was that (a) 3H‐labelled histamine levels in the hindlimb venous blood rose substantially after guanethidine; (b) infusion of exogenous histamine caused an inhibition of the guanethidine‐induced vasodilatation; and (c) competitive antagonism of the response was obtained with the H2‐antagonist burimamide.

There was good correlation between the [3H]‐histamine release and the time course of the vasodilator response. Glyceryl trinitrate infusions that lowered HVR substantially, did not cause release of histamine.

Reserpine, desipramine and indomethacin pretreatment did not alter the vasodilator response to guanethidine.

The guanethidine vasodilator response was not influenced by the H1‐antagonist mepyramine or by the other H2‐antagonists, metiamide or cimetidine. The vascular receptors stimulated by endogenous histamine may be distinctive from those stimulated by exogenous histamine, or the action of guanethidine may involve greater production of histamine at an intracellular site that is more readily reached by burimamide than by the other H2‐antagonists.
CAN SOCIAL INTERACTION BE USED TO MEASURE ANXIETY?
Authors: FILE SANDRA E. , HYDE J.R.G.
Published: July 2012

Pairs of male rats were placed in a test box for 10 min and the time they spent in active social interaction was scored. Maximum active interaction was found when the rats were tested under low light in a box with which they were familiar. When the light level was increased or when the box was unfamiliar active social interaction decreased.

Exploration (time spent sniffing objects) decreased in the same way in relation to test conditions as did social interaction. As these decreased, defecation, and freezing increased.

Anosmic controls showed that the decrease in social interaction across test conditions could not be attributed to olfactory changes in the partner.

Chlordiazepoxide (5 mg/kg) given chronically prevented or significantly reduced the decrease in social interaction that occurred in undrugged rats as the light level or the unfamiliarity of the test box was increased. Controls showed that this effect could not be entirely attributed to chlordiazepoxide acting selectively to increase low levels of responding.

The effect of chronic chlordiazepoxide contrasts with its action when given acutely; in the latter case it has only sedative effects.

Whether this test can be used as an animal model of anxiety is discussed and this test is compared with existing tests of anxiety.
RELEASE OF MEDIATORS OF ANAPHYLAXIS: INHIBITION OF PROSTAGLANDIN SYNTHESIS AND THE MODIFICATION OF RELEASE OF SLOW REACTING SUBSTANCE OF ANAPHYLAXIS AND HISTAMINE
Authors: ENGINEER DINAZ M. , NIEDERHAUSER U. , PIPER PRISCILLA J. , SIROIS P.
Published: July 2012

When isolated perfused lungs from sensitized guinea‐pigs were challenged with antigen, histamine, slow reacting substance of anaphylaxis (SRS‐A) and prostaglandin‐like substances were released into the effluent.

Treatment of the lungs before and during challenge with indomethacin (0.5–10 μg/ml), sodium aspirin (1–10 μg/ml), sodium meclofenamate (0.1–1 μg/ml) or ketoprofen (0.5–5 μg/ml) inhibited the release of prostaglandins while increasing the output of histamine and SRS‐A between three‐and five‐fold.

Diethylcarbamazine (0.2–1 mg/ml) reduced the release of SRS‐A and histamine but increased the amount of prostaglandin‐like substances produced.

Eicosatetraynoic acid (10 μg/ml) inhibited formation of prostaglandins but did not modify release of histamine and SRS‐A.

The results with non‐steroid anti‐inflammatory drugs and diethylcarbamazine suggest that prostaglandins, or some other product of the cyclo‐oxygenase system, depress the anaphylactic release of SRS‐A and histamine.
PHOSPHOLIPASE A2 ACTIVITY OF GUINEA‐PIG ISOLATED PERFUSED LUNGS: STIMULATION, AND INHIBITION BY ANTI‐INFLAMMATORY STEROIDS
Authors: BLACKWELL G.J. , FLOWER R.J. , NIJKAMP F.P. , VANE J.R.
Published: July 2012

A simple double‐isotope assay for phospholipase A2 activity of perfused organs is described.

Guinea‐pig lungs perfused through the pulmonary circulation exhibit a low background enzyme activity. This activity is blocked by dexamethasone, betamethasone and hydrocortisone, mepacrine, procaine or chlorpromazine. Aspirin and indomethacin are without effect.

Mechanical trauma, antigen challenge or injections of bradykinin, rabbit aorta contracting substance‐releasing factor (RCS‐RF) or histamine increase ‘basal’ phospholipase activity. The effect of these agents, except that of bradykinin, is blocked by dexamethasone or mepacrine.

The blocking effect of steroids is cumulative and dose‐dependent. They do not work in cell‐free systems. Inhibition by mepacrine is rapid and is effective in cell‐free lung homogenates.

It is suggested that agents which liberate prostaglandin endoperoxides and thromboxane A2 from perfused lungs do so by activating phospholipase A2.
FUNCTIONAL CHANGES IN CEREBRAL 5‐HYDROXYTRYPTAMINE METABOLISM IN THE MOUSE INDUCED BY ANTICONVULSANT DRUGS
Authors: CHADWICK D. , GORROD J.W. , JENNER P. , MARSDEN C.D. , REYNOLDS E.H.
Published: July 2012

Acute administration of clonazepam, diazepam and diphenylhydantoin to mice elevated cerebral 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA); chronic administration had less effect.

Acute administration of clonazepam and diazepam but not diphenylhydantoin raised cerebral tryptophan levels; chronic administration of clonazepam caused a smaller elevation of cerebral tryptophan but chronic administration of diazepam still caused a large rise in cerebral tryptophan.

Neither clonazepam nor diazepam caused induction of drug metabolizing enzymes on chronic administration but diphenylhydantoin had a marked effect.

These data suggest that the altered 5‐HT metabolism caused by these compounds is unrelated to a common action on tryptophan levels, and that the reduced effect of clonazepam and diazepam on chronic administration cannot be attributed to increased metabolism of these compounds.

