bluuebunny/crossref_metadata_2025 huggingface dataset:
THE OUTPUT PER STIMULUS OF ACETYLCHOLINE FROM CEREBRAL CORTICAL SLICES IN THE PRESENCE OR ABSENCE OF CHOLINESTERASE INHIBITION
Authors: BOURDOIS P.S. , MITCHELL J.F. , SOMOGYI G.T. , SZERB J.C.
Published: July 2012

The release of endogenous acetylcholine (ACh) from cerebral cortical slices stimulated at 0.25, 1, 4, 16 and 64 Hz was measured in the presence either of physostigmine or of physostigmine and atropine.

Atropine potentiated the evoked release of endogenous ACh especially at low frequencies resulting in an output per stimulus which sharply declined with increasing frequency of stimulation, while in the absence of atropine the output of ACh per stimulus was low and fairly constant.

The evoked release of [3H]‐ACh per stimulus following the incubation of the slices with [3H]‐choline, as estimated by means of rate constants of the evoked release of total radioactivity, showed a frequency dependence similar to endogenous ACh when the two were tested under identical conditions.

In the absence of an anticholinesterase the evoked release of [3H]‐ACh per stimulus was dependent on frequency of stimulation in a similar way to that in the presence of physostigmine and atropine.

Results suggest that under physiological conditions, i.e. in the absence of an anticholinesterase, the release of ACh per stimulus decreases with increasing frequency of stimulation and that this decrease is due to a lag in the mobilization of stored ACh rather than in the synthesis of new ACh.
PROTECTION BY PHENTOLAMINE AGAINST THE EFFECTS OF PHENOXYBENZAMINE ON TRANSMITTER RELEASE ELICITED BY NERVE STIMULATION IN THE PERFUSED CAT HEART
Authors: FARAH M.B. , LANGER S.Z.
Published: July 2012

The effects of cocaine, phentolamine and phenoxybenzamine on neuronal uptake of [3H]‐noradrenaline and on 3H‐transmitter and noradrenaline overflow elicited by nerve stimulation were determined in the perfused heart of the cat.

During perfusion with cocaine 3.4 × 10−7m, there was a 2‐fold increase in transmitter overflow while neuronal uptake of [3H]‐noradrenaline was inhibited by 31.3 ± 2.1%.

After exposure to phenoxybenzamine 8.7 × 10−7m for 20 min and washing with drug‐free solution for 165 min there was an 8‐fold increase in transmitter overflow during nerve stimulation. Under these conditions neuronal uptake of [3H]‐noradrenaline was inhibited by only 17.5 ± 5.4%.

There was no significant change in transmitter overflow or in neuronal uptake of [3H]‐noradrenaline, 155 min after a 30 min exposure to phentolamine (3.2 × 10−5m).

Perfusion with phentolamine (3.2 × 10−5m) before and during exposure to phenoxybenzamine (8.7 × 10−7m), prevented the increase in transmitter overflow observed after perfusion with phenoxybenzamine alone.

Protection by phentolamine against the effects of phenoxybenzamine supports the view that the effects on transmitter release obtained after perfusion with phenoxybenzamine are due to the blockade of presynaptic α‐adrenoceptors which regulate transmitter release through a negative feed‐back mechanism.
THE EFFECT OF PITHING AND OF NERVE STIMULATION ON THE DEPLETION OF NORADRENALINE BY RESERPINE IN THE RAT ANOCOCCYGEUS MUSCLE AND VAS DEFERENS
Authors: GILLESPIE J.S. , McGRATH J.C.
Published: July 2012

The depletion of noradrenaline (NA) in the rat anococcygeus muscle and vas deferens by reserpine and the effect on this of the abolition of nerve activity by pithing and reinforcement of nerve activity by stimulation of the spinal cord outflows has been studied.

NA depletion of the anococcygeus and vas deferens measured 24 h after reserpine was similar and was related to dose. The heart was depleted faster than the two smooth muscle tissues.

In the absence of reserpine neither abolition of nerve activity by pithing nor its reinforcement by nerve stimulation had a detectable influence on NA content of the anococcygeus or vas deferens.

In rats given reserpine (200 μg/kg), increasing nerve activity by spinal stimulation significantly increased NA depletion in both the anococcygeus and the vas deferens when compared with animals pithed but not stimulated. These results confirm that nerve impulse traffic can be an important factor in determining the rate of depletion of NA by reserpine.

The mechanical response to nerve stimulation in both the vas deferens and anococcygeus was resistant to quite severe depletion of their NA content, with the exception of the initial fast component of the response in the vas. The implications of these results for motor transmission in the vas deferens are discussed.
ERGOMETRINE AND APOMORPHINE AS SELECTIVE ANTAGONISTS OF DOPAMINE IN THE CANINE RENAL VASCULATURE
Authors: BELL C. , CONWAY E.L. , LANG W.J.
Published: July 2012

Increases in renal blood flow were produced by intra‐arterial injections of dopamine (5–50 μg) in anaesthetized dogs pretreated with α‐ and β‐adrenoceptor antagonists.

Intra‐arterial administration of ergometrine (0.5 mg) or apomorphine (1 mg) produced a depression of the renal dilator responses to dopamine, without affecting renal dilatations in response to intra‐arterial acetylcholine (0.1–1 μg) or histamine (2–50 μg).

The depression of dopamine responses lasted 10–15 min, and was greater with ergometrine than with apomorphine.

It is concluded that both ergometrine and apomorphine can be used as specific blocking agents at vascular dopamine receptors. Ergometrine is the preferred drug for this purpose.
THE ROLE OF SUPERSENSITIVITY TO ACETYLCHOLINE IN THE PRODUCTION OF TOLERANCE TO MORPHINE IN STIMULATED GUINEA‐PIG ILEUM
Authors: SHOHAM SANDRA , WEINSTOCK MARTA
Published: July 2012

Morphine caused a dose‐dependent reduction in both the height of contraction and acetylcholine release from coaxially stimulated strips of guinea‐pig ileum.

