bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECT OF ANAESTHETIC AGENTS ON CEREBRAL CORTICAL RESPONSES IN THE RAT
Authors: ANGEL A. , GRATTON DENISE A.
Published: July 2012

In rats, surgically anaesthetized with Urethane, an increase in the depth of anaesthesia upon administration of ethyl carbamate (Urethane), pentobarbitone sodium (Nembutal), thiopentone sodium (Intraval), althesin, ketamine, trichloroethylene, halothane, methoxyflurane, diethyl ether, ethyl‐vinyl ether, cyclopropane, enflurane or chloroform resulted in a dose‐dependent increase in the latency, and decrease in the amplitudes of the initial positive and negative components of the short latency cortical response to electrical stimuli applied to the forepaw.

The same changes were seen when starting from initially unanaesthetized rats and anaesthetizing them with Urethane.

With all the inhalational agents used these changes lasted for as long as the administration except with nitrous oxide where the changes in the cortical response were transient.

The tranquillizing agents diazepam, chlordiazepoxide, and haloperidol showed no such action. Chloral hydrate and chlorpromazine, on the other hand, produced moderate changes in the evoked cortical response similar to those seen with the other anaesthetic agents used.
THE EFFECT OF CIMETIDINE ON BASAL GASTRIC ACID SECRETION IN THE RAT
Authors: BROUGHTON N.S. , MORRIS J.F.
Published: July 2012

The effect of cimetidine on the basal gastric acid secretion of the rat has been investigated in an anaesthetized lumen‐perfused preparation.

Six rats previously given large doses of cimetidine orally showed no significant difference in basal gastric acid secretion when compared with six control rats.

Intravenous administration of 1 mg and 8 mg of cimetidine failed to inhibit significantly basal gastric acid secretion.

Although rats with a basal gastric acid secretion above 2.5 μEq/10 min showed a consistent small reduction in basal gastric acid secretion after intravenous cimetidine, this was not seen in rats with a basal gastric acid secretion below 2.5 μEq/10 min.

These results contrast sharply with the pronounced inhibition of basal gastric acid secretion by cimetidine in man and the possible reasons for this are discussed.

The results are also contrasted with previous work on gastric fistula rats which showed higher basal gastric acid secretion and significant inhibition by cimetidine.
ROLE OF ADRENAL MEDULLA IN MORPHINE‐INDUCED HYPERTHERMIA THROUGH CENTRAL ACTION
Authors: WALLENSTEIN MARTIN C.
Published: July 2012

The role of the adrenal glands, in morphine‐induced hyperthermia was studied in normal, chemically‐sympathectomized, adrenalectomized, adrenal‐demedullated or splanchnicotomized rats.

In restrained female rats, 5 mg/kg morphine produced hyperthermia whereas 20 mg/kg and 40 mg/kg produced hypothermia.

After adrenalectomy, 5 mg/kg morphine did not produce hyperthermia.

After adrenal‐demedullation or adrenal‐denervation (splanchnicotomy), 5 mg/kg morphine did not produce hyperthermia.

The results suggest that, in the rat, the adrenal medulla plays an important role in morphine‐induced hyperthemia, and that morphine acts centrally to stimulate the medulla.
INHIBITION BY SUBSTANCE P OF SOME PERIPHERAL ACTIONS OF ACETYLCHOLINE IN THE CAT
Authors: CLARK S.L. , RYALL R.W.
Published: July 2012

The effect of substance P on contractions of the nictitating membrane and pressor responses to acetylcholine (ACh) and dimethylphenyl‐piperazinium (DMPP) which were mediated via nocotinic receptors was studied in cats anaesthetized with chloralose.

Substance P (2–20 nmol) injected into the lingual artery giving estimated concentrations in arterial blood of 10−6 to 10−5 m, or intravenously giving estimated concentrations in blood of 10−8 to 10−7 m, reduced hexamethonium‐sensitive but not atropine‐sensitive responses.

The pressor effects of ACh and DMPP injected intra‐arterially in atropinized and non‐atropinized cats respectively were consistently attenuated by substance P given intra‐arterially or intravenously.