Clonazepam induced abnormal head movements in mice in a dose‐dependent manner. Pretreatment of animals with tranylcypromine increased the intensity of movement, although pargyline was without effect. Similar effects were observed with diazepam and diphenylhydantoin, suggesting that the increase in cerebral 5‐HT caused by these compounds is of functional significance in stimulating 5‐HT receptors.
COMPARISON OF THE VASODEPRESSOR EFFECTS OF PROSTACYCLIN AND 6‐OXO‐PROSTAGLANDIN F1α WITH THOSE OF PROSTAGLANDIN E2 IN RATS AND RABBITS
Authors: ARMSTRONG J.M. , LATTIMER N. , MONCADA S. , VANE J.R.
Published: July 2012

Vasodepressor effects of prostacyclin (5z‐5,6‐didehydro‐9‐deoxy‐6,9a‐epoxyprostaglandin F1) and its decomposition product 6‐oxo‐prostaglandin F1α (6‐oxo‐PGF1α) have been compared with those of prostaglandin E2 (PGE2) in anaesthetized rats and rabbits.

In rats intravenous prostacyclin produced hypotension and was 4–8 times more potent than PGE2 and about 128 times more potent than 6‐oxo‐PGF1α.

In rabbits also, intravenous prostacyclin (less than 2 μg/kg) produced hypotension and was twice as active as PGE2 and approximately 250 times more active than 6‐oxo‐PGF1α.

In rats and rabbits vasodepressor responses induced by prostacyclin were similar in magnitude after either intravenous or intra‐aortic administration.

Thus, in both species prostacyclin resembles PGE2 in producing vasodepression but does not lose activity on passage through the lungs. The results emphasize the need to consider prostacyclin in addition to PGE2 as a major determinant influencing blood pressure.
THE EFFECT OF LITHIUM ON THE INCREASE IN FOREBRAIN 5‐HYDROXYINDOLEACETIC ACID PRODUCED BY RAPHE STIMULATION
Authors: COLLARD K.J.
Published: July 2012

The change in forebrain 5‐hydroxyindoleacetic acid (5‐HIAA) concentration induced by raphe stimulation has been studied in rats treated with Li+ or 0.9% w/v NaCl solution (saline) for 10 days.

Raphe stimulation increased the forebrain concentration of 5‐HIAA in both groups of animals. Chlorimipramine abolished this effect in the control group, but not in the Li+ group.

The inhibition of 5‐hydroxytryptamine (5‐HT) uptake by chlorimipramine was not affected by pretreatment with Li+ or by the addition of Li+ to synaptosomal suspensions in vitro.

It is suggested that the production of 5‐HIAA following raphe stimulation in Li+‐treated animals is derived from the metabolism of 5‐HT which remains within the intracellular environment. The consequence of this in relation to transmitter release is discussed.
THE EFFECT OF DIFFERENT CALCIUM CONCENTRATIONS ON THE INHIBITORY EFFECT OF PRESYNAPTIC α‐ADRENOCEPTORS IN THE RAT VAS DEFERENS
Authors: DREW G.M.
Published: July 2012

The effects of different calcium concentrations on the twitch‐inhibitory potency of clonidine and of guanethidine have been examined in the rat isolated vas deferens. Vasa deferentia did not respond to field stimulation at 0.3 Hz in Krebs solution containing 0.325 mmol/1 of calcium. Increasing the calcium concentration to 5.2 mmol/1 caused a concentration‐dependent increase in size of the twitch response. The twitch‐inhibitory potency of clonidine was inversely proportional to the calcium concentration. The inhibitory effect of guanethidine was not influenced by changes in calcium concentration. The results show that the modulation of motor function by presynaptic α‐adrenoceptors in the rat vas deferens is calcium‐dependent.
THE EFFECTS OF ISOPRENALINE AND A NEW p‐SYMPATHOMIMETIC AMINE UPON SPONTANEOUS ACTIVITY, DIASTOLIC DEPOLARIZATION AND PLATEAU HEIGHT IN CARDIAC PURKINJE FIBRES
Authors: GRABOWSKI W. , LUTTGAU H. Ch. , SCHULZE J.J.
Published: July 2012

In spontaneously active Purkinje fibres of young cows the dose‐response curves of the action of isoprenaline upon different electrophysiological parameters were measured.

The increase in slope of diastolic depolarization could roughly be described by a one‐for‐one binding curve with a half maximum effect near 10−8m and the increase in the height of the plateau level by a two‐for‐one binding curve with a half maximum effect near 10−7m (—)‐isoprenaline.

These dose‐response curves were similar to those of two parameters measured under voltage clamp conditions by other authors. The increase in slope of diastolic depolarization behaved like the shift of the activation curve for the pacemaker potassium current towards positive potentials and the growth in plateau height like the increase in the slow inward current mainly carried by Ca ions. From this conformity we propose that the parameters evaluated by us from action potential records could be used for a qualitative analysis of the action of catecholamines on pacemaker potassium current and Ca influx.

The effects of the isomers of a new drug, 1‐isopropylamino‐3(4′hydroxyphenoxy)‐propan‐2‐ol (IHP), were evaluated in the same way as those of isoprenaline. The (—)‐isomer was at optimal concentrations (10−5m) nearly half as effective as isoprenaline in increasing frequency and slope of diastolic depolarization but caused no increase in plateau height. An identical relationship, but at 5 to 10 times higher concentrations, was obtained with the (+)‐isomer.

When 10−4m(—)‐IHP was added to a preparation equilibrated with a maximum dose of (‐)‐iso‐prenaline (10−6m), frequency and plateau height declined. This result together with the observation that the effects of IHP could be blocked by the specific β‐antagonist propranolol, revealed the jff‐agonistic nature of the new drug. Its inefficiency in increasing the plateau height and thus the slow (Ca) inward current was explained by its relatively low potency and intrinsic activity.
THE EFFECT OF ERGOTAMINE ON TISSUE BLOOD FLOW AND THE ARTERIOVENOUS SHUNTING OF RADIOACTIVE MICROSPHERES IN THE HEAD
Authors: JOHNSTON BARBARA M. , SAXENA P.R.
Published: July 2012

The radioactive microsphere method was used to study the effects of ergotamine (5, 10 and 20 μg/kg, i.v.) on systemic and regional haemodynamic variables in chloralose‐urethane anaesthetized cats. The influence of the drug was also studied on the number of 15 um microspheres escaping entrapment in the head to emerge in the left external jugular vein.