Exposure of the tissue to morphine for 90 min produced acute tolerance to the effect of subsequent doses of morphine on contraction height.

There was no change in the ability of morphine to suppress acetylcholine release.

The responses of morphine‐tolerant ileum to exogenous acetylcholine were enhanced 3 to 10‐fold.

If the ileum did not show tolerance to morphine it did not become more sensitive to acetylcholine.

The results presented suggest that tolerance to morphine could result from a form of disuse supersensitivity.
CHOLINOMIMETIC EFFECTS OF AQUEOUS EXTRACTS FROM Carum copticum SEEDS
Authors: DEVASANKARAIAH G. , HANIN I. , HARANATH P.S.R.K. , RAMANAMURTHY P.S.V.
Published: July 2012

An aqueous extract from roasted seeds of Carum copticum (omum) has cholinomimetic effects. It shows muscarinic effects on rabbit duodenum, guinea‐pig ileum and rat jejunum, and on the blood pressure of rat and cat. These effects are blocked by atropine. It also has a nicotinic action on the frog rectus preparation and atropinized cat blood pressure. Its effect is potentiated by physostigmine and antagonized by cholinesterase or alkalinization. Paper and gas chromatography have confirmed the presence of acetylcholine and choline in the roasted omum seed extract.
THE EFFECT OF TRICYCLIC ANTI DEPRESSANTS ON CHOLINERGIC RESPONSES OF SINGLE CORTICAL NEURONES
Authors: BEVAN P. , BRADSHAW C.M. , SZABADI E.
Published: July 2012

The technique of microelectrophoresis was used in order to study the effects of tricyclic antidepressants on responses of single cortical neurones to acetylcholine.

Both potentiation and antagonism of excitatory responses to acetylcholine could be observed after a brief application of imipramine or desipramine. A higher dose of the antidepressant was required to evoke antagonism than to evoke potentiation.

Responses to carbachol were affected by desipramine similarly, suggesting that inhibition of Cholinesterase is not responsible for the potentiation of cholinergic responses.

A brief application of atropine also had a dual effect on responses to acetylcholine.

It is suggested that the potentiation of excitatory cholinergic responses by atropine and the antidepressants may be due to the blockade of masked inhibitory receptors.
POSSIBLE ROLE OF A β‐ADRENOCEPTOR IN THE REGULATION OF NORADRENALINE RELEASE BY NERVE STIMULATION THROUGH A POSITIVE FEED‐BACK MECHANISM
Authors: ADLER‐GRASCHINSKY EDDA , LANGER S.Z.
Published: July 2012

The effects of isoprenaline, propranolol and phentolamine, were studied on tritiated noradrenaline overflow elicited by postganglionic nerve stimulation in guinea‐pig isolated atria.

Isoprenaline (1.2 × 10−8) increased while propranolol (1.0 × 10‐7 M) reduced the overflow of tritiated noradrenaline evoked by nerve stimulation. These effects were less than those of phentolamine (3.1 × 10‐6 M), which increased by approximately three‐fold the overflow of [3 H] ‐noradrenaline elicited by nerve stimulation.

Neuronal accumulation of tritiated noradrenaline in guinea‐pig atria was not affected by isoprenaline, propranolol or phentolamine at the concentrations employed in this study.

Isoprenaline (1.2 × 10‐8 M) induced a positive chronotropic effect of about 80% of the maximum. On the other hand, propranolol produced a shift to the right in the frequency‐response curve to nerve stimulation and in the concentration‐response curve to exogenous noradrenaline in guinea‐pig atria.

In the isolated nictitating membrane of the cat, the frequency‐response curve to nerve stimulation was not modified by propranolol, while in the presence of 3.9 × 10−6 m of N,‐2‐(2,6‐dimethylphenoxy)propyl‐N,N,N ‐trimethylammonium (β‐methyl‐TM 10) there was a shift to the right and a depression of slope. Neither propranolol nor β‐methyl‐TM 10 affected responses to exogenous noradrenaline.

The effects of isoprenaline and of propranolol on transmitter release are compatible with the view that in addition to the presynaptic negative feed‐back mechanism for noradrenaline release by nerve stimulation mediated via α‐adrenoceptors a positive feed‐back mechanism exists in adrenergic nerve endings which is triggered through the activation of presynaptic β‐adrenoceptors.
THE ACTION OF AMINOPHYLLINE ON THE ACUTELY TRANSPLANTED DOG HEART: EFFECT OF α‐ AND β‐ADRENOCEPTOR BLOCKADE
Authors: PAOLONI H.J. , WILCKEN D.E.L.
Published: July 2012

Aminophylline inhibits the coronary vasodilator actions of adenosine. Our previous studies suggested that low dose infusions of aminophylline reduce coronary blood flow in the isolated heart. In the present study we investigated the actions of aminophylline on coronary blood flow and myocardial contractility in a transplanted heart model. Drugs were given by close coronary arterial infusion.

Aminophylline in low doses (200 μg/min) reduced coronary blood flow by 21 ± 2% (mean ± s.e. mean) but did not alter myocardial contractility or heart rate. Higher doses (500 and 1000 μg/min) increased coronary blood flow and myocardial contractility without changing heart rate.

α‐Adrenoceptor blockade with phenoxybenzamine did not affect the response to a low dose of aminophylline (200 μg/min).

Propranolol in doses of 10 and 30 μg/min blocked β‐adrenoceptors but did not change coronary blood flow. The higher dose reduced myocardial contractility.

The effects of a high dose of aminophylline (1000 μg/min) on coronary blood flow were not changed by either α‐ or β‐adrenoceptor blockade, although propranolol (30 μg/min) reduced the augmentation in myocardial contractility.