The contractile effect of ACh in atropinized and of DMPP in non‐atropinized cats was attenuated by substance P injected intra‐arterially but only rarely when the polypeptide was injected intravenously.

The depressor effects of substance P per se were variable in magnitude and duration as were the inhibitory effects upon nicotinic receptors. The depressor and inhibitory effects of substance P were unrelated.

There was desensitization to all of these effects of substance P which probably contributed to the variation in the magnitude of the effects observed.

Substance P had no effect on muscarinic actions of acetyl‐β‐methylcholine on the nictitating membrane or blood pressure.

The results are discussed in relation to the ubiquity of the modulatory actions of substance P on nicotinic receptors and in relation to the possible physiological significance of the action.
HOMOGENEOUS AND NON‐HOMOGENEOUS DISTRIBUTION OF INHIBITORY AND EXCITATORY ADRENOCEPTORS IN THE LONGITUDINAL MUSCLE OF THE GUINEA‐PIG ILEUM
Authors: BAUER V. , KURIYAMA H.
Published: July 2012

The effects of adrenoceptor agonists and antagonists on spontaneous and evoked membrane activities of longitudinal muscle cells from different parts of the guinea‐pig ileum were observed, using microelectrode methods.

Isoprenaline inhibited the generation of spikes in cells in the terminal (0–3 cm from the ileocaecal valve) and proximal (more than 50 cm from the ileocaecal valve) regions of the ileum, with no change on the membrane potential and ionic conductance of the membrane. These actions of isoprenaline were abolished by propranolol.

Noradrenaline and phenylephrine depolarized the membrane and increased both the spike frequency and ionic conductance of cell membranes of the terminal ileum, whereas noradrenaline and clonidine hyperpolarized the membrane, increased the ionic conductance of the membrane and inhibited the spontaneously generated spikes from cells of the proximal ileum. The excitatory effect of phenylephrine in the cells of the proximal ileum and the inhibitory effect of clonidine on cells of the terminal ileum were less pronounced.

The excitatory actions of noradrenaline or phenylephrine were antagonized by prazosin and phentolamine, but not by yohimbine, whereas the inhibitory actions of noradrenaline or clonidine were antagonized by yohimbine and phentolamine but not by prazosin.

The cholinergic e.j.ps evoked by field stimulation to the tissue were not affected by isoprenaline or phenyleprine but were inhibited by noradrenaline and clonidine, in both the terminal and proximal regions of the ileum. These actions of noradrenaline and clonidine were antagonized by yohimbine but not by prazosin.

The results indicate that in the myenteric plexus and longitudinal muscle tissues of the guinea‐pig ileum there are prejunctional inhibitory (α2), postjunctional inhibitory (α2 and β) and postjunctional excitatory (α1) adrenoceptors. The homogeneous distributions of prejunctional α2‐ and postjunctional β‐adrenoceptors in the ileum are responsible for inhibitions of cholinergic excitatory junction potentials (e.j.ps) and spontaneous spike activities, respectively. The density of distribution of the postjunctional α1‐adrenoceptors is higher in the terminal than in the proximal regions, and these distributions are reversed in the case of the postjunctional α2‐adrenoceptors. The postjunctional α1‐adrenoceptors are probably responsible for the membrane depolarization and α2‐adrenoceptors for the hyperpolarization induced by catecholamines.
TRICYCLIC ANTIDEPRESSANTS VARY IN DECREASING α‐ADRENOCEPTOR SENSITIVITY WITH CHRONIC TREATMENT: ASSESSMENT WITH CLONIDINE INHIBITION OF ACOUSTIC STARTLE
Authors: DAVIS MICHAEL , MENKES DAVID B.
Published: July 2012

Clonidine inhibition of the acoustic startle reflex in the rat was used as a behavioural measure of α2‐adrenoceptor sensitivity following acute or chronic administration of tricyclic antidepressants.

Chronic (14 day) administration of desipramine (10 mg/kg, i.p.) attenuated the depressant effect of clonidine (20 or 40 Mg/kg) on the startle reflex.

No change in response to clonidine was obtained after chronic treatment with two other tricyclic antidepressants, amitriptyline (10 mg/kg) or iprindole (5 mg/kg).