Ergotamine decreased the heart rate and cardiac output. Since arterial blood pressure remained unchanged, calculated total peripheral resistance increased.

The regional distribution of cardiac output obtained with 15 um microspheres agreed well with previous studies in cats where 25 um spheres were used. The most pronounced difference was that in the present investigation more microspheres, apparently escaping through arteriovenous anastomoses (AVAs), were detected in the lungs than when larger spheres had been used.

Coronary blood flow decreased, while uterine blood flow was increased by the drug. The microsphere content of the lungs, which receive the spheres not only via bronchial arteries but also via AVAs, was greatly reduced by all doses of ergotamine. Ergotamine did not influence tissue blood flow to other major organs such as the brain, kidneys, skin, liver, skeletal muscle or the gastrointestinal tract.

In the 16 experiments, 0.46 ± 0.05 (s.e. mean) % of the total microspheres injected (equivalent to 11.7 ± 1.4% of microspheres detected in the left‐side of the head) appeared within 2min of microsphere injection into the left external jugular vein. The highest dose of ergotamine significantly reduced the shunting of the microspheres in the head.

Since 15 um microspheres are only likely to reach the lungs by passing into the venous circulation through large glomus‐type AVAs, we conclude that ergotamine reduces the fraction of microspheres appearing in the lungs by causing strong vasoconstriction in the AVAs in the head.

In conformity with the closure of head AVAs is the finding that ergotamine reduced the jugular venous Po2 and 02 saturation thereby increasing the A‐V 02 saturation difference.

It is quite possible that decreased A‐V shunting may be the prominent mechanism of the antimigraine action of the drug, since sudden opening of AVA's has been implicated in the pathophysiology of migraine‐syndrome.
EFFECTS OF SULPHINPYRAZONE AND ASPIRIN ON PROSTAGLANDIN I2 (PROSTACYCLIN) SYNTHESIS BY ENDOTHELIAL CELLS
Authors: GORDON J.L , PEARSON J.D.
Published: July 2012

Synthesis of prostaglandin I2, (PGI2, prostacyclin) by vascular endothelium (assayed by the ability of cultured endothelial cells to inhibit platelet aggregation) was inhibited by aspirin. At 100 μmol/1 aspirin completely blocked measurable PGI2 production, but endothelial cells had substantially recovered their ability to synthesize PGI2 24 h after removal of the drug. In contrast, the effect of 1 mmol/1 aspirin was still evident 24 h after drug withdrawal. Sulphinpyrazone also inhibited PGI2 synthesis, but was about 100 fold less potent than aspirin, and the effect of the drug was lost within 24 h of its addition, even when endothelial cells were left in contact with the drug during this period.
PHARMACOLOGICAL ANALYSIS OF HISTAMINE RECEPTORS IN MUSCULATURE AND VASCULATURE OF THE DOG TRACHEA in situ
Authors: HIMORI N. , TAIRA N.
Published: July 2012

The rôle of histamine Hr and H2‐receptors in the musculature and vasculature of the dog trachea was investigated in the blood‐perfused trachea in situ.

Histamine and acetylcholine caused increases in blood flow (tracheal vasodilatation) and in intraluminal pressure (tracheal constriction) in a dose‐dependent manner. Histamine was almost equi‐potent to acetylcholine in causing tracheal vasodilatation but was about 30 times less potent in causing tracheal constriction.

The histamine H2‐receptor agonist, dimaprit, caused a dose‐dependent increase in tracheal blood flow but failed to cause tracheal constriction.

The tracheal constriction produced by histamine was inhibited strongly by diphenhydramine but not modified by metiamide. The tracheal vasodilatation produced by histamine was antagonized by both diphenhydramine and metiamide; diphenhydramine was more effective than metiamide.

It is concluded that in the tracheal musculature, histamine receptors are exclusively of the Hj‐type and mediate constriction, whereas in the tracheal vasculature, both histamine Hr and H2‐receptors mediate vasodilatation but histamine Hrreceptors are predominant.
RESPONSES OF THE SIMULTANEOUSLY‐PERFUSED HEPATIC ARTERIAL AND PORTAL VENOUS VASCULAR BEDS OF THE DOG TO HISTAMINE AND 5‐HYDROXYTRYPTAMINE
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

The sympathetically‐innervated hepatic arterial and portal venous vascular beds of the dog were perfused simultaneously in situ.

Histamine and 5‐hydroxytryptamine (5‐HT) were injected intra‐arterially and intraportally in graded, increasing doses.

Intra‐arterial histamine evoked decreases in hepatic arterial vascular resistance (HAVR) and increases in hepatic portal vascular resistance (HPVR).

Intraportal injections of histamine caused increases in HPVR and decreases in HAVR.

The time courses of the arterial responses to intraportal histamine and of the portal responses to intra‐arterial histamine, compared with any systemic effects, showed that these effects on the liver vasculature could not be the result of recirculation of histamine.

Intra‐arterial 5‐HT evoked biphasic changes in HAVR and small falls in HPVR. Intraportal 5‐HT caused falls in HPVR at low doses and rises at high doses, together, typically, with biphasic effects on HAVR.

It is unlikely that the arterial effects of intraportal 5‐HT and the portal effects of intra‐arterial 5‐HT were due to recirculation of the vasoactive material.

Pathophysiologically, both histamine and 5‐HT are released from the gastrointestinal tract into the portal vein. These experiments show that such release may affect the hepatic arterial vascular resistance (and therefore blood flow) even though vasoactive levels of the autacoids are not attained in the systemic circulation.
THE EFFECTS OF DORSAL BUNDLE INJECTIONS OF 6‐HYDROXYDOPAMINE ON AVOIDANCE RESPONDING IN RATS
Authors: FIBIGER HANS C. , MASON STEPHEN T.
Published: July 2012

The effects of injection of 6‐hydroxydopamine (6‐OHDA) into the fibres of the dorsal noradrenergic bundle on acquisition, retention and extinction of active avoidance in rats were examined.