The results show that when given in doses which do not alter myocardial contractility, aminophylline reduces coronary blood flow in the isolated heart and that this is not mediated through an α‐adrenoceptor mechanism, They also show that the increases in coronary blood flow and positive inotropic effects obtained with higher doses of aminophylline are not mediated through catecholamines and suggest that higher doses of aminophylline have a small direct coronary vasodilator action. The low dose vasoconstrictor response may be produced by inhibition of the coronary vasodilator action of locally produced adenosine.
AN AMBIGUITY IN RECEPTOR THEORY
Authors: SCHILD H.O.
Published: July 2012

Two expressions for calculating receptor occupancy by antagonist in competitive drug antagonism are contrasted.
THE EFFECT OF ANOXIA ON THE VENTRICULAR FIBRILLATION THRESHOLD IN THE RABBIT ISOLATED HEART
Authors: MURNAGHAN M.F.
Published: July 2012

The ventricular fibrillation threshold (VFT) was measured in the isolated heart of the rabbit perfused via the aorta with McEwen's solution at 37° C by applying a single 10 ms pulse of current during the vulnerable period of late systole. The arrhythmia induced was either fibrillation or a rapid tachycardia.

Gassing the McEwen's solution with 5% CO2 in N2 (anoxia) instead of with carbogen caused a negative inotropic and chronotropic effect and significantly lowered the VFT. Although anoxia releases noradrenaline from the heart the effect of anoxia on the VFT was not prevented by β‐adrenoceptor blockade with propranolol or pindolol or by previous treatment with reserpine.

Perfusion with adenosine (5 μM) which is released from the heart muscle by anoxia, or with dipyridamole (10 μM) which protects the adenosine from binding or destruction by the tissues, or with both combined failed to alter the VFT significantly. Furthermore neither adenosine nor dipyridamole significantly altered the effect of anoxia on the VFT.

Anoxia, adenosine and dipyridamole significantly increased the duration of the induced arrhythmia when compared with that of the controls.

Anoxia and adenosine significantly shortened the vulnerable time, i.e. the minimal time after the R‐wave of the ECG at which the pulse had to be applied to induce the arrhythmia.

Perfusion with the McEwen's solution gassed with 5% CO2 in air (hypoxia) significantly lowered the VFT but the effect was not as great as with anoxia. Isoprenaline when infused lowered the VFT but this effect was not potentiated by hypoxia.

The results indicate that (a) anoxia lowers the VFT in the perfused isolated heart of the rabbit and that this effect is not due to adenosine or noradrenaline released by the anoxia and (b) hypoxia does not sensitize the heart to the arrhythmic effect of isoprenaline.
INFLUENCE OF ANTI‐HYPERTENSIVE DRUG TREATMENT ON VASCULAR REACTIVITY IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: HAMILTON T.C.
Published: July 2012

The effect of prolonged anti‐hypertensive drug treatment on the blood pressure of conscious spontaneously hypertensive rats (SH‐rats), and of age‐matched normotensive Sprague‐Dawley rats was determined during the development of hypertension in SH‐rats and in the early stages of established hypertension. A comparison of the vascular reactivity to noradrenaline (NA) and 5‐hydroxytryptamine (5‐HT) was also made in isolated perfused mesenteric artery preparations from treated and control SH‐ and Sprague‐Dawley rats.

Chronic treatment from age 4 to 16 weeks with hydrallazine alone, or a combination of hydrallazine/hydrochlorothiazide/reserpine, ad libitum in the drinking water, prevented the development of hypertension in SH‐rats and also reduced the vascular reactivity to NA and 5‐HT in isolated vessel preparations from treated compared to control rats.

Similar drug treatments started in early established hypertension reduced blood pressure in SH‐rats over the 12 week treatment period (from age 8 to 20 weeks) without affecting vascular reactivity to NA and 5‐HT in the isolated vessel preparation.

Drug treatments had little effect on blood pressure of age‐matched Sprague‐Dawley rats and no effect on vascular reactivity to NA and 5‐HT in the isolated perfused mesenteric artery preparation from treated compared to control rats.

These results indicate that the development of increased vascular reactivity and of hypertension in SH‐rats occurs simultaneously and, therefore, the vascular changes may be a consequence of the structural changes induced by the raised blood pressure.

In established hypertension, no regression of vascular changes was observed despite prolonged reduction of blood pressure. The rǒle of an increased vascular reactivity in the maintenance of hypertension is therefore questionable.
AN INCREASED REACTIVITY IN HYPERTENSIVE RATS UNAFFECTED BY PROLONGED ANTIHYPERTENSIVE THERAPY
Authors: FINCH L.
Published: July 2012

Isolated perfused mesenteric arteries obtained from chronic experimental hypertensive rats (deoxycorticosterone/NaCl) exhibited an increased reactivity to noradrenaline, 5‐hydroxytryptamine and adenosine 5′‐triphosphate (ATP) when compared with similar preparations from age‐matched normotensive animals.

The dose‐response curves to all three vasoconstrictor agents obtained from hypertensive animals exhibited a steeper slope, and higher maximum without any significant change in the threshold dose suggesting that adaptive/structural changes in the blood vessels had taken place.

Ten week treatments with antihypertensive combinations of hydrallazine, hydrochlorothiazide and reserpine or hydrallazine and mecamylamine lowered the systolic blood pressures of the hypertensive rats to those of normotensive animals and also reversed secondary changes such as periarteritis nodosa of the mesentery and cardiac hypertrophy.

The reactivity of these blood vessels to all these vasoconstrictor agents from the hypertensive rats with a normalized blood pressure was similar to those obtained with untreated hypertensive animals.

The persistent increased reactivity in the hypertensive rats after long‐term anti‐hypertensive treatment suggests that the hyperresponsiveness is secondary to the elevated blood pressures and that the adaptive/structural changes of the blood vessels in chronic hypertensive rats cannot be reversed by prolonged antihypertensive therapy.
RELEASE OF PROSTAGLANDIN‐LIKE SUBSTANCES BY SHIGELLA ENDOTOXIN AND ITS INHIBITION BY NON‐STEROIDAL ANTI‐INFLAMMATORY COMPOUNDS
Authors: BHATTACHERJEE P.
Published: July 2012

The effects of intravenous and intraocular injections of Shigella endotoxin on the inflammatory response, the release of prostaglandin‐like substances into the aqueous humour, and the effects of indomethacin on the inflammatory response were studied in the rabbit eye.