Acute administration of these tricyclics (1 h) did not modify the effect of clonidine on startle.

It is suggested that the development of α2‐adrenoceptor subsensitivity produced by chronic tricyclics may be unique to those compounds, such as desipramine, which are active in blocking the uptake of noradrenaline.
INFLUENCE OF CHLORALOSE AND PENTOBARBITONE SODIUM ON ATRIOVENTRICULAR CONDUCTION IN DOGS
Authors: DUCHENE‐MARULLAZ P. , FABRY‐DELAIGUE R. , GUEORGUIEV G. , KANTELIP J.P.
Published: July 2012

Atrial pacing at progressively increasing frequencies was performed on unanaesthetized dogs through electrodes placed aseptically in the wall of the right atrium and exteriorized in the neck region.

Heart rate and two atrioventricular conduction (AVC) parameters, namely the Wenckebach Point (one or two systole block at the end of expiration)‐and the maximum atrioventricular conduction frequency (the frequency of pacing for which ventricles do not follow any auricular stimulation) were measured by electrocardiography.

Chloralose (0.08 g/kg i.v.) did not affect either heart rate or AVC but significantly reduced the effect of atropine (0.1 mg/kg i.v.) on all three parameters measured. The effect of isoprenaline (0.25 μg kg−1 min−1) remained unchanged.

Pentobarbitone Na (25 mg/kg i.v.) increased heart rate and usually caused the Wenckebach Point to disappear. It reduced the effects of atropine but did not modify those of isoprenaline.

In view of these results we suggest that pentobarbitone Na be avoided as an anaesthetic agent in AVC studies. It is possible to dispense with an anaesthetic agent if the technique described here is used.
FREQUENCY‐DEPENDENT DEPRESSION OF GANGLIONIC TRANSMISSION BY PROPRANOLOL AND DILTIAZEM IN THE SUPERIOR CERVICAL GANGLION OF THE GUINEA‐PIG
Authors: ITO H. , NISHI K.
Published: July 2012

Effects of propranolol and diltiazem on ganglionic transmission in the superior cervical ganglion of the guinea‐pig were investigated with intracellular recording techniques.

Propranolol and diltiazem (5 × 10−6‐10−5 m) induced a transmission failure in the ganglion upon preganglionic nerve stimulation at high frequency (25–30 Hz) without affecting action potentials induced by direct stimulation of the soma membrane, or potentials induced by iontophoretically applied acetylecholine.

The results suggest that propranolol and diltiazem may act on preganglionic nerve terminals to inhibit Ca2+ influx in a frequency‐dependent manner. These agents may depress excess sympathetic activity without much affecting normal ganglionic transmission.
THE EFFECTS OF THEOPHYLLINE AND 4‐(3‐BUTOXY‐4‐METHOXYBENZYL)‐2‐IMIDAZOLIDINONE (RO 20–1724) ON PROTEIN SECRETION FROM RAT PAROTID GLAND
Authors: AFARI G. , TENENHOUSE A. , VACHON C.
Published: July 2012

The effects of two chemically distinct cyclic nucleotide phosphodiesterase (PDE) inhibitors on protein secretion from superfused rat parotid gland were studied.

In the presence of 1.0 mm Ca2+, Ro 20–1724 (10 μm), an imidazolidinone derivative, increased the secretory response to isoprenaline 100% and the isoprenaline‐dependent accumulation of adenosine cyclic 3′,5′‐monophosphate (cyclic AMP) 300–400%. At this concentration Ro 20–1724 alone did not cause protein secretion, accumulation of cyclic AMP or significantly inhibit PDE activity in cell‐free preparations from parotid gland.

In the absence of added Ca2+ and in the presence of 1.0 mm EGTA, Ro 20–1724 inhibited the secretory response to isoprenaline 65% while increasing isoprenaline‐dependent cyclic AMP accumulation 200%.

In the presence of Ca2+, theophylline (10 mm) stimulated protein secretion but did not cause the accumulation of cyclic AMP. When combined with isoprenaline the rate of secretion was greater than the sum of the effects of the individual drugs but there was no effect of theophylline on the isoprenaline‐dependent accumulation of cyclic AMP.

