bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECTS OF HIGH PRESSURE HELIUM AND NITROGEN ON THE RELEASE OF ACETYLCHOLINE FROM THE GUINEA‐PIG ILEUM
Authors: LITTLE HILARY J. , PATON W.D.M.
Published: July 2012

The effects of high pressures of helium and of nitrogen on acetylcholine release were tested using the guinea‐pig ileum as a model preparation. A superfusion system was designed in which this tissue could be maintained under physiological conditions in a high pressure chamber.

Helium, at a pressure of 136 atm slightly increased the spontaneous output of acetylcholine but produced no significant changes at 68 atm (136 atm is close to the lethal pressure for small mammals).

The acetylcholine release evoked by electrical stimulation or by 55 mm potassium was not altered by 136 atm of helium. Effects on tetrodotoxin‐treated tissues were not consistent.

Nitrogen, which in contrast to helium possesses general anaesthetic properties, caused considerable increases in spontaneous and in electrically evoked acetylcholine output at pressures which produce anaesthesia. These increases were not changed when helium was used to increase the total pressure to 136 atm, although this reverses the general anaesthetic actions of nitrogen in vivo.

The increases in rate of acetylcholine release produced by nitrogen were observed in tetrodotoxin‐treated tissues and in tissues from reserpine‐treated animals. In a calcium‐free medium the increases were considerably smaller.

The conclusions from these results are that while high pressures of helium caused little or no change in acetylcholine release rates, nitrogen produced large changes, which were not due to effects on axonal conduction. The effect of nitrogen is not apparently related to its general anaesthetic actions. Differences such as these in transmitter release would be likely to contribute to the differing physiological effects of these two gases.
URETHANE AND CONTRACTION OF VASCULAR SMOOTH MUSCLE
Authors: ALTURA BURTON M. , WEINBERG JULIO
Published: July 2012

In vitro studies were undertaken on rat aortic strips and portal vein segments in order to determine whether or not the anaesthetic, urethane, can exert direct actions on vascular smooth muscle.

Urethane was found to inhibit development of spontaneous mechanical activity. This action took place with a urethane concentration as little as one tenth of that found in anaesthetic plasma concentrations, i.e., 10−3 m.

Urethane (10−3 to 10−1 m) dose‐dependently attenuated contractions induced by adrenaline, angiotensin and KCl. These inhibitory actions were observed with urethane added either before or after the induced contractions.

Ca2+‐induced contractions of K+‐depolarized aortae and portal veins were also attenuated, dose‐dependently, by urethane.

All of these inhibitory effects were completely, and almost immediately, reversed upon washing out the anaesthetic from the organ baths.

A variety of pharmacological antagonists failed to mimic or affect the inhibitory effects induced by urethane.

These data suggest that plasma concentrations of urethane commonly associated with induction of surgical anaesthesia can induce, directly, relaxation of vascular muscle.
ATTENUATION BY BRADYKININ OF ADRENERGICALLY‐INDUCED VASOCONSTRICTION IN THE ISOLATED PERFUSED KIDNEY OF THE RABBIT: RELATIONSHIP TO PROSTAGLANDIN SYNTHESIS
Authors: MALIK K.U. , NASJLETTI A.
Published: July 2012

In the isolated kidney of the rabbit perfused with oxygenated Tyrode solution, we studied the effect of bradykinin on the vasoconstriction evoked by sympathetic nerve stimulation (3 Hz, 1 ms) and by injections of noradrenaline (50 to 75 ng) in the presence and in the absence of indomethacin (1 μg/ml), an inhibitor of prostaglandin biosynthesis. Prostaglandin E(PGE)‐like material in the renal effluent was measured by bioassay after extraction with organic solvents and separation by thin layer chromatography.

Bradykinin in concentrations of 10 to 100 ng/ml reduced the vasoconstrictor response to sympathetic nerve stimulation and to injected noradrenaline. Also, the peptide (1 to 10 ng/ml) increased the basal release of PGE‐like material and the release induced by sympathetic nerve stimulation.

Indomethacin, 1 μg/ml, diminished the inhibitory effect of bradykinin on the vasoconstrictor response to nerve stimulation, minimized the reduction of the noradrenaline‐induced vasoconstriction caused by bradykinin (100 ng/ml), and abolished the release of PGE‐like material.

This study indicates that bradykinin reduces the renal vascular reactivity to adrenergic stimuli and suggests that part of the action of the kinin at the vascular adrenergic neuroeffector junction in the rabbit kidney depends upon the biosynthesis of renal prostaglandins.
PRESYNAPTIC α‐ADRENOCEPTOR BLOCKING PROPERTIES AMONG TRI‐ AND TETRA‐CYCLIC ANTIDEPRESSANT DRUGS
Authors: HARPER BARBARA , HUGHES I.E.
Published: July 2012

The effect of various antidepressants (5 × 10−8 to 2 × 10−5 m) on the resting overflow of tritium, on the evoked overflow and the contractile response to electrical stimulation (2.5 Hz, 2.0 ms) has been determined in mouse vas deferens previously incubated with [3H]‐(–)‐noradrenaline.

Mianserin and ORG GC 94 produced a concentration‐dependent increase of more than two fold in the electrically evoked overflow and the contractile response and, at the highest concentration, slightly increased resting release. These effects were largely unchanged in the presence of a concentration of cocaine effective in blocking noradrenaline uptake (1.1 × 10−5 m).

The ability of phentolamine (1 × 10−5 m) to increase both the evoked overflow of tritium and the contractile response was greatly reduced when these parameters were already elevated by the presence of mianserin or ORG GC 94.

The inhibitory effect of exogenous (–)‐noradrenaline on evoked overflow was greatly reduced in the presence of mianserin or ORG GC 94 (4 × 10−6 m).

The inhibitory effect of clonidine on the twitch response of the mouse vas deferens was antagonized by mianserin and ORG GC 94 in a competitive manner (pA2 values 7.3 and 7.1 respectively).