Both intravenous and intraocular injection of endotoxin released 12.8 ng to 72 ng of prostaglandin‐like substances per ml of aqueous humour and increased the permeability of the blood‐aqueous barrier as shown by the rise in aqueous humour protein (26–52 mg protein/ml of aqueous humour).

Indomethacin, 0.25% administered topically completely inhibited the release of prostaglandin‐like substances but was found to have inconsistent inhibitory effects on the clinical signs of inflammation and on the blood‐aqueous barrier. Indomethacin was less effective in eyes receiving the higher dose of endotoxin.

It is suggested that prostaglandins and possibly other chemical mediators are involved in endotoxin‐induced ocular inflammation.
SODIUM AND CALCIUM IONS IN THE CONTROL OF TEMPERATURE SET‐POINT IN THE PIGEON
Authors: SAXENA P.N.
Published: July 2012

The effect of altering the ionic balance of the cerebrospinal fluid (CSF) on cloacal temperature of unanaesthetized pigeons kept at room temperature (20–25°C) was examined by injection or infusion of solutions of different ionic composition into a cannulated lateral cerebral ventricle.

An increase in the concentration of calcium ions caused a fall in temperature and behavioural sedation. The effects were the same whether the calcium was present as calcium chloride or as the calcium disodium salt of ethylenediamine tetra‐acetic acid (CaNa2EDTA).

When the concentration of sodium ions in the CSF perfusate was increased by addition of NaCl or that of calcium ions was decreased by addition of Na2EDTA a rise in temperature was often produced but this was not consistent. NaCl sometimes had either no effect or lowered the temperature. Na2EDTA while producing a rise when first injected failed to do so when repeated a few hours, 24 h and often 72 h later. Prolonged infusion of either agent caused intense behavioural excitement leading to death.

Potassium ions, like sodium ions, caused a rise in temperature but only when infused continuously. Behavioural excitement was only rarely observed.

Magnesium produced a fall in temperature. The concentration required was much higher than that of calcium but the hypothermia was more prolonged suggesting a slower elimination of the magnesium ions from the CSF. Magnesium ions caused tremors, nystagmus and ataxia as opposed to sedation caused by calcium.

All these were central effects as they were not obtained when the substances were injected intravenously.

Since changes in body temperature of the pigeon produced by injection of calcium or sodium ions into the CSF were similar to those seen in various species of mammal, it is concluded that the relative concentration of these ions within the brain plays an important role in establishing the temperature set‐point in both birds and mammals.
SHAPE CHANGE AND AGGREGATION OF BLOOD PLATELETS: INTERACTION BETWEEN THE EFFECTS OF ADENOSINE DIPHOSPHATE, 5‐HYDROXYTRYPTAMINE AND ADRENALINE
Authors: MICHAL F. , MOTAMED MINA
Published: July 2012

The interaction of effects between 5‐hydroxytryptamine (5‐HT) and adenosine diphosphate (ADP) on human or rabbit platelets was investigated in vitro. The initial platelet shape change and their aggregation were measured in stirred, citrated platelet‐rich plasma (PRP) at 37°C by recording the rate and extent of changes in light scattering and light transmission.

Both the velocity and extent of aggregation and the velocity and extent of the rapid morphological change caused by ADP were enhanced by simultaneous addition of 5‐HT. Methysergide but not imipramine inhibited the 5‐HT effects.

Platelets were made refractory to the aggregating and shape changing effect of either ADP or 5‐HT by repeated aggregation with the particular agent; platelets made refractory to ADP retained their responsiveness to 5‐HT and platelets made refractory to 5‐HT responded to ADP. Platelets pre‐incubated for 3–10 min with 5‐HT without aggregation showed greatly reduced aggregation on subsequent addition of ADP. Methysergide inhibited all the effects of 5‐HT whilst imipramine was inactive.

When the shape change or aggregation of platelets induced by ADP was submaximal, addition of 5‐HT increased it further. Pre‐incubation of PRP with 5‐HT before the addition of ADP resulted in failure of the secondary induction of aggregation or shape change by 5‐HT. The secondary induction by 5‐HT also did not occur in the presence of methysergide; imipramine had no inhibitory effect. Similar secondary induction of aggregation was shown by adrenaline injected during aggregation by ADP; the adrenaline effect was removed by phentolamine but not by propranolol.

Our results show that the initial change in shape of platelets and their aggregation can be induced by ADP or 5‐HT in specific manner. The interaction of the effect of these substances on platelets can result in either increase in platelet sensitivity or, under certain conditions, decrease in platelet responsiveness. The increase or depression of platelet reactivity appears to be a highly specific effect and is probably mediated at specific receptors involved with platelet activation.
IMPAIRED ABSORPTION OF CHLORPROMAZINE IN RATS GIVEN TRIHEXYPHENIDYL
Authors: RIVERA‐CALIMLIM LEONOR
Published: July 2012

The absorption and tissue distribution of orally administered [14C]‐chlorpromazine (CPZ) were compared in trihexyphenidyl (THP; Artane)‐treated and control rats.

Total radioactivity (CPZ) in the plasma and brain of rats treated with THP was significantly lower whereas total radioactivity in the stomach was significantly higher than in rats not previously treated with THP.

Gastric emptying in rats treated with THP was significantly delayed as measured by gastric clearance of a marker, [14C]‐polyethylene glycol.

Transport of [14C]‐CPZ in everted sacs was not affected by treatment with THP.

Metabolism of [14C]‐CPZ by liver homogenates was not affected by treatment with THP.