Theophylline‐stimulated protein secretion is increased by omitting Ca2+ from the superfusion medium without any detectable change in cyclic AMP accumulation. Under these conditions Ro 20–1724 inhibits theophylline‐stimulated protein secretion and the maximum rate of protein secretion in the presence of isoprenaline and theophylline is no greater than that seen with either agent alone.

It is concluded that the theophylline effects do not result from inhibition of PDE. It is suggested that the primary action of both drugs on parotid gland acinar cells is to alter the distribution of intracellular Ca2+. Ro 20–1724 may also inhibit Ca2+/calmodulin activated enzymes such as PDE.
α‐ADRENOCEPTOR BLOCKING PROPERTIES OF RAUBASINE IN PITHED RATS
Authors: DEMICHEL PATRICIA , GOMOND PATRICK , ROQUEBERT JACQUES
Published: July 2012

Raubasine was compared with yohimbine and corynanthine in pithed rats. Antagonist activity at α1‐adrenoceptors was evaluated on the pressor response to electrical stimulation of the spinal sympathetic outflow and to phenylephrine administration, both being reduced by raubasine in the dose range 1 to 4 mg/kg. Corynanthine was quantitatively similar, but yohimbine was not only less potent but also in doses of 0.125 to 0.5 mg/kg enhanced the effects of electrical stimulation.

Antagonist activity at α2‐adrenoceptors was determined against the inhibitory effects of clonidine on tachycardia induced by electrical stimulation of cardiac sympathetic nerves and against the pressor responses to B‐HT‐933 injection. Raubasine up to 4 mg/kg, like corynanthine, did not affect the pressor responses to B‐HT‐933 nor did it reduce the inhibitory effect of clonidine. By contrast yohimbine reduced the response to BHT‐933 and antagonized clonidine as well as enhancing the tachycardia caused by electrical stimulation.

The results indicate that, in vivo, raubasine, like corynanthine, is a selective antagonist at α1‐adrenoceptors and that yohimbine is more potent in blocking α2‐than α1‐adrenoceptors.
EFFECT OF MUSCARINE ON RELEASE OF CATECHOLAMINES FROM THE PERFUSED ADRENAL GLAND OF THE CAT
Authors: KIRPEKAR S.M. , PRAT J.C. , SCHIAVONE M.T.
Published: July 2012

The secretory effect of muscarine was studied in the perfused adrenal gland of the cat. During perfusion of the adrenal gland with Krebs‐bicarbonate solution containing muscarine 480 μm, the rate of catecholamine (CA) secretion was 2.02 ± 0.43 μg/2 min in the first 2 min; thereafter, CA output declined only moderately, to reach about 70% of the initial value after 10 min. Secretory responses to brief infusions of muscarine remained reproducible for at least the first 3 infusions.

When the adrenal gland was perfused with muscarine (480 μm), infusions of high K+, nicotine, or veratridine produced their usual responses. A 100 fold lower dose of muscarine also failed to modify these responses.

During perfusion with high K+, muscarine evoked a secretory response that was only slightly smaller than the response to muscarine alone.

It is concluded that muscarine and nicotine activate CA secretion in the cat adrenal gland by independent mechanisms and that the muscarinic response, unlike the nicotinic response, is not readily desensitized.
DISSIMILAR INFLUENCES OF SOME INJECTABLE ANAESTHETICS ON THE RESPONSES OF RETICULOSPINAL NEURONES TO INHIBITORY TRANSMITTERS IN THE LAMPREY
Authors: CULLEN K.D. , MARTIN R.J.
Published: July 2012

Intracellular recordings were made from identified bulbar reticulo‐spinal neurones in the medulla of lamprey ammocoetes. Responses to iontophoretically applied inhibitory transmitters were measured as changes in membrane potential and input resistance.

Dose‐dependent alterations in the responses to γ‐aminobutyric acid (GABA) and glycine during bath application of injectable anaesthetic drugs were measured; the compounds used were pentobarbitone, ketamine, metomidate and the steroid mixture alphaxalone/alphadolone (Saffan).