Maprotiline, desipramine and nortriptyline (> 3 × 10−6 m) produced a parallel fall in both evoked tritium overflow and in the contractile response and increased the resting overflow at higher concentrations. These effects were largely unchanged in the presence of cocaine (1.1 × 10−5 m).

Doxepin, imipramine and iprindole all increased resting overflow at high concentrations (2 × 10−5 m) but produced only small changes in evoked overflow and in the contractile response at lower concentrations.

It is concluded that mianserin and ORG GC 94 produce a blockade of presynaptic α‐adrenoceptors which could contribute to an antidepressant effect but that this type of action is not common to all antidepressants.
A PHARMACOLOGICAL ANALYSIS OF THE CONTRACTILE ACTION OF HISTAMINE UPON THE ILEAL REGION OF THE ISOLATED, BLOOD‐PERFUSED SMALL INTESTINE OF THE RAT
Authors: SAKAI K.
Published: July 2012

The mode of action of histamine was investigated on the rat isolated small intestine perfused at a fixed flow rate through the superior mesenteric artery with blood from the carotid artery of a heparinized donor rat. Compounds were closely injected into the superior mesenteric artery.

Increasing doses (1 to 100 μg) of histamine caused a monophasic fast contraction of the ileum.

The fast contraction was abolished by tetrodotoxin, hexamethonium, morphine or mepyramine, but was not prevented by atropine.

The present study indicates that histamine produces the fast contraction of the ileum by primarily acting on the myenteric nerve plexus involving cholinergic interneurones.
MORPHINE DEPRESSION AND TOLERANCE OF NERVE‐INDUCED PAROTID SECRETION
Authors: BOWEN S.R. , CARPENTER F.G.
Published: July 2012

The nerve‐induced secretion produced by the rat parotid gland is proportional to the frequency of stimulation. Morphine decreased the flow rate during stimulation at 2.5 and 5 Hz, but not at 20 Hz. This frequency‐dependent action of morphine was partially reversed by naloxone.

The secretion produced by the rat parotid gland during an intravenous infusion of acetylcholine was not diminished by morphine. Therefore, the action of morphine on nerve‐induced secretion is most probably on the motor nerve terminals, which release acetylcholine.

Animals that had been implanted with morphine base pellets tolerated 4 times as much morphine as controls; after 6 days the minute ventilation was less depressed by graded doses of morphine than non‐implanted controls.

Nerve‐induced secretion in morphine‐implanted animals was less depressed by morphine than control animals 6 and 24 h after the pellets were removed. The flow rates in the 6 h group treated with morphine were greater after naloxone than control (precipitated withdrawal) but at 24 h when withdrawal symptoms were no longer evident, naloxone produced only a slight reversal.
EFFECTS OF NORADRENALINE AND CARBACHOL ON TEMPERATURE REGULATION OF RATS
Authors: POOLE S. , STEPHENSON J.D.
Published: July 2012

Noradrenaline (0.2 to 20 ug) and carbachol (0.1 to 1 ug) injected into the preoptic/anterior hypothalamic area, evoked dose‐dependent falls in core temperature at all sites tested, followed in most experiments by delayed increases that were not dose‐related. Muscarine (0.1 to 10 ug) produced effects similar to those evoked by carbachol.

These falls in core temperature were associated with increases in tail temperature, locomotor activity and C02 elimination (a measure of metabolic rate).

The temperature responses to noradrenaline (10 ug) and to carbachol (1 ug) were antagonized by intrahypothalamic injections of phentolamine (10 ug) and atropine (1 ug), respectively.

Analysis of the temperature responses and their respective latencies indicates that carbachol‐induced hypothermia was mediated by cholinoceptors in the anterior hypothalamus, whereas hypothermia after noradrenaline was mediated by adrenoceptors throughout the preoptic/anterior hypothalamic area.

Vasodilatation of the tail blood vessels contributed significantly to the hypothermia evoked by carbachol, and to that evoked by injections of noradrenaline into the anterior hypothalamus.

Hypothermia induced by noradrenaline injection into the preoptic area, was mediated by effector mechanisms additional to non‐evaporative heat loss.
EFFECTS OF 2,4‐DINITROPHENOL AMYLOBARBITONE AND CERTAIN OTHER DRUGS ON THE RATE OF OXYGEN CONSUMPTION AND FORCE OF CONTRACTION OF ISOLATED CURARIZED DIAPHRAGM MUSCLE OF THE RAT
Authors: BERESFORD ROSEMARY , BILLS G.N.B. , FASTIER F.N. , MILNE R.J.
Published: July 2012

A technique has been developed for studying over periods of 10 min or longer the effects of drugs on both the force of electrically‐induced contractions and the oxygen consumption of an isolated, curarized, mammalian, skeletal muscle preparation.

The resting oxygen consumption of the muscle was increased substantially by 2,4‐dinitrophenol in concentrations (0.02 mm and higher) that eventually produced contracture. Two other uncoupling agents, 4,6‐dinitro‐o‐cresol and carbonylcyanide‐p‐trifluoromethoxyphenylhydrazone, behaved similarly.

The oxygen consumption over 10 min of the stimulated muscle was also increased by 2,4‐dinitrophenol (0.05 mm), although the strength of the ‘maximal’ contractions was lessened.

Amylobarbitone increased the strength of contraction at a concentration (0.2 mm) that did not affect oxygen consumption significantly. Amylobarbitone and pentobarbitone also increased it at a concentration (1 mm) that depressed oxygen consumption. They decreased both strength of contraction and oxygen consumption at a concentration of 5 mm. Phenobarbitone had a weaker action.

S‐w‐decyl‐thiouronium increased oxygen consumption when given at a concentration (1 mm) that diminished strength of contraction and eventually produced contracture of the muscle.