The relationship of delayed gastric emptying in THP‐treated rats and their lower plasma and brain levels of [14C]‐CPZ after oral administration is discussed.
STUDIES ON THE RELATIVE EFFECTS OF PROSTAGLANDINS, BRADYKININ, 5‐HYDROXYTRYPTAMINE AND HISTAMINE ON THE SYNOVIAL MICROCIRCULATION IN DOGS
Authors: DICK W.C. , GRENNAN D.M. , ZEITLIN I.J.
Published: July 2012

The relative effects of prostaglandins E1, E2, F1α, F2α, bradykinin, histamine and 5‐hydroxytryptamine (5‐HT) on the canine synovial microcirculation were investigated using the rate of clearance of radioactive xenon (133Xe) as an index of synovial perfusion.

All the compounds tested, except prostaglandin F1α, produced a vasodilator effect. The descending order of potency of the active compounds was (i) prostaglandin E1, (ii) prostaglandin E2 and bradykinin, (iii) histamine and 5‐HT, (iv) prostaglandin F2α. The most potent compound tested, prostaglandin E1 produced an effect in nanogram amounts in each joint.

Prostaglandin F2α has been reported to have an anti‐inflammatory action; however no evidence was found of antagonism of prostaglandin E1 by two dose levels of prostaglandin F2α.

Preliminary studies showed that threshold doses of prostaglandin E1 did not potentiate the vasodilator action of threshold or sub‐threshold doses of bradykinin in the dog synovium.
INVESTIGATION OF OCCURRENCE OF TOLERANCE TO BRONCHODILATOR DRUGS IN CHRONICALLY PRETREATED GUINEA‐PIGS
Authors: ANDERSON A.A. , LEES G.M.
Published: July 2012

The actions of sympathomimetic amines on isolated preparations of atria, trachea and ileum were studied in vitro in guinea‐pigs, which had been pretreated for 5 or 12 days, by subcutaneous injection, with adrenaline (5 μg/kg), salbutamol (0.5 μg/kg), methoxamine (250 μg/kg) or saline (0.9% w/v NaCl solution).

In the trachea, a decrease in sensitivity (tolerance) to the relaxant effect of adrenaline was induced by pretreatment, for 12 but not for 5 days, with adrenaline. In these animals, cross‐tolerance to isoprenaline or salbutamol was not observed. Tolerance to the relaxant actions of adrenaline, isoprenaline or salbutamol was not observed after pretreatment with salbutamol.

In the trachea, pretreatment with methoxamine or adrenaline for 12 days did not change the sensitivity to the α‐adrenoceptor‐mediated contractor action of methoxamine.

In the atria from those guinea‐pigs pretreated with adrenaline or salbutamol, there was no reduced sensitivity to the β‐adrenoceptor agonist actions of adrenaline, isoprenaline or salbutamol. In animals pretreated with methoxamine or adrenaline, there was no observable tolerance or cross tolerance to methoxamine with respect to its α‐adrenoceptor‐mediated positive inotropic action in the atria and no unequivocal evidence of a reduced sensitivity to that action of adrenaline.

It was confirmed that the twitch‐like contractions of the longitudinal muscle of the electrically stimulated ileum were inhibited by sympathomimetic amines acting on α‐ and β‐adrenoceptors. There was no reduced sensitivity to the inhibitory actions of noradrenaline or isoprenaline on the twitch of ileum isolated from animals pretreated with adrenaline, salbutamol or methoxamine for 5 or 12 days.

From our results on these three preparations from the same animals, it is concluded that generalizations regarding changes in sensitivity to sympathomimetic amines following their prolonged administration should not be made in any one species.
HYPOTHERMIC ACTION OF CHLORPROMAZINE IN MONKEYS
Authors: CHAI C.Y. , FANN Y.D. , LIN M.T.
Published: July 2012

In the conscious monkey (Macaca cyclopis) intravenous administration of chlorpromazine 0.1–8.0 mg/kg produced a fall of rectal temperature of 0.3 to 3.5°C after a latency of 3.5 to 10.8 minutes. The course of hypothermia lasted from 125 to 600 min or more.

Direct injection of chlorpromazine 100–800 μg into the lateral or fourth cerebral ventricle produced a similar fall of 0.3 to 2.0°C but with shorter latency (2 to 3.5 min) and with a duration of 94 to 375 minutes.

Two distinct structures in the brain stem, namely, the preoptic anterior hypothalamus (POAH) and medulla oblongata, responded to direct injection of chlorpromazine 200 μg. The sensitivity was slightly higher in the POAH than in the medulla. Structures in between were not sensitive.

The results suggest that chlorpromazine works principally through the central nervous system, i.e. the POAH and medulla oblongata, to mediate its hypothermic effect.
PROSTAGLANDIN ANTAGONISM BY SODIUM p‐BENZYL‐4‐[1‐OXO‐2‐(4‐CHLOROBENZYL)‐3‐PHENYLPROPYL]PHENYL PHOSPHONATE (N‐O164)
Authors: EAKINS K.E. , RAJADHYAKSHA V. , SCHROER R.
Published: July 2012

The ability of sodium p‐benzyl‐4‐[1‐oxo‐2‐(4‐chlorobenzyl)‐3‐phenylpropyl]phenyl phosphonate (N‐0164) to antagonize contractions produced by prostaglandins E2 and F2α on isolated preparations of gerbil, rat and guinea‐pig gastrointestinal muscle has been studied.

N‐0164 was found to be a potent, partially selective prostaglandin antagonist in these isolated smooth muscle preparations. The blockade produced by N‐0164 in the isolated stomach strip of the rat had some, but not all, the characteristics of a competitive antagonism.

N‐0164 produced a dose‐dependent decrease in tone in the rat stomach strip that was abolished by pretreatment of the preparation with indomethacin.

N‐0164 prevented diarrhoea induced by prostaglandin E2 in mice when given by intraperitoneal injection but was less effective when given orally.

N‐0164 inhibited oedema induced with croton‐oil and pyridine‐ether in the mouse ear.

N‐0164 delayed the onset of erythema following ultraviolet irradiation of guinea‐pig skin only when an equimolar amount of pralidoxime chloride was added to the vehicle.