6‐OHDA injections severely depleted noradrenaline in all forebrain areas assayed, with the interesting exception of the septum. No significant effect on dopamine concentrations in various forebrain regions was found.

Acquisition and retention of active avoidance was not altered by the lesion. Marked resistance to extinction was seen when the unconditioned stimulus (shock) was removed.

A comparison with work by other authors in which both forebrain noradrenaline and dopamine were depleted suggest that the alteration in extinction seen in both studies is a noradrenergic effect, whereas the deficits in acquisition and retention found previously are dopaminergic in origin.
EVIDENCE FOR TWO DISTINCT TYPES OF POSTSYNAPTIC α‐ADRENOCEPTOR IN VASCULAR SMOOTH MUSCLE in vivo
Authors: DREW G.M. , WHITING SUSAN B.
Published: July 2012

The effects of the highly selective α1‐adrenoceptor antagonist, prazosin, and the relatively selective α2‐adrenoceptor antagonist, yohimbine, on the pressor responses to intravenous injections of phenylephrine and noradrenaline have been examined in anaesthetized cats and pithed rats in an attempt to determine whether α1‐ and α2‐adrenoceptors are located postsynaptically on vascular smooth muscle.

In anaesthetized cats prazosin caused a much greater reduction in the pressor responses to phenylephrine than to noradrenaline or splanchnic nerve stimulation (after adrenalectomy). Yohimbine was of similar potency in reducing the pressor responses to each stimulus.

A differential blocking activity of prazosin against intra‐arterial injections of phenylephrine and noradrenaline was also demonstrated in the blood‐perfused cat hind limb. As in the whole animal, prazosin was more potent against phenylephrine than noradrenaline. A similar, though less marked, effect was seen in the mesenteric circulation, but not in the renal circulation, where prazosin was almost equipotent in reducing responses to phenylephrine and noradrenaline.

In pithed rats prazosin was a potent, competitive antagonist of phenylephrine, but had little effect against noradrenaline; only the responses to high doses of noradrenaline were reduced by prazosin. Yohimbine was approximately equipotent as an antagonist of phenylephrine and noradrenaline. In the anococcygeus muscle, prazosin was as potent an antagonist of noradrenaline as it was of phenylephrine on vascular smooth muscle.

The results suggest that there are two types of α‐adrenoceptor in the vasculature of cats and rats. Phenylephrine produces pressor responses by stimulating one type of postsynaptic α‐adrenoceptor that is blocked by prazosin and yohimbine; these are α1‐adrenoceptors. Noradrenaline exerts some of its effect via these receptors but most of its effect appears to be exerted through prazosin‐insensitive receptors. The latter receptors appear to differ from α2‐adrenoceptors.
THE CARDIOVASCULAR PHARMACOLOGY OF 7‐PROPYL‐THEOPHYLLINE‐DOPAMINE (D4975); COMPARISON WITH DOPAMINE AND DOBUTAMINE
Authors: McCAIG DOROTHY , PARRATT J.R.
Published: July 2012

The effects of a newly developed dopamine‐xanthine derivative, 7‐propyl‐theophylline‐dopamine (D4975), have been examined in cats anaesthetized with sodium pentobarbitone. When administered intravenously (in doses as low as 0.5 to 1.0 μg/kg) it increased systemic arterial pressure, left ventricular (LV) dP/dtmax, dP/dt at fixed ventricular isovolumic pressures and cardiac output. Heart rate effects were minimal.

D4975 was about 5 times more active than dopamine or dobutamine in elevating LV dP/dtmax or dP/dt at common peak isovolumic pressures (CPIP) and about 10 times more active than dopamine at increasing systemic arterial blood pressure. The effects of D4975 were also more prolonged than those of the other two agents.

The effects of D4975 on LV dP/dtmax were greatly reduced by the prior administration of propranolol. D4975 has no effect on peripheral β2‐adrenoceptors.

It is suggested that the effects of D4975 on the myocardium involve both β1‐adrenoceptor stimulation and inhibition of phosphodiesterase and that the marked and prolonged pressor response is due to resistance to enzymatic breakdown by monoamine oxidase.

The results suggest that D4975 might prove valuable in the treatment of the hypotension and reduced myocardial contractility of shock, especially as it is possible to select a dose that increases LV dP/dtmax without increasing either heart rate or systemic arterial pressure.
INHIBITION OF INSULIN SECRETION FROM THE PERFUSED PANCREAS OF THE RAT BY PIZOTIFEN
Authors: JOOST H.G.
Published: July 2012

In the perfused rat pancreas the effects of pizotifen on insulin release induced by 20 mm glucose were studied.

Pizotifen (10 and 100 μm) significantly reduced the insulin release during a 25 min perfusion period to 49% and 7% of the controls.

The same concentrations of the structurally related agents cyproheptadine, doxepin, and chlorpromazine produced a comparable inhibition.
AMINO ACIDS AS NEUROTRANSMITTERS OF CORTICOFUGAL NEURONES IN THE RAT: A COMPARISON OF GLUTAMATE AND ASPARTATE
Authors: STONE TREVOR W.
Published: July 2012

The relative sensitivities to aspartate and glutamate of neurones receiving a corticofugal innervation were examined by microiontophoresis, and compared with the relative sensitivities of neurones not appearing to receive such an input.

On all the cells tested, glutamate appeared to be a more potent excitant than aspartate in terms of neuronal response size or effective dose.

dl‐α‐Aminoadipate (αAA) reduced the excitatory amino acid responses on all the neurones tested. On many of these cells a control excitation could be produced, by acetylcholine or hydrogen ions, which was in most cases unaffected by doses of αAA producing antagonism of amino acid excitation.

On 70% of the cells, aminoadipate showed no selectivity for aspartate compared with glutamate but a differential action, involving blockade of aspartate but not glutamate, was apparent on the other 30%.