Both S‐methyl‐thiouronium (1 mm) and 4‐aminopyridine (0.1 mm and 0.5 mm) increased strength of contraction without increasing oxygen consumption. Neither strength of contraction nor oxygen uptake was affected by ouabain (up to 0.01 mm) or by phenformin (0.1 mm).

It is concluded that the response to 2,4‐dinitrophenol is due mainly, if not wholly, to its known ability to uncouple oxidative phosphorylation; that the response to the barbiturates is due to a combination of a known metabolic action (viz., blocking of the respiratory chain) and a stimulant action on muscle; and the response to S‐w‐decyl‐thiouronium to a disruptive action on cell membranes. The disproportionate actions of 4‐aminopyridine and S‐methyl‐thiouronium on strength of contraction relative to oxygen consumption are also attributed to a non‐metabolic action.
UTILIZATION OF ADENOSINE TRIPHOSPHATE IN RAT MAST CELLS DURING HISTAMINE RELEASE INDUCED BY THE IONOPHORE A23187
Authors: JOHANSEN TORBEN
Published: July 2012

The rôle of endogenous adenosine triphosphate (ATP) in histamine release from rat mast cells induced by the ionophore A23187 in vitro has been studied.

The amount of histamine released by calcium from rat mast cells primed with the ionophore A23187 was dependent on the ATP content of the mast cells.

In aerobic experiments a drastic reduction in mast cell ATP content was found during the time when histamine release induced by A23187 takes place.

Anaerobic experiments were performed with metabolic inhibitors (antimycin A, oligomycin, and carbonyl cyanide p‐trifluorometroxyphenylhydrazone), which are known to block the energy‐dependent calcium uptake by isolated mitochondria. The mast cell ATP content was reduced during A23187‐induced histamine release under anaerobic conditions in the presence of glucose. This indicates an increased utilization of ATP during the release process.

The observations are consistent with the view that energy requiring processes are involved in ionophore‐induced histamine release from rat mast cells although part of the ATP reduction in the aerobic experiments may be due to an uncoupling effect of calcium on the oxidative phosphorylation.
THE EFFECTS OF OPIATE RECEPTOR AGONISTS AND ANTAGONISTS ON THE STRESS‐INDUCED SECRETION OF CORTICOSTERONE IN MICE
Authors: GIBSON A. , GINSBURG M. , HALL M. , HART S.L.
Published: July 2012

Intraperitoneal administration of normorphine, morphine or naloxone or exposure to ethervapour for 1 miri, elevated plasma corticosteroid concentrations in mice.

Injection of saline or exposure to ether vapour rendered mice less sensitive to a subsequent exposure to ether vapour 15 min later.

Treatment with normorphine (50 mg/kg) potentiated the corticosteroid response to ether stress whilst pentazocine (20 mg/kg), naltrexone (10 mg/kg), morphine (24 mg/kg), levorphanol (20 mg/kg) and naloxone (50 mg/kg) prevented the stress‐induced elevation of plasma corticosteroids.

Both naloxone and morphine inhibited the potentiation by normorphine of the response to ether, the dose of naloxone required being higher than that for inhibition of normorphine analgesia.

It is concluded that endogenous opioid peptides may be involved in the control of the response to ether stress in mice.
THE METABOLISM OF 5‐HYDROXYTRYPTAMINE AND β‐PHENYL‐ETHYLAMINE IN PERFUSED RAT LUNG AND IN VITRO
Authors: BAKHLE Y.S. , YOUDIM M.B.H.
Published: July 2012

Metabolism of 5‐hydroxytryptamine (5‐HT) and βt‐phenylethylamine (PHE) by monoamine oxidase (MAO) was investigated in rat isolated lungs and in mitochondrial preparations from rat lung.

In perfused lungs 5‐HT metabolism had an apparent Km of 2 μm and PHE metabolism a Km of 54 μm, whereas in vitro the Km values were 330 μm and 28 μm respectively.

In vitro, MAO activity had substrate and inhibitor specificities compatible with the presence of A and B types of MAO.

In perfused lung, metabolism of 5‐HT but not that of PHE was inhibited by desmethylimipramine.

These results show that PHE metabolism in perfused lung, unlike that of other metabolized amines, is not limited by transport and the transport process for PHE is unlike that of 5‐HT or noradrenaline.

These results also show that the kinetic parameters obtained for MAO activity in vitro do not generally apply to the isolated lung where transport of substrate can be the deciding factor. This discrepancy emphasizes that the enzymic properties of the whole organ cannot reliably be deduced from its enzymic content.
DIFFERENTIAL SENSITIVITY OF HYPOTHALAMIC DOPAMINERGIC AND NORADRENERGIC NEURONES TO PHARMACOLOGICAL MANIPULATION
Authors: KAROUM FAROUK , SPECIALE SAMUEL G. , WYATT RICHARD JED
Published: July 2012

The effects of apomorphine (Apo), haloperidol (Hal), reserpine, phenoxybenzamine, oxotremorine and scopolamine on hypothalamic catecholamines and metabolites were assessed. All these drugs, except Apo, significantly changed the hypothalamic concentration of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG), thus suggesting parallel changes in noradrenaline (NA) metabolism and turnover. Hal increased MHPG, an effect which was reversed by Apo pretreatment. Oxotremorine and scopolamine respectively increased and decreased MHPG, reserpine decreased NA and increased MHPG. Phenoxybenzamine increased MHPG without altering NA concentrations. Dopamine and its metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were not changed by Apo and Hal, but were influenced by the other drugs. These results indicate that NA in the hypothalamus is influenced by both cholinergic and dopaminergic events occurring in the brain and that dopaminergic neurones in this organ are different in their biochemical and pharmacological characteristics from neurones present in other central and peripheral systems.
BLOCKADE BY YOHIMBINE OF PRAZOSIN‐RESISTANT PRESSOR EFFECTS OF ADRENALINE IN THE PITHED RAT
Authors: FLAVAHAN N.A. , McGRATH J.C.
Published: July 2012