It is concluded that N‐0164 is a potent, partially selective prostaglandin antagonist on several isolated smooth muscle preparations. N‐0164 exhibits activity in vivo particularly following local application when problems associated with penetration and distribution are minimized.
ANALGESIA PRODUCED BY MORPHINE WHEN ACTING FROM THE LIQUOR SPACE
Authors: DEY P.K. , FELDBERG W.
Published: July 2012

In cats analgesia was produced by morphine sulphate introduced into different parts of the liquor space in doses too small to be effective on intravenous injection. Analgesia was measured with the tail pinch method of Russell & Tate (1975).

On infusion into the fourth ventricle or into the subarachnoid space beneath the ventral surface of the brain stem caudal to the pons, doses of 100 to 200 μg of morphine sulphate were sufficient to produce strong long‐lasting analgesia. On injection into the cisterna magna somewhat larger doses (400 to 800 μg) were required.

It is concluded that the site where morphine acts when producing analgesia in all three circumstances is at the ventral surface of the brain stem.

The possibility is discussed that the structures acted upon are tryptaminergic nerve fibres. They arise from the raphe nuclei, belong to a descending inhibitory pathway, and on their way to the spinal cord, reach the ventral surface of the brain stem lateral to each pyramid, where they could be reached and acted upon by the morphine. This theory postulates a morphine sensitivity of tryptaminergic nerve fibres.
VASCULAR REACTIVITY OF PERFUSED VASCULAR BED IN SPONTANEOUSLY HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: BHATTACHARYA B.K. , DADKAR N.K. , DOHADWALLA A.N.
Published: July 2012

1Hypertensive and normotensive rats of the same age group were isolated from an inbred colony of spontaneously hypertensive rats.

2The perfused hindquarter and mesenteric artery preparations obtained from hypertensive and normotensive rats exhibited an increased reactivity to noradrenaline (NA) and angiotensin II.

3Dose‐response curves to NA obtained from hypertensive and normotensive rats exhibited a steeper slope and higher maximum than those from control rats.

4These findings suggest that increased vascular reactivity of blood vessels is independent of the development or maintenance of elevated blood pressure.
THE EFFECTS OF INTRAPORTAL INJECTIONS OF NORADRENALINE, ADRENALINE, VASOPRESSIN AND ANGIOTENSIN ON THE HEPATIC PORTAL VASCULAR BED OF THE DOG: MARKED TACHYPHYLAXIS TO ANGIOTENSIN
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

1The hepatic portal vein of the anaesthetized dog was cannulated and perfused with blood derived from the cannulated superior mesenteric vein.

2The portal vein was perfused at constant flow, the hepatic portal venous pressure being monitored continuously together with the inferior vena caval pressure. From these measurements, the hepatic portal venous vascular resistance was calculated.

3Noradrenaline and adrenaline were injected intraportally in graded doses which caused dose‐dependent increases in the hepatic portal vascular resistance. At all doses, adrenaline was significantly (P<0.05) more potent than noradrenaline.

4Intraportal injections of vasopressin caused reductions in calculated hepatic portal venous vascular resistance in most experiments; these effects were dose‐dependent.

5No tachyphylaxis to the effects of noradrenaline, adrenaline or vasopressin was observed.

6Intraportal injections of angiotensin caused dose‐dependent increases in calculated hepatic portal vascular resistance up to 5 μg; thereafter larger doses caused smaller increases in portal resistance.

7Repeated intraportal injections of angiotensin revealed the existence of tachyphylaxis in the hepatic portal vascular bed.

8Intraportal infusions of angiotensin caused rises in calculated hepatic portal vascular resistance from which there was almost complete ‘escape’ despite the continued infusions. Infusions of noradrenaline which caused similar rises in calculated portal vascular resistance did not exhibit equivalent degrees of ‘escape’.

9The development of tachyphylaxis explains the fact that doses of 10 and 20 μg of angiotensin injected after 5 μg doses produced smaller effects. If a much longer time interval was allowed between injections (30 min), the dose‐response curve to angiotensin had a sigmoid shape.

10These findings are discussed with respect to their possible importance in the functional status of the hepatic portal vascular bed in this species.
THE HAEMODYNAMIC AND METABOLIC EFFECTS OF MG 8926, A PROSPECTIVE ANTIDYSRHYTHMIC AND ANTIANGINAL AGENT
Authors: MARSHALL R.J. , PARRATT J.R.
Published: July 2012

1The antidysrhythmic, haemodynamic and metabolic effects of a new prospective antianginal and antidysrhythmic agent, N‐(3,3‐diphenylpropyl)‐α‐methyl‐β‐cyclohexylethylamine hydrochloride (MG 8926), have been compared with the chemically related substance, prenylamine, in anaesthetized greyhounds and guinea‐pigs.

2When given intravenously 20 min beforehand, both MG 8926 and prenylamine (5 mg/kg) significantly suppressed the early dysrhythmias induced by coronary artery ligation in anaesthetized greyhounds. At a dose of 1 mg/kg, MG 8926 also protected anaesthetized guinea‐pigs from dysrhythmias induced by ouabain infusions.

3In dogs pretreated with MG 8926, metabolic changes indicative of myocardial ischaemia (increased Pco2 and potassium efflux, decreased oxygen content and pH) were less marked than those occurring in control animals.

4Evidence was obtained that MG 8926, when given either before or after coronary occlusion, was capable of decreasing the severity of myocardial ischaemia as assessed by ST‐segment changes in epicardial electrocardiograms.
THE β‐ADRENOCEPTOR STIMULANT PROPERTIES OF OPC‐2009 ON GUINEA‐PIG ISOLATED TRACHEAL, RIGHT ATRIAL AND LEFT ATRIAL PREPARATIONS
Authors: YABUUCHI Y.
Published: July 2012

The β‐adrenoceptor stimulant properties of 5‐(1‐hydroxy‐2‐isopropylaminobutyl)‐8‐hydroxycarbostyril hydrochloride hemihydrate (OPC‐2009) were compared with those of isoprenaline and salbutamol on guinea‐pig isolated tissues.