Doses of αAA which selectively reduced responses to aspartate had no effect on short latency evoked spikes, but doses which also reduced responses to glutamate reduced the short‐latency synaptic excitation induced by electrical stimulation of either the surface of the cerebral cortex, or of the pyramidal tracts in the medulla.

These findings suggest that corticofugal neurones having an excitatory action on cells in various parts of the brain may use an amino acid, probably glutamate, as a common neurotransmitter.

As no significant difference could be demonstrated in the potency ratios of glutamate aspartate on monosynaptically activated cells compared with other cells, doubt is cast on the validity of drawing conclusions about transmitter identity from potency ratios alone, without the support of antagonist studies.
EFFECTS OF UPTAKE INHIBITORS ON RESPONSES OF SHEEP CORONARY ARTERIES TO CATECHOLAMINES AND SYMPATHETIC NERVE STIMULATION
Authors: BRINE F. , CORNISH E.J. , MILLER R.C.
Published: July 2012

Transmural stimulation of intrinsic sympathetic nerves and exogenous catecholamines produce β1‐adrenoceptor mediated relaxant responses in strips of contracted sheep coronary artery.

The neuronal uptake inhibitors, metaraminol, cocaine and desipramine and the extraneuronal uptake inhibitor, cortisol, failed to potentiate responses to noradrenaline or sympathetic stimulation; responses to isoprenaline were enhanced by cortisol.

Oxytetracycline, which inhibits binding to connective tissue fibres, did not affect responses to noradrenaline or nerve stimulation.

17β‐Oestradiol, caffeine and U0521 proved to be unsuitable compounds for studying catecholamine inactivation since they non‐selectively potentiated responses to noradrenaline and isoprenaline.

It is concluded that catecholamine inactivation processes do not modify transmitter function in sheep coronary arteries.
ANTAGONISM OF EXCITATORY AMINO ACID‐INDUCED RESPONSES AND OF SYNAPTIC EXCITATION IN THE ISOLATED SPINAL CORD OF THE FROG
Authors: EVANS R.H. , FRANCIS A.A. , HUNT K. , OAKES D.J. , WATKINS J.C.
Published: July 2012

A range of compounds has been tested for excitatory amino acid agonist or antagonist activity and for effects on synaptic activity on isolated hemisected spinal cords of frogs.

l‐Monoamino dicarboxylic acids of chain length up to 8 carbon atoms (l‐α‐aminosuberate) were all agonists.

Within a series of d‐monoamino dicarboxylic acids, and with diamino dicarboxylic acids (mainly unresolved mixtures of diasteroisomers), there was a progression from agonist activity, for compounds of chain length equal to or shorter than glutamate, to antagonist activity, for compounds of longer chain length. d‐α‐Aminosuberate (DαAS) was the most potent antagonist.

The antagonist actions of these substances showed a Mg2+ ‐like selectivity with respect to depolarizations produced by different excitants. N‐methyl‐d‐aspartate (NMDA) was the most susceptible agonist and quisqualate and kainate the least susceptible. Responses to other excitatory amino acids, including l‐glutamate and l‐aspartate, showed intermediate sensitivity to the antagonists.

A parallelism was observed between the relative potencies of mono‐ and diamino dicarboxylic acids as NMDA antagonists and their relative potencies as depressants of synaptic responses.

The results support the concept of different types of excitatory amino acid receptors, with NMDA and its antagonists acting predominantly on one type. These NMDA receptors are probably transmitter receptors activated by an excitatory amino acid transmitter.
PHARMACOLOGICAL PROPERTIES OF KRYPTOPYRROLE AND ITS OXIDATION PRODUCTS ON ISOLATED SCIATIC NERVE OF RAT AND ON GUINEA‐PIG ILEUM
Authors: GORCHEIN A. , MITCHELL L.D. , ROGERS A.T.
Published: July 2012

Kryptopyrrôle (2, 4‐dimethyl, 3‐ethylpyrrôle) inhibited conduction in rat sciatic nerve by a local anaesthetic action.

Tone and both spontaneous and electrically‐induced contractions of guinea‐pig ileum were also inhibited by kryptopyrrôle. The concentration of kryptopyrrôle required for 50% inhibition of a maximum twitch tension (ID50) was 0.085 him.

Oxidation products of kryptopyrrôle with chromatographic properties similar to those of urinary constituents reported in schizophrenia and hepatic porphyrias had little or no effect at similar concentrations.

Dose‐response curves to exogenous acetylcholine in guinea‐pig ileum were shifted to the right by kryptopyrrôle, with loss of parallelism and reduction in the maximum contraction.

Acetylcholine overflow from ileal segments at rest and during electrical stimulation was reduced by kryptopyrrôle.

These results on ileal segments are consistent with kryptopyrrôle having both a post‐junctional site of action, presumably directly on the muscle, and a pre‐junctional site reducing the output of acetylcholine from the myenteric plexus.

The significance of these findings is discussed in relation to a possible clinical pathological rôle for these compounds.
MYOCARDIAL SYNTHESIS OF PROSTAGLANDIN‐LIKE SUBSTANCES AND CORONARY REACTIONS TO CARDIOSTIMULATION AND TO HYPOXIA
Authors: SUNAHARA F.A. , TALESNIK J.
Published: July 2012

Continuous recording of cardiac contractions and coronary flow from isolated perfused hearts of rats permitted the study of coronary reactions to: (a) cardiostimulation induced by single doses or slow infusions of noradrenaline, CaCl2, glucagon or electrically induced tachycardia; (b) short interruptions of coronary inflow (hypoxia).

Except during tachycardia the heart rate was kept constant at 210 beats/min by electrical pacing.

Metabolic coronary vasodilatation (MCD) resulting from cardiac hyperactivity induced by noradrenaline, Ca2+, tachycardia or glucagon was inhibited by administration of prostaglandin E2. Reactive hyperaemia response to hypoxia was unaffected by prostaglandin administration.

Inhibition of MCD could also be obtained by prolonged infusion with arachidonic acid (1.6 × 10−7m), presumably by its conversion into prostaglandin‐like substance since arachidonic acid failed to block MCD in hearts from rats pretreated with non‐steroidal anti‐inflammatory drugs (indomethacin, naproxen, phenylbutazone).