In the pithed rat, following β‐adrenoceptor blockade, the pressor effect of adrenaline can be blocked by phentolamine or by prazosin plus yohimbine but not by prazosin or yohimbine given alone. It is concluded that adrenaline produces its pressor effect by acting on two sets of post‐junctional α‐adrenoceptors, each of which is sensitive to phentolamine, one of which is sensitive to prazosin but resistant to yohimbine and the other of which is sensitive to yohimbine but resistant to prazosin.
THE INTERACTION BETWEEN INDOMETHACIN AND CONTRACTILE AGENTS ON HUMAN ISOLATED AIRWAY MUSCLE
Authors: BRINK CHARLES , GRIMAUD CHARLES , GUILLOT CHANTAL , OREHEK JEAN
Published: July 2012

Concentration‐effect curves to acetylcholine and histamine were produced in fresh human bronchial muscle (2 to 4 h after removal from the patients) and in preparations previously stored at 4°C for 12 h.

Sensitivities of fresh human airway muscle preparations to acetylcholine (pD2 value, 5.89 ± 0.03); n = 4) and histamine (pD2 value, 5.41 ± 0.03; n = 13) were similar. There was no significant difference in the sensitivities of stored preparations (acetylcholine: pD2 value, 5.70 ± 0.06; n = 23 and histamine: pD2 value, 5.44 ± 0.07; n = 16) when compared to the fresh preparations.

Indomethacin did not significantly change the basal tone in preparations of either fresh or stored human airway muscle.

A low concentration of indomethacin (0.17 μm) significantly reduced responsiveness and sensitivity to histamine in stored bronchi but not in fresh bronchi. The acetylcholine concentration‐effect curves were unaltered by exposure to this concentration of indomethacin in either fresh or stored tissues. High concentrations (1.7 μm and 17 μm) depressed the maximal responsiveness of the bronchi to both agonists.

These results suggest indirectly that the regulatory role of prostaglandins in human airway muscle may be different from that in other species.
EFFECTS OF ACETYLCHOLINE AND SODIUM CYANIDE ON CAT CAROTID BARORECEPTORS
Authors: McQUEEN D.S.
Published: July 2012

The effects of intracarotid (i.a.) injections of acetylcholine (ACh) and sodium cyanide (NaCN) on baroreceptor activity recorded from the sinus nerve have been investigated in cats anaesthetized with pentobarbitone.

Two types of baroreceptor unit were recorded. The predominant type discharged at least 3 to 4 spikes per pulse wave at normal BP; they are referred to as ‘polyspike’ units and may have been associated with A fibres. The other type discharged a maximum of 1 to 3 spikes per pulse wave, even at high BP; they are referred to as ‘few‐spike’ units and may have been from C fibres.

NaCN had no direct effect on either type of baroreceptor unit, even when injected in high doses (2.04 to 5.1 μmol i.a.) which cause maximal chemoreceptor stimulation, and it is concluded that as far as the cat's carotid baroreceptors and chemoreceptors are concerned, NaCN is a specific chemoreceptor stimulant.

ACh had no direct effect on polyspike baroreceptor units unless very high doses (1.83 μmol i.a.) were injected, when there was occasionally a transient slight increase in discharge. This effect appeared to be secondary to muscle contraction caused by ACh since it was not seen when an adequate neuromuscular‐blocking dose of gallamine had been administered.

ACh stimulated the few‐spike type of baroreceptor unit, an effect which was dose‐related and lasted for up to 3 s; the threshold dose for baroreceptor stimulation was higher than that needed to excite chemoreceptor units. The increased discharge also occurred during experiments in which gallamine had been administered. Only five of these units were recorded during the investigation, despite an intensive search for them.

There was a delayed increase in baroreceptor sensitivity following the administration of ACh in doses (37 to 366 nmol i.a.) which had no immediate direct effect on polyspike baroreceptor discharge. The effect was evidently not secondary to changes in sympathetic nerve activity to the sinus region since it was observed during an experiment in which the ganglioglomerular nerves had been cut. Whether the increased sensitivity resulted from direct or indirect actions of ACh remains to be determined.

It is concluded that low doses of ACh or other drugs with nicotinic properties are unlikely to evoke baroreceptor reflexes on intracarotid injection, although they may cause delayed changes in baroreceptor sensitivity. Higher doses of ACh do not directly affect baroreceptor polyspike (A fibre) units, but transient baroreflex changes might result from stimulation of baroreceptor few‐spike (C fibre) units. It is most unlikely that NaCN has any direct effect on baroreceptor reflex activity when injected into the carotid artery in doses used to elicit chemoreceptor reflexes.
MORPHINE AND SUPRASPINAL INHIBITION OF SPINAL NEURONES: EVIDENCE THAT MORPHÌNE DECREASES TONIC DESCENDING INHIBITION IN THE ANAESTHETIZED CAT
Authors: DUGGAN A.W. , GRIERSMITH B.T. , NORTH R.A.
Published: July 2012

A study was made in cats anaesthetized with barbiturate or α‐chloralose, of the excitation of dorsal horn neurones by impulses in unmyelinated (C) primary afferent fibres of the tibial nerve.

Block of conduction in the first lumbar segment by cooling produced large increases in the number of action potentials evoked by C fibre afferents in neurones of more caudal segments.

Morphine (0.3 to 1.0 mg/kg) reduced the excitation of neurones by C fibre afferents and also reduced the increase produced by blocking conduction in the spinal cord. Naloxone (0.1 to 0.3 mg/kg) reversed these effects of morphine.

This decrease in descending inhibition supports findings in the decerebrate cat but gives no support to the hypothesis that an important component of morphine analgesia is an activation of descending inhibitory pathways.
METABOLISM OF ARACHIDONIC ACID AND ITS ENDOPEROXIDE (PGH2) TO MYOTROPIC PRODUCTS IN GUINEA‐PIG AND RABBIT ISOLATED LUNGS
Authors: ALABASTER VALERIE A.
Published: July 2012

Conversion of arachidonic acid (AA) and its endoperoxide (PGH2) to myotropic metabolites has been studied in isolated Krebs‐perfused lungs of guinea‐pig and rabbit. A continuous differential bioassay technique was used to measure myotropic metabolites in the lung perfusate.