In producing tracheal relaxation, OPC‐2009 was approximately 7 times more potent and salbutamol 5 times less potent than isoprenaline. Both compounds were less potent than isoprenaline in increasing either the rate of beating of isolated right atria or the contractile force of left atria, OPC‐2009 being 4 and 127 times and salbutamol being 100 and 700 times less potent on the respective preparations.

Selectivity calculated from EC50 ratio indicates that OPC‐2009 was approximately 26 times and salbutamol approximately 21 times more selective than isoprenaline for tracheal smooth muscle as compared to right atrial muscle, whereas OPC‐2009 was approximately 850 times and salbutamol 140 times more selective than isoprenaline for tracheal smooth muscle as compared to left atria.

The responses to OPC‐2009 on trachea and right atria were not altered by treatment of animals with reserpine 24 h previously. Propranolol was a competitive antagonist of OPC‐2009 on these tissues.

OPC‐2009 at high concentrations competitively antagonized the positive chronotropic and inotropic responses to isoprenaline, indicating that OPC‐2009 like salbutamol, may be classified as a partial agonist.

The results indicate that the action of OPC‐2009 is more selective for tracheal smooth muscle than cardiac muscle and are interpreted in the light of subdivisions of β‐adrenoceptors.
RELAXATION OF SMOOTH MUSCLE FOLLOWING CONTRACTION ELICITED BY SYMPATHETIC NERVE STIMULATION in vivo
Authors: ECCLES R. , MacLEAN A.G.
Published: July 2012

A method for studying in vivo the process of neuroeffector transmission in the nictitating membrane and nasal blood vessels of the cat is described.

Administration of desmethylimipramine or cocaine caused increases in both the amplitude and duration of the nasal and membrane responses which may be explained by inhibition of neuronal uptake of noradrenaline.

Phenoxybenzamine depressed the responses to nerve stimulation, but had little effect on the relationship between response amplitude and rate of recovery.

The relationship between response amplitude and rate of recovery is discussed and related to the sigmoid shape of a log concentration‐response curve.
EFFECTS OF ANTIDEPRESSANT DRUGS ON NORADRENALINE ACCUMULATION AND CONTRACTILE RESPONSES IN THE RAT ANOCOCCYGEUS MUSCLE
Authors: DOGGRELL S.A. , WOODRUFF G.N.
Published: July 2012

The effect of a series of antidepressant drugs on noradrenaline accumulation was studied in the isolated anococcygeus muscle of the rat.

The most potent inhibitors of noradrenaline accumulation were nortriptyline, desipramine and protriptyline. Opipramol, trimipramine and iprindole were active only in high concentrations.

Contractions of the anococcygeus muscle produced by noradrenaline were strongly potentiated by nortriptyline, desipramine and protriptyline. Other uptake inhibitors were less active in potentiating the noradrenaline response.

Nortriptyline, in concentrations that potentiated the action of noradrenaline, reduced or abolished the response to tyramine.
CORONARY REACTIONS TO CARDIAC HYPERACTIVITY AND TO HYPOXIA IN ISOLATED PERFUSED HEART OF RAT
Authors: SEN A.K. , SUNAHARA F.A. , TALESNIK J. , ENDRENYI L.
Published: July 2012

Continuous recording of cardiac force of contraction, heart rate and coronary flow from isolated perfused hearts of rats was used to study coronary reactions: (a) to cardiostimulation with noradrenaline, CaCl2, or electrically induced tachycardia; (b) to short duration stoppage of coronary inflow (hypoxia).

The heart rate was controlled by electrical pacing. Coronary vasodilatation resulted from cardiostimulation or hypoxia. This coronary response was greater at higher heart rates.

In parallel experiments administration of noradrenaline to hearts paced at different frequencies resulted in a rate‐dependent elevation of adenosine‐3′,5′‐cyclic monophosphate (cyclic AMP).

Duration of hypoxia leading to different degrees of reactive hyperaemia did not change the cardiac cyclic AMP levels.

Coronary vasodilatation due to increased cardiac metabolism produced by noradrenaline, Ca2+ or tachycardia was enhanced by the phosphodiesterase inhibitors diazoxide and papaverine while it was inhibited during the administration of prostaglandin E2.

Reactive hyperaemia was unaffected by diazoxide, papaverine or prostaglandin E2.

Catecholamine depletion by reserpine did not influence metabolic coronary dilatation nor the reactive hyperaemic responses.

We postulate that there are at least two types of coronary reactions: one in response to hypoxia, ‘reactive hyperaemia’, and another resulting from cardiac hyperactivity, ‘metabolic coronary dilatation’. The latter, blocked by prostaglandin E2 and enhanced by diazoxide or papaverine, would be triggered by cyclic AMP while reactive hyperaemia would result from other mechanisms.
COMPARISON OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF COCAINE AND AMPHETAMINE IN RATS
Authors: D'MELLO G.D. , STOLERMAN I.P.
Published: July 2012

Water‐deprived rats were trained to press either the left or the right bar in a test chamber according to whether they were injected with a central nervous system stimulant or 0.9% w/v NaCl solution (saline). Correct responses were reinforced with water.

Different groups of rats learned to discriminate amphetamine or cocaine from saline. Dose‐response curves and ED50 values were then determined in brief test sessions when no responses were reinforced.

In a crossover study, cocaine was tested in the rats trained to discriminate amphetamine from saline, and vice versa. The two drugs were largely interchangeable, but the ED50 values were increased, indicating a possible, subtle difference in their discriminative stimulus properties.

The results indicate the importance of complete crossover designs in combination with dose‐response determinations when attempting to classify drugs according to their discriminable properties.
EVIDENCE FOR TWO DIFFERENT Na+‐DEPENDENT [3H]‐OUABAIN BINDING SITES OF A Na+‐K+‐ATPASE OF GUINEA‐PIG HEARTS
Authors: FRICKE U. , KLAUS W.
Published: July 2012

The influence of various Na+ concentrations on [3H]‐ouabain binding was studied in experiments on a microsomal Na+‐K+‐adenosine triphosphatase (ATPase) from guinea‐pig hearts.