Reactive hyperaemia was unaffected either by arachidonic acid or by blockade of the synthesis of prostaglandin‐like substances by anti‐inflammatory drugs.

Since prostaglandin synthetase inhibition does not prevent but may enhance MCD, we do not advocate prostaglandin‐like substances as agents directly responsible for the coronary vasodilatation that follows cardiac hyperactivity.

We postulate that cardiac overproduction of prostaglandins may lead to a failure in the adaptive coronary flow response to cardiac hyperactivity (coronary insufficiency?).
EFFECTS OF ADENOSINE 5′‐TRIPHOSPHATE (ATP) AND β‐γ‐METHYLENE ATP ON THE RAT URINARY BLADDER
Authors: BROWN C. , BURNSTOCK G. , COCKS T.
Published: July 2012

High concentrations of adenosine 5′‐triphosphate (ATP, 100 to 1000 μm) were required to cause contraction of the rat urinary bladder, while adenosine and adenosine 5′‐monophosphate (AMP, 1 to 50/im) produced relaxation.

One hundred fold lower concentrations of β‐γ‐methylene ATP, which is resistant to degradation to AMP and adenosine, caused dose‐dependent, phasic contractions which mimicked atropine‐resistant responses to nerve stimulation.

Adenosine and AMP caused dose‐dependent inhibition of carbachol‐induced contractions; theophylline competitively antagonized this inhibition but not the contractile responses to β‐γ‐methylene ATP, ATP or atropine‐resistant nerve stimulation.

These results suggest that the insensitivity of the rat bladder to ATP is due to its rapid degradation to AMP and adenosine and support the hypothesis that the bladder receives a purinergic excitatory innervation.
DEPRESSION OF DRUG METABOLISM IN THE MOUSE BY A COMBINATION OF Mycobacterium butyricum AND ANAESTHETICS
Authors: BARBIERI EDWARD J. , CIACCIO EDWARD I.
Published: July 2012

Subcutaneous injection of Mycobacterium butyricum suspended in mineral oil into the mouse hind paw caused an oedematous local inflammation. Hind paw swelling was maximum 5 days after injection and was still apparent at day 30.

Drug metabolism in vivo (as monitored by ketamine‐ or pentobarbitone‐induced sleeping times) was not affected by the inflammatory disease. However, administration of ketamine or pentobarbitone at day 1 led to significantly elevated sleeping times when the mice showing local inflammation were retested at day 5 with the anaesthetics.

Indomethacin inhibited hind paw oedema in the mouse but did not affect ketzmine‐Mycobacter‐ium butyricum‐induced depression of drug metabolism.

Prolongation of ketamine‐induced anaesthesia by combination with Mycobacterium butyricum at day 5 correlated with the degree of hind paw inflammation at this time.

The data suggest that anaesthetics (i.e., ketamine and pentobarbitone) may sensitize hepatic membranes to the effect of Mycobacterium butyricum or some toxic compound elaborated during the active phase of inflammation.
DIFFERENTIATION OF THE ROLES OF HISTAMINE Hr AND H2‐RECEPTORS IN THE MEDIATION OF THE EFFECTS OF HISTAMINE IN THE ISOLATED WORKING HEART OF THE GUINEA‐PIG
Authors: FLYNN SHEILA B. , GRISTWOOD R.W. , OWEN D.A.A.
Published: July 2012

Differentiation of the rôles of histamine Hr and H2‐receptors in the mediation of the effects of histamine on the isolated working heart of the guinea‐pig was achieved through the use of histamine and selective histamine receptor agonists and antagonists.

Histamine over the dose range 10−9mol to 10−6mol produced dose‐related increases in sinus rate, left intraventricular pressure (LVP)max, LVdP/dtmax, coronary flow, aortic flow, total cardiac output and external pressure‐volume work.

Dimaprit, a selective histamine H2‐receptor agonist, produced very similar responses to histamine.

2‐Pyridylethylamine, a selective histamine Hj‐receptor agonist, had little effect on cardiac function unless large doses were administered. Such doses produced increases in all measured parameters.

Cimetidine, a selective histamine H2‐receptor antagonist, antagonized the effects of histamine and dimaprit and some but not all effects of 2‐pyridylethylamine. In the presence of cimetidine a decrease in all parameters with the exception of sinus rate was observed with both histamine and 2‐pyridylethylamine.

The selective histamine Hi‐receptor antagonist, mepyramine, had little effect on responses to all three agonists. However, the depressant effects observed with histamine and 2‐pyridylethylamine in the presence of cimetidine were antagonized by mepyramine.

The results indicate the important rôle of the histamine H2‐receptor in the mediation of the gross cardiac effects of histamine and also indicate that histamine Hx‐receptors can mediate cardiac depression.
EFFECT OF Gymnodinium breve TOXIN IN THE RAT PHRENIC NERVE DIAPHRAGM PREPARATION
Authors: GALLAGHER JOEL P. , SHINNICK‐GALLAGHER PATRICIA
Published: July 2012

The effects of a crude fraction of Gymnodinium breve toxin (GBTX) were studied on the rat phrenic nerve diaphragm preparation.

Indirectly stimulated muscle contractions were more sensitive to blockade by increasing concentrations of GBTX (0.25 μg/ml to 10 μg/ml) than direct muscle contractions.

GBTX increased miniature endplate potential (m.e.p.p.) frequency and depolarized the resting membrane potential of the muscle fibres at the endplate and in non‐synaptic regions of muscle fibre.

A concentration‐dependent biphasic effect on m.e.p.p. amplitude was evident. At lower concentrations m.e.p.p. amplitudes were depressed whereas at high concentrations they were increased.

GBTX blocked endplate potentials (e.p.ps) in concentrations (0.5 μg/ml to 2 μg/ml) that did not block m.e.p.ps.

Muscle fibre action potentials recorded from cells held at control membrane potential by hyperpolarizing current were not altered by toxin treatment. No repetitive e.p.ps, or muscle action potentials were observed.