AA was metabolized in guinea‐pig lungs to thromboxane A2 (TxA2), prostacyclin (PGI2) and small amounts of a prostaglandin E2 (PGE2)‐like substance. The amounts of products were dose‐related over the AA range used (1 to 10 μg). PGH2 was detected only after AA (10 μg).

Rabbit lungs converted AA (2.5 to 10 μg) to the same products in similar relative proportions but the amounts were 15 to 25% of those produced by guinea‐pig lungs.

Indomethacin (10 nm) preferentially inhibited metabolism of AA to prostaglandins in guinea‐pig lungs but preferentially inhibited metabolism to TxA2 in rabbit lungs. Higher concentrations (50 nm) greatly reduced conversion to all the myotropic metabolites in lungs from both species.

Imidazole (50 μm) selectively inhibited conversion of AA to TxA2 and increased conversion to PGI2 in rabbit lungs. A similar effect was produced in guinea‐pig lungs but with much higher concentrations of imidazole (2.5 to 5 mm).

PGH2 (800 ng) was converted in guinea‐pig lung to TxA2 (100 ng) and very small amounts of PGI2 (10 to 16 ng) but only unchanged PGH2 and some PGE2 were present in the lung perfusate after injection of PGH2 in rabbit lung.

It is concluded that guinea‐pig and rabbit lung differ in their ability to metabolize AA to myotropic substances and also in their response and sensitivity to drugs which interfere with prostaglandin and TxA2 synthesis. The lungs do not appear to have an important role in converting PGH2 to PGI2.
THE EFFECTS OF SENSORY DENERVATION ON THE RESPONSES OF THE RABBIT EYE TO PROSTAGLANDIN E1, BRADYKININ AND SUBSTANCE P
Authors: BUTLER J.M. , HAMMOND B.R.
Published: July 2012

Six to eight days after diathermic destruction of the fifth cranial nerve in the rabbit, the ocular hypertensive and miotic responses to intracameral administration of capsaicin, bradykinin, and prostaglandin E1 were greatly reduced or completely abolished. The response to substance P was not abolished.

A response could still be obtained to chemical irritants 36 h after coagulation of the nerve and it is deduced that manifestation of the response is dependent upon functional sensory nerve terminals, and is independent of central connections.

It is suggested that prostaglandin E1 and bradykinin act directly upon the sensory nerve endings and that propagation of the response is augmented by axon reflex.

In view of the ability of substance P to induce miosis in the denervated eyes, it is presumed that its actions are not mediated via sensory nerves.

It is considered possible that the mediator(s) released from sensory nerve endings after chemical irritation or antidromic stimulation may act in the same way as substance P with regard to the miotic effect.

Synthetic substance P will only produce ocular hypertension in doses which induce a maximal miotic response. This may either be a question of access or a partial resemblance to the endogenous mediator.
SUBSENSITIVITY TO CHOLINOCEPTOR STIMULATION OF THE HUMAN IRIS SPHINCTER in situ FOLLOWING ACUTE AND CHRONIC ADMINISTRATION OF CHOLINOMIMETIC MIOTIC DRUGS
Authors: SMITH SHIRLEY A. , SMITH S.E.
Published: July 2012

Maximal pupillary miosis was obtained with single topical applications of 4 cholinomimetic drugs in therapeutic concentrations to normal human subjects.

When the pupil had recovered from the miosis, there remained a reduced light reflex response of 22.7% at 24 h after aceclidine, 18.0% at 31 h after pilocarpine, 10.3% at 48 h after physostigmine and 4.9% at 7 h after arecoline.

This reduced sensitivity to light was accompanied by an overshoot of the resting pupil diameter and, after aceclidine miosis, a reduced response to a second application of miotic.

Similar findings were observed in glaucoma patients following withdrawal of chronic pilocarpine therapy.

It is suggested that the slowly reversible after‐effects of acute and chronic administration of cholinomimetic miotics can be explained by desensitization of iris sphincter cholinoceptors.
EFFECTS OF THYROTROPHIN‐RELEASING HORMONE, AND METHIONINE‐ENKEPHALIN ON GASTRIC ACID AND PEPSIN SECRETION IN THE CAT
Authors: GASCOIGNE A.D. , HIRST B.H. , REED J.D. , SHAW B.
Published: July 2012

The effect of intravenous administration of thyrotrophin‐releasing hormone (TRH) and methionine‐enkephalin on gastric acid and pepsin secretions was investigated in conscious cats prepared with chronic gastric fistulae.

TRH, 20 μg kg−1 h−1, did not influence unstimulated gastric acid secretion, nor gastric acid secretion stimulated by submaximal doses of pentagastrin or histamine. Pepsin secretion stimulated by pentagastrin was not influenced by TRH.

TRH, 20 μg kg−1 h−1, significantly reduced the gastric acid and pepsin responses to intravenous infusion of insulin. TRH also significantly reduced the degree of hypoglycaemia seen in response to insulin. TRH, 20 μg kg−1 h−1, but not 5 μg kg−1 h−1, infused alone resulted in a significant hyperglycaemia.

It is concluded that the reduction of insulin‐stimulated gastric secretion by TRH is not dependent on the hyperglycaemic action of the peptide. The mechanism of action of TRH on insulin‐stimulated secretion is discussed with respect to its site of action.

Methionine‐enkephalin or the potent analogue, d‐Ala2, Met‐enkephalinamide were without effect on unstimulated gastric secretion, or secretion stimulated by pentagastrin, histamine, and insulin. The opiate receptor antagonist, naloxone, did not significantly alter the gastric acid or pepsin response to insulin.