The ATP‐independent cardiac glycoside binding was not influenced by increasing Na+ concentrations. However, a good correlation was found between the ATP‐dependent [3H]‐ouabain binding and Na+ concentration.

A more detailed analysis of these results according to Hofstee (1952) revealed two distinct processes involved in this interaction: one ouabain binding process was activated at rather low Na+ concentrations, (K0.5 = 4.5 mM); this type of [3H]‐ouabain binding was strongly correlated to the Na+ concentration necessary for half maximum phosphorylation (K0.5 = 1 mM). The other ouabain binding process was predominant at high Na+ concentrations (K0.5 = 69 mM).

On the basis of the commonly accepted ATPase reaction cycle a model for the interaction of cardiac glycosides with the Na+‐K+‐ATPase is proposed, assuming two different binding sites for cardiac glycosides (E2‐P and E1‐P) and involving a translocation of these drugs from an outer to an inner compartment of the cell membrane.
INTERDEPENDENCE OF ION TRANSPORT AND THE ACTION OF OUABAIN IN HEART MUSCLE
Authors: BENTFELD M. , LÜLLMANN H. , PETERS T. , PROPPE D.
Published: July 2012

The influence of ouabain (0.4 μM) on contractile force and cellular Na and K concentrations was investigated in isolated left atria of the guinea‐pig at rest and at different beat frequencies. Simultaneously the binding of ouabain to the tissue was determined.

Strict dependence of rates of onset of positive iontropic action and of binding of ouabain on beat frequency are limited to conditions where no alterations of cellular Na and K concentrations occur. A correlation was observed between sodium flux per unit time and the development of positive inotropism and binding to the receptors of ouabain.

Ouabain exerts its positive inotropic effect without affecting the intracellular Na and K concentrations in spite of the fact that under these conditions even the majority of binding sites, i.e. Na‐K‐adenosine triphosphatases (Na‐K‐ATPases), are occupied by the drug. The positive inotropic effect may be explained by a ouabain‐induced conformational alteration of the Na‐K‐ATPase which leads to structural alterations of the plasmalemma connected with an increased availability of coupling calcium.

Increasing the frequency of stimulation over a critical value, which appears to be determined by an overloading of the Na pump, induces a decrease in contractile force, cellular accumulation of Na and loss of K, and eventually contracture.

The rate of binding of ouabain appears to depend on the actual concentration of particular conformations of the Na‐K‐ATPase with high affinity for ouabain. These conformations transiently occur during a pumping cycle and their concentration may therefore be dependent on the frequency of cycling which in turn is determined by the frequency of contraction.

Ouabain can easily be washed out from the tissue irrespective of the condition of the muscle. If, however, the intracellular Na and K homeostasis is impaired, the inhibition of the pump persists even if ouabain is released from the binding sites upon wash‐out. It is suggested that the inhibition of the pump is maintained by an increased intracellular Ca ion concentration and a depletion of ATP.

A kinetic model is proposed for the interaction between cardiac glycosides and the Na‐K‐ATPase in intact heart muscle cells.
SUPPRESSION OF TRANSMISSION OF NOCICEPTIVE IMPULSES BY MORPHINE: SELECTIVE EFFECTS OF MORPHINE ADMINISTERED IN THE REGION OF THE SUBSTANTIA GELATINOSA
Authors: DUGGAN A.W. , HALL J.G. , HEADLEY P.M.
Published: July 2012

In spinal cats anaesthetized with α‐chloralose, a study was made of the effects of morphine and naloxone, administered electrophoretically from micropipettes, on the responses of dorsal horn neurones to noxious (raising of skin temperature above 45°C) and innocuous (deflection of hairs) peripheral stimuli.

Administered near cell bodies, morphine reduced the nociceptive responses of only 2 of 37 cells. Excitation occurred more commonly than depression and abnormalities in action potentials were commonly observed following ejection of morphine. None of these effects of morphine was antagonized by electrophoretically applied naloxone.

Administered in the substantia gelatinosa from one micropipette while recording responses of deeper neurones with a second micropipette, morphine reduced the nociceptive responses of 15 of 19 neurones. Firing in response to deflection of hairs was not reduced by morphine. Depression of nociceptive responses by morphine was long lasting (> 20 minutes). Naloxone ejected into the substantia gelatinosa or given intravenously in doses as low as 0.1 mg/kg antagonized the effects of morphine. The effectiveness of this dose of intravenous naloxone suggests that the concentrations of morphine in the substantia gelatinosa which reduced nociceptive responses were not unlike those present after analgesic doses of systemic morphine. Naloxone alone, and excitant and depressant amino acids ejected into the substantia gelatinosa had little effect on cell firing.

Both the selective action of morphine on nociceptive responses and the reversal of this action by intravenous naloxone suggest that the opiate receptor present in the substantia gelatinosa is relevant to analgesia produced by opiates given systemically.
INHIBITION BY A STABLE ANALOGUE OF ADENOSINE TRIPHOSPHATE OF PLATELET AGGREGATION BY ADENOSINE DIPHOSPHATE
Authors: BORN G.V.R. , FOULKS J.G.
Published: July 2012

In citrated platelet‐rich plasma, freshly prepared from rabbit blood, the velocity of platelet aggregation was within limits proportional to the log of the concentration of added adenosine diphosphate (ADP).

Addition of either adenosine triphosphate (ATP) or its β,γ‐methylene analogue inhibited aggregation similarly except that the analogue was about half as potent as ATP. β,γ‐Methylene ATP also reversed the optical effects associated with the shape change of platelets very similarly to ATP itself.

As β,γ‐methylene ATP is not a substrate for nucleoside diphosphokinase, these observations do not support the proposition that inhibition of aggregation by added ATP is due to its utilization by the nucleoside diphosphokinase of platelets.