These data suggest that GBTX may block indirectly stimulated muscle contractions and e.p.ps by depolarizing the nerve terminal in a manner similar to the observed depolarization of the muscle fibre. The depolarization of the nerve terminal may be sufficient to inhibit transmitter release.
EFFECTS OF OXYTOCIN ON THE ISOLATED VAS DEFERENS OF THE RAT
Authors: BENEIT JUAN V. , HIDALGO AGUSTIN , TAMARGO JUAN L.
Published: July 2012

The effect of oxytocin was studied on the isolated vas deferens of the rat.

Oxytocin (25 to 200 mu/ml) reversibly reduced the contractile response induced by noradrenaline, dopamine and acetylcholine.

Oxytocin (400 mu/ml) abolished the response to potassium.

The contractions evoked in the vas deferens by field stimulation were also reduced by oxytocin (50 to 200 mu/ml). The inhibitory effect of the drug was related to the external calcium concentration.

It is suggested that oxytocin depresses the contractile responses in the vas deferens at least partly by reducing the availability of calcium from an extracellular source.
STRUCTURE‐ACTIVITY RELATIONSHIP OF IMIDAZOLIDINE DERIVATIVES RELATED TO CLONIDINE AT HISTAMINE H2‐RECEPTORS IN GUINEA‐PIG ISOLATED ATRIA
Authors: McCULLOCH M.W. , MEDGETT I.C. , RAND M.J. , STORY D.F.
Published: July 2012

Cumulative concentration‐response relationships for the chronotropic effects of histamine, oxymetazoline, clonidine and thirteen clonidine‐like imidazolidine derivatives were examined in isolated spontaneously beating guinea‐pig atria.

The following compounds induced positive chronotropic effects: histamine, clonidine (2,6‐dichlorophenyliminoimidazolidine) and the 2,6‐dibromo, 2,6‐dimethyl, 2,6‐diethyl, 2,6‐dihydroxy, 2,4,6‐trimethyl, 3,4‐dihydroxy and 2‐methyl‐5‐fluoro analogues of clonidine. These compounds appeared to act as partial agonists on histamine H2‐receptors, with potencies ranging from one tenth to one hundredth and intrinsic activities from approximately 20% to 75% of those of histamine.

The following compounds did not induce positive chronotropic effects but rather decreased the atrial rate, usually at high concentrations: oxymetazoline and the 2,3‐dichloro, 4‐dichloro, 5‐dichloro, 2‐chloro‐4‐methyl, 2‐methyl‐5‐chloro, 2,4,6‐trichloro analogues of clonidine.

The effects of histamine were antagonized by cimetidine, the pA2 value being 6.68 (s.e. mean = 0.16, n = 3), and also in a concentration‐dependent manner by clonidine. Cimetidine antagonized the response to clonidine in a concentration‐dependent manner; however, high concentrations of cimetidine depressed the maximal response to clonidine and the slope of the concentration‐response curve was no longer parallel to the control curve.

The effects of the other compounds which induced positive chronotropic effects were also antagonized by cimetidine (1 μmol/l); however, the effect of the 3,4‐dihydroxy derivative was unaffected by cimetidine (1 μmol/l) but was abolished by propranolol (0.3 μmol/l).

In general, phenyliminoimidazolidine derivatives with 2,6‐substitution on the phenyl ring are active on histamine H2‐receptors, whereas derivatives with 2,3‐, 2,4‐ or 2,5‐substitutions are weakly active or inactive. Thus the restriction imposed on the free rotation of the phenyl ring about the carbon‐imino nitrogen bond by the introduction of two ortho substituents appears to result in increased agonist activity on the histamine H2‐receptor. The introduction of substituents in the 3, 4 or 5 positions in the phenyl ring may lead to compounds sterically hindered from combining with the histamine H2‐receptor.

There is no apparent relationship between the activities of clonidine‐like imidazolidine derivatives as agonists on histamine H2‐receptors and their hypotensive activities (as reported in the literature).
ACTIONS OF NITROGLYCERINE ON THE MEMBRANE AND MECHANICAL PROPERTIES OF SMOOTH MUSCLES OF THE CORONARY ARTERY OF THE PIG
Authors: ITO YUSHI , KITAMURA KENJI , KURIYAMA HIROSI
Published: July 2012

Effects of nitroglycerine (NG) on the membrane and contractile properties of the smooth muscle cell of the isolated coronary artery of the pig were observed.

NG, up to a concentration of 10−5 m, modified neither the membrane potential nor the membrane resistance. Increased concentrations of NG (> 2.8 × 10−5 m) hyperpolarized the membrane, reduced the membrane resistance and enhanced the rectifying property of the membrane measured by depolarization pulses. These phenomena observed with a high concentration of NG are the result of an increase in the K‐conductance of the membrane.

NG (2.8 × 10−5 m) did not modify the membrane potential displaced by various concentrations of excess [K]o. In low [K]o, NG (2.8 × 10−5 m) hyperpolarized the membrane to a greater extent than that observed in Krebs solution. The effects of NG (10−6 to 2.8 × 10−5 m) on the membrane potential were not modified by simultaneous application of 2 × 10−6 m acetylcholine (ACh).

NG (2.8 × 10−6 m) consistently raised the mechanical threshold required for tension development and suppressed the amplitude of the contraction evoked by excess [K]o, ACh or electrical depolarization of the membrane. The dose‐response curve shifted to the right in the presence of NG noncompetitively in all the conditions employed to develop the tension.

When the tissue was immersed in Ca‐free (EGTA) solution, ACh (5 × 10−6 m) evoked a contraction even after the tissue had lost the ability to contract to repetitive applications of 118 mm [K]o in Ca‐free (EGTA) solution. However, the tissue finally failed to contract to repetitively applied ACh. At this stage, 2.5 mm [Ca]o evoked a small contraction, after which the response was briefly restored to 5 × 10−6 m ACh. This transient response to ACh was reduced by NG (5.6 × 10−6 m) when NG was added either simultaneously with ACh or with the previous Ca application. However, the inhibition was greater in the former than the latter case.