It is concluded that there is no evidence that opiates stimulate oxyntic glands directly, nor that the oxyntic cells may possess high affinity binding sites for opiates, nor that endogenous opiates are involved in the control of gastric secretion.
OBSERVATIONS ON CHLORALOSE‐INDUCED MYOCLONUS IN GUINEA‐PIGS
Authors: CHADWICK D. , HALLETT M. , JENNER P. , MARSDEN C.D.
Published: July 2012

The physiological, biochemical and pharmacological features of α‐chloralose‐induced myoclonus in the guinea‐pig have been studied.

EMG bursts in muscles jerking in chloralose‐induced myoclonus are long, and are not time‐locked to any cortical event recorded in the EEG, although they are evoked by auditory or peripheral nerve stimuli.

The efferent conduction velocity down the spinal cord of the signals generating the EMG bursts is fast but the afferent conduction velocity up the cord for stimulus‐evoked jerks is slow, in distinction to the reverse characteristics of the spino‐bulbo‐spinal reflex arc.

α‐Choralose did not cause any consistent change in 5‐hydroxytryptamine (5‐HT) or 5‐hydroxy‐indoleacetic acid levels in any brain area, nor did it alter 5‐HT turnover as judged by the depletion of 5‐HT after p‐chlorophenylalanine pretreatment.

Pretreatment of animals with drugs that increase brain 5‐HT action (l‐tryptophan with a monoamine oxidase inhibitor, or 5‐hydroxytryptophan), or antagonize the action of 5‐HT (cyproheptadine) did not abolish or obviously increase chloralose‐induced myoclonus.

Chloralose‐induced myoclonus is not similar to 5‐HT‐sensitive reticular reflex myoclonus in man.
THE MECHANISM OF THE MOTOR RESPONSE TO PERIARTERIAL NERVE STIMULATION IN THE SMALL INTESTINE OF THE RABBIT
Authors: BARTHÓ L. , SZOLCSÁNYI J.
Published: July 2012

In the presence of guanethidine, periarterial nerve stimulation caused a frequency‐dependent motor response in the rabbit isolated ileum. Tachyphylaxis to capsaicin greatly diminished the effect of periarterial stimulation; the remaining portion of the contractile response was susceptible to hexamethonium. The motor effect of periarterial stimulation is mediated by two different mechanisms: one via parasympathetic preganglionic nerves and the other sensitive to capsaicin.
ADAPTATIONAL RESPONSES TO PROLONGED β‐ADRENOCEPTOR BLOCKADE IN ADULT RABBITS
Authors: RAINE A.E.G. , WILLIAMS E.M. VAUGHAN
Published: July 2012

A method for measuring propranolol concentrations in plasma has been modified to permit estimations to be made on small volumes. The method has been used to correlate blockade of heart rate increases in response to intravenous isoprenaline, in both young and adult rabbits, with plasma concentrations of propranolol after subcutaneous injections of 2 or 4 mg/kg. It has been found that the relation between β‐adrenoceptor blockade and plasma concentrations is the same in rabbits as that determined by previous workers in man.

Adult Dutch dwarf rabbits were treated for 9 weeks twice daily subcutaneously with 2 mg/kg propranolol, or 10 mg/kg practolol, or with saline.

The treatment caused no change in heart weight in relation to body weight or in the water content of the hearts, in contrast to effects previously observed in young rabbits.

As in the young rabbits, treatment did cause a prolongation of action potential duration, as measured with intracellular electrodes in hearts of animals killed 24 h after the last dose of drug.

In another series of experiments, with a similar regime of treatment for 6 weeks, a significant reduction of diastolic blood pressure was observed in the propranolol group.

During the course of treatment and at the end, there was no change in the heart‐rate increases observed in response to intravenous isoprenaline administered not less than 15 h after the previous dose of β‐blockers. Thus no functional alteration in sensitivity to β‐adrenoceptor stimulation was apparent.
EVIDENCE FOR MULTIPLE SOURCES OF CALCIUM FOR ACTIVATION OF THE CONTRACTILE MECHANISM OF GUINEA‐PIG taenia coli ON STIMULATION WITH CARBACHOL
Authors: BRADING ALISON F. , SNEDDON P.
Published: July 2012

The evidence presented suggests there are three sources of Ca available for contraction of the smooth muscle of the guinea‐pig taenia coli on stimulation with carbachol; the inward Ca current of the spike, a second voltage‐dependent Ca channel and an internal Ca store.

The initial increment of tension in response to carbachol is thought to be due to an increase in spike frequency which is probably the main source of Ca at low carbachol concentrations (< 10−6 m).

The maintained tension in the continuous presence of high concentrations of carbachol seems to involve continuous influx of membrane‐bound Ca by a potential‐dependent mechanism which can be very quickly deactivated, resulting in rapid relaxation. This mechanism can be blocked by 2 × 10−7 m methoxyverapamil (D600).

An internal Ca store can be released by high concentrations of carbachol (<10−6 m) and is probably responsible for the initial transient peak of tension, of about 5 min duration seen on continuous application of high concentrations of carbachol and for the tension increase in response to carbachol in tissues depolarized in high‐K.

Investigation of the properties of the store indicates that it; (i) is very rapidly filled by application of high extracellular Ca; (ii) empties after a few minutes in zero‐Ca EGTA Krebs solution; (iii) can be refilled in depolarized tissues in the presence of low concentrations of D600 and Mn, but does not refill during application of carbachol at concentrations greater than 10−6 m; (iv) contains enough Ca for one near‐maximal contraction and once emptied can assist relaxation by Ca re‐uptake.
IMIPRAMINE NORMALIZES NATURALLY‐OCCURRING AND DRUG‐INDUCED DIFFERENCES IN THE EXPLORATORY ACTIVITY OF RATS
Authors: HARRISON‐READ P.E. , STEINBERG HANNAH
Published: July 2012

Exploratory activity of female hooded rats was measured in a Y maze on two occasions, 1 week apart. Locomotion (maze arm entries), rearing, and head‐dipping into pots were scored for 5 min at each trial.

In control rats, differences between individuals in the amount of locomotion and rearing were consistent, as shown by significant test‐retest correlations (r = +0.55, and +0.83 respectively). There was no correlation between head‐dipping scores obtained in the two tests.

Imipramine (Imip) pretreatment before the second trial (10 mg/kg i.p. on the 3 preceding days, and 2.5 mg/kg 1 h before) abolished these correlations. The scatter of the scores about the mean was also reduced by Imip, but there was no significant change in mean scores. Thus Imip appeared to have a ‘normalizing’ effect on locomotion and rears: after pretreatment, scores tended to be more uniform, and no longer reflected naturally‐occurring individual differences.

Imip abolished the changes in exploratory activity produced by drugs which alter brain 5‐hydroxytryptamine metabolism: p‐chlorophenylalanine (100 mg/kg 24 h before testing) increased and dl‐5‐hydroxytryptophan (12.5 mg/kg 1 h before testing) decreased the fall in activity over the trial in saline‐treated rats but not that in Imip‐treated rats. In this case, Imip also produced an overall reduction in activity scores.

The normalizing effects of Imip on rat behaviour may be analogous to its therapeutic effects in human depressive disorders.
THROMBOXANE B2 INHIBITS THE PULMONARY INACTIVATION OF PROSTAGLANDIN E2 IN THE DOG
Authors: FITZPATRICK THOMAS M. , FRIEDMAN LAWRENCE S. , KOT PETER A. , RAMWELL PETER W.
Published: July 2012

The systemic vasodepressor response to intravenously administered prostaglandin E2 (PGE2, 0.3, 1.0 and 3.0 μg/kg) is potentiated during intravenous infusion of thromboxane B2 (TXB2, 1.0 μg kg−1 min−1) in the anaesthetized dog.

The augmented haemodynamic response returns toward control values following cessation of the TXB2 infusion.

The systemic haemodynamic responses to intra‐arterially administered PGE2, PGF2α and PGI2 as well as intravenously administered PGF2α and PGI2 are not altered by TXB2 infusion.

This study suggests that TXB2 inhibits the pulmonary inactivation of PGE2.

Arachidonic acid metabolites may interact, producing haemodynamic responses differing from their individual effects.
RELATION BETWEEN CALCIUM AND CARDIOVASCULAR REACTIVITY IN MINERALOCORTICOID‐INDUCED HYPERTENSION IN THE RAT
Authors: BERTHELOT A. , GAIRARD A. , GOYAULT M. , PERNOT F.
Published: July 2012

Previous work has shown that parathyroidectomy (PTX) decreases cardiovascular reactivity to noradrenaline in Sprague‐Dawley rats with mineralocorticoid‐induced (D) hypertension.

In order to explain this diminution of cardiovascular reactivity, we studied in vivo the influence of serum calcium levels on the cardiac and vascular response to noradrenaline (500 ng/kg). We used rats with or without parathyroids but fed a standard or a high‐calcium (+Ca) diet that re‐established a serum calcium level of about 100 mg/l. Work was performed in vagotomized, anaesthetized rats after ganglionic blockade with pentolinium and atropine sulphate.

Cardiac output was unchanged in all the experimental groups after 11 weeks of mineralocorticoid treatment. The enhancing effect of noradrenaline was not modified.

Since a serum calcium level of about 100 mg/l was sufficient to re‐establish vascular reactivity to exogenous noradrenaline in the PTX‐D rats, parathyroid hormone was not necessary.

The total and lanthanum‐resistant calcium fractions of the walls of the aorta were reduced in the PTX‐D rats. When serum calcium levels were re‐established at about 100 mg/l, there was no difference between PTX‐D and D rats.

It is postulated that the decreased storage of calcium in vascular smooth muscle cells of PTX‐D rats depresses the vascular effect of noradrenaline.
THE SELECTIVE ANTIMUSCARINIC ACTION OF STERCURONIUM
Authors: LI C.K. , MITCHELSON F.
Published: July 2012

The antimuscarinic activity of stercuronium, a competitive neuromuscular blocking drug, has been compared in the anaesthetized guinea‐pig, guinea‐pig atria, bladder and ileum, rabbit atria and the sympathetically innervated rabbit ear artery preparation using carbachol (CCh) as agonist.

In the anaesthetized guinea‐pig, stercuronium (0.2 and 2.0 μmol/kg) produced significantly greater inhibition (P < 0.05) of the bradycardia than of the vasodepressor response produced by CCh, the difference being 2 fold at the low dose and 5.8 fold at the higher dose.

In guinea‐pig atria the negative chronotropic response to CCh was inhibited to a similar degree to the negative inotropic response by stercuronium, whereas in bladder and ileum stercuronium was 17 fold less active as an antimuscarinic drug.

The affinity of stercuronium for the prejunctional muscarinic receptor on sympathetic nerve endings in the rabbit ear artery was similar to that for the muscarinic receptor mediating negative inotropic responses to CCh in the rabbit left atrium, and 2.3 fold less than the affinity for the muscarinic receptors in guinea‐pig atria.

A similar trend was observed with gallamine, another neuromuscular blocking drug, when results obtained in the rabbit ear artery preparation were compared to previously reported data. Also, the affinity of gallamine for muscarinic receptors mediating relaxation of the cat anococcygeus muscle was found to be similar to that for prejunctional muscarinic receptors in the rabbit ear artery.