Cysteine (1 to 2 mm), without modifying the membrane potential or membrane resistance, partly restored the contraction evoked by excess [K]o or ACh which had been reduced by NG.

The mechanism of action of NG on the smooth muscle cell of the coronary artery of the pig is postulated to be due to a nonselective suppression of the Ca‐mobilization from the store site with no noticeable change in the membrane properties.
PRESSURE REVERSAL OF THE EFFECT OF URETHANE ON THE EVOKED SOMATOSENSORY CORTICAL RESPONSE IN THE RAT
Authors: ANGEL A. , GRATTON DENISE A. , HALSEY M.J. , WARDLEY‐SMITH BRIDGET
Published: July 2012

The cerebral response evoked by stimulation of the forepaw in the rat shows an increase in latency and decrease in the amplitude of its initial components as anaesthetic dose (urethane) is increased.

These changes are reversed if the ambient pressure is increased with helium and the electrocorticogram shows an increase in basic frequency.

The dose of urethane needed to prevent reflex response to tail stimulation is increased as pressure increases.

The implications of these behavioural and somatosensory responsiveness changes as pressure is increased are discussed.
ACTIONS OF 4‐AMINOPYRIDINE ON VASCULAR SMOOTH MUSCLE TISSUES OF THE GUINEA‐PIG
Authors: HARA YUSUKE , KITAMURA KENJI , KURIYAMA HIROSI
Published: July 2012

Effects of 4‐aminopyridine (4‐AP) and procaine on the membrane and contractile properties of smooth muscle cells of the guinea‐pig pulmonary artery and portal vein were observed.

The membrane potential and length constant of smooth muscle cells of the guinea‐pig pulmonary artery were −53.2 mV and 1.2 mm, respectively, and those of the portal vein were −52.6 mV and 0.71 mm, respectively. The membrane was electrically quiescent in the pulmonary artery and it was electrically active in the portal vein.

Both 4‐AP and procaine depolarized the membrane, increased the membrane resistance and suppressed the rectifying properties in both tissues. Both agents evoked a graded response from the muscle membranes of the pulmonary artery by outward current pulse. Procaine had a greater effect than 4‐AP on the above membrane properties.

4‐AP (10−5 m) produced contraction without depolarization of the membrane. The contraction evoked by 10−5 m 4‐AP was completely suppressed but that evoked by 5 × 10−4 m 4‐AP was only partly suppressed by phentolamine (10−7 m). However, the contraction evoked by procaine was not suppressed by phentolamine.

4‐AP enhanced but procaine suppressed the amplitude of 118 mm [K]0‐induced contraction.

The results suggest that 4‐AP and procaine suppress K‐conductance of the muscle membrane, and 4‐AP but not procaine increases noradrenaline release from the nerve terminal. Presumably intracellular free Ca concentrations are also modified by these agents. The effects of 4‐AP and procaine on the vascular muscle were compared with those on other excitable tissues.
DIFFERENTIAL EFFECTS OF THE CALCIUM‐ANTAGONISTIC VASODILATORS, NIFEDIPINE AND VERAPAMIL, ON THE TRACHEAL MUSCULATURE AND VASCULATURE OF THE DOG
Authors: HIMORI N. , TAIRA N.
Published: July 2012

In anaesthetized dogs the trachea in situ was perfused arterially with blood, and drugs were injected intra‐arterially. Isoprenaline and the calcium‐antagonistic vasodilators, nifedipine and verapamil, increased tracheal blood flow and decreased resting tone of the trachea. Isoprenaline was equi‐effective in producing tracheal vasodilatation and tracheal dilatation. The two calcium‐antagonistic vasodilators were less effective tracheal dilators than tracheal vasodilators.
INHIBITION OF THE ACETYLCHOLINE RECEPTOR BY HISTRIONICOTOXIN
Authors: ANWYL ROGER , NARAHASHI TOSHIO
Published: July 2012

The action of C5‐decahydrohistrionicotoxin (C5‐HTX) has been investigated on the extrajunctional acetylcholine (ACh) receptors of denervated rat muscle.

C5‐HTX causes both a rapid and slow reduction in amplitude of iontophoretic ACh potentials evoked at all frequencies from the extrajunctional receptors.

C5‐HTX also causes a time‐dependent inhibition of the iontophoretic potentials evoked at frequencies greater than 0.02 Hz. This inhibition was observed either alone or superimposed upon desensitization, and may be caused by a similar mechanism to desensitization.
EFFECTS OF MORPHINE ON CANINE INTESTINAL ABSORPTION AND BLOOD FLOW
Authors: MAILMAN DAVID
Published: July 2012

Intestinal absorption and blood flow were determined in anaesthetized fed or fasted dogs following rapid intravenous injections of morphine (0.01, 0.1, 1 mg/kg).

3H2O and 22Na were used to determine the unidirectional fluxes of Na+ and H2O from saline perfused through the ileal lumen and the clearances of 3H2O were used to determine total and absorptive site blood flow.

Net Na+ and H2O absorption were increased at each dose of morphine in fed but not in fasted dogs, due primarily to increased absorptive fluxes.

Arterial pressure was decreased by morphine but mesenteric vein pressure was little affected. Absorptive site blood flow was increased by morphine due to decreased blood flow resistance but total blood flow resistance was little affected by morphine.

The absorptive fluxes of Na+ and H2O were correlated with absorptive site blood flow in both fed and fasted animals. The secretory fluxes of Na+ and H2O were correlated with estimated capillary pressure in fasted dogs but morphine decreased the secretory fluxes at a given capillary pressure in dogs which had been fed.

Naloxone (0.12 mg, i.v.) reversed the effects of morphine. The effects of morphine on the gut were reversed more slowly than on systemic blood pressure.

It was concluded that morphine can increase net absorption in fed dogs by a selective increase in intestinal absorptive site blood flow and thus increase absorptive fluxes by a washout effect but that there is also an epithelial effect, sensitized by feeding, which reduces the secretory fluxes of Na+ and H2O.