It is suggested that stercuronium and gallamine have a greater affinity for cardiac receptors and the inhibitory muscarinic receptors on sympathetic nerve endings than for muscarinic receptors mediating contraction of bladder and ileum.
FURTHER STUDIES ON OPIATE RECEPTORS THAT MEDIATE ANTI‐NOCICEPTION: TOOTH PULP STIMULATION IN THE DOG
Authors: SKINGLE M. , TYERS M.B.
Published: July 2012

The antinociceptive activities of morphine, codeine and dextropropoxyphene (μ‐agonists), buprenorphine and Mr 2034 [(‐)5,9‐dimethyl‐2‐(tetrahydrofurfuryl)‐2′‐hydroxy‐6,7‐benzomorphan](k‐agonists) have been determined against nociceptive responses to electrical stimulation of the tooth pulp in the conscious dog.

Dose‐dependent increases in nociceptive thresholds were obtained for all of the analgesic drugs tested at doses within their antinociceptive range as determined in nociceptive pressure and chemical tests in rodents.
ENHANCEMENT OF THE TOXIC EFFECTS OF VERATRINE ON GUINEA‐PIG ATRIUM BY THRESHOLD INOTROPIC DOSES OF OUABAIN
Authors: HALLIDAY J. , HARDING S.E.
Published: July 2012

Isolated atria of guinea‐pigs were treated with veratrine until the initial signs of toxicity were seen. Ouabain was then added cumulatively, starting with a threshold inotropic concentration, 50 nm, until the tissue became dysrhythmic. It was found that a concentration of ouabain which by itself gave a positive inotropic effect of only 3%, significantly enhanced the toxicity of veratrine. Veratrine had no effect on the (Na+ + K+)‐adenosine triphosphatase ((Na+ + K+)‐ATPase) enzyme isolated from guinea‐pig ventricle. The conclusion drawn is that at threshold inotropic concentrations of ouabain it is likely that the (Na+ − K+)‐ATPase is inhibited rather than stimulated.
EFFECT OF PROPRANOLOL ON β‐ADRENOCEPTORS IN RAT HEARTS
Authors: BAKER STEPHEN P. , POTTER LINCOLN T.
Published: July 2012

The question of whether the chronic administration of propranolol modifies the numbers or properties of cardiac β‐adrenoceptors was examined because of many reports suggestive of cardiac hypersensitivity following the withdrawal of β‐antagonists. In three studies, rats were given (±)‐propranolol, 30 mg/day, orally or intraperitoneally, for 1 to 7 weeks. The numbers and affinities of specific binding sites for radioactive dihydroalprenolol in whole hearts from 60 control and 75 test animals were found to be the same. Thus catecholamine deprivation does not exert an important regulatory effect on most β‐receptors in the heart, as it does in the brain.
EFFECTS OF 5‐HYDROXYTRYPTOPHOL, A 5‐HYDROXYTRYPTAMINE METABOLITE, ON ISOLATED CEREBRAL ARTERIES OF THE DOG
Authors: FU L.H. WANG , HAYASHI SHIGEHIRO , TODA NOBORU
Published: July 2012

5‐Hydroxytryptophol (5‐HTOL) caused a dose‐dependent contraction of helically‐cut strips of dog cerebral arteries. The 5‐HTOL‐induced contraction was suppressed by cinanserin, as was the contraction induced by 5‐hydroxytryptamine (5‐HT). Treatment with 5‐HTOL shifted the dose‐response curve for 5‐HT to the right and downward in a dose‐dependent manner, but did not attenuate the contractile response to prostaglandin F2α. It may be concluded that 5‐HTOL elicits cerebroarterial contractions by activating tryptaminergic receptors and also interferes with the action of 5‐HT on the receptors.
KINETICS OF MORPHINE‐SENSITIVE [3H]‐ACETYLCHOLINE RELEASE FROM THE GUINEA‐PIG MYENTERIC PLEXUS
Authors: DOWN JAMES A. , SZERB JOHN C.
Published: July 2012

Longitudinal muscle‐myenteric plexus preparations from the guinea‐pig ileum were superfused at a constant rate while isotonic contractions were monitored.

The preparations were superfused with [3H]‐choline while stimulated supramaximally at 0.1 Hz followed by washout in the presence of hemicholinium‐3. The evoked release of the label due to a second 0.1 Hz stimulation in the absence of an anticholinesterase was measured.

Evoked efflux of the label was initially fast followed by a slower phase.

Morphine reduced the size of the pool and the rate of the initial fast efflux and the size of the pool but not the rate of the slow efflux evoked by supramaximal stimulation.

Submaximal stimulation reduced only the size of the pools from which the fast and slow efflux originated.

Naloxone reversed the depression of contractions and evoked release produced by morphine.

Results suggest that 0.1 Hz stimulation releases [3H]‐acetylcholine simultaneously from two pools. The fast release may originate from spontaneously firing units whose rate of discharge is depressed by morphine, while the slow release originates from neurones which do not fire spontaneously and whose threshold to field stimulation is increased by morphine.
CARDIAC β‐ADRENOCEPTORS DURING NORMAL GROWTH OF MALE AND FEMALE RATS
Authors: BAKER STEPHEN P. , POTTER LINCOLN T.
Published: July 2012

A binding assay involving (−)‐[3H]dihydroalprenolol (DHA) and KCl‐washed cardiac membranes was used to assess the numbers and affinities of β‐adrenoceptors in hearts from male and female rats varying in age from about 2 weeks to 18 months.

Although female rats grow more slowly and attain lower adult weights than male rats, heart weights increased in approximate proportion to body weight with little sex difference.

As heart weight increased about three fold, β‐receptors increased three fold. Since the number of myocardial cells is believed to be nearly constant during postnatal growth, the numbers of receptors/cell presumably increases similarly.

As heart weight increased, the number of β‐receptors per g of tissue decreased according to the equation: total pmol/g = 4.33 − 1.43 × heart weight, equally in males and females.

Dissociation constants for DHA (2 to 4 nm) remained the same, and equal, in male and female rats during their growth.

An excellent correlation was found between the decline in β‐receptors/g tissue during growth and the decline in the area of the external sarcolemma/g tissue. The data suggest that the number of receptors per unit area remains constant during growth, and thus that cell surface area is a major factor determining normal numbers of receptors per cardiocyte.