GABA responses were potentiated by pentobarbitone (1–3 × 10−4m) and prolonged by ketamine (3.7 × 10−5m); but depressed by high concentrations (10−3m) of all drugs, as well as by anaesthetic concentrations of alphaxalone (1–3 × 10−5m).

Glycine responses were depressed by alphaxalone (1–3 × 10−5m) and by supra‐anaesthetic concentrations of ketamine (3.7 × 10−4 m) and metomidate (1.8 × 10−3m). No drug potentiated the glycine responses.

In the absence of an effect common to the 4 anaesthetics, it is concluded that neither potentiation nor inhibition of all GABA or glycine responses is an essential feature of anaesthesia. However, effects comparable to those described here may contribute to the overall clinical picture during anaesthesia of higher vertebrates. The findings do not support the notion that all anaesthetic agents act on biological membranes by a single mechanism.
INTERACTION OF NEUROTENSIN WITH THE SUBSTANCE P RECEPTOR MEDIATING HISTAMINE RELEASE FROM RAT MAST CELLS AND THE FLARE IN HUMAN SKIN
Authors: FOREMAN J.C. , JORDAN C.C. , PIOTROWSKI W.
Published: July 2012

Substance P induced histamine release from rat peritoneal mast cells in a dose‐dependent manner over the concentration range 1 to 10 μm.

At concentrations in the range 2.5 to 10 μm, neurotensin produced only about 5% release of histamine, which was substantially less than the maximum effect obtained with substance P.

Neurotensin, 2.5 to 10 μm produced graded inhibition of histamine release induced by substance P. The inhibitory effect of neurotensin was not seen when histamine release was induced by an antigen‐antibody reaction or by the ionophore, A 23187. Some evidence was obtained to suggest that compound 48/80 may interact with the same receptor as substance P and neurotensin.

[d‐Arg8]neurotensin, [d‐Arg9]neurotensin, xenopsin and the C‐terminal octapeptide of substance P (SP4–11) all inhibited histamine release by substance P, but physalaemin did not.

Neurotensin inhibited the wheal and flare reactions induced by substance P in human skin.

[d‐Trp7,9]substance P released histamine from rat mast cells and was about 12 times more potent than substance P itself. [d‐Trp7,9]SP1–11 also produced wheal and flare responses in human skin, being 1.8 times more potent than substance P in the production of flare.
THE ACTIONS OF SOME ESTERS OF 4‐HYDROXYQUINUCLIDINE ON GUINEA‐PIG ILEUM, ATRIA AND RAT FUNDUS STRIP
Authors: BARLOW R.B. , KITCHEN R.
Published: July 2012

The acetyl, phenylacetyl, and diphenylacetyl esters of 4‐hydroxyquinuclidine and their methiodides have been prepared.

4‐Diphenylacetoxyquinuclidine methiodide has higher affinity for muscarinic receptors than 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (4‐DAMP methiodide) but it is less selective. At 30°C its affinity for receptors in ileum is about 5 times that for receptors in atria, a difference similar to that found with diphenylacetoxytrophine methiodide. With 4‐DAMP methiodide affinity for receptors in the ileum is over 10 times that for receptors in atria.

4‐Diphenylacetoxyquinuclidine methiodide has higher affinity for muscarinic receptors than 3‐diphenylacetoxyquinuclidine hydrochloride or its methiodide.

4‐Acetoxyquinuclidine hydrochloride has less than one‐hundredth of the activity of 3‐acetoxyquinuclidine hydrochloride (acecyclidine) on guinea‐pig ileum, atria, and rat fundus: however, 4‐acetoxyquinuclidine methiodide is consistently more active than its 3‐isomer, though it is only about 1/25 times as active as acecyclidine.

4‐Acetoxyquinuclidine hydrochloride is only a poor substrate for electric eel acetylcholinesterase: its affinity is similar to that of acecyclidine but it is greatly reduced by methylation.

The relations between the structure and activity of the agonists are very different from the relations between the structure and affinity of the antagonists, which supports the view that agonists and antagonists bind to different conformations of the muscarinic receptor.
POTASSIUM ACTIVATION OF [3H]‐CHOLINE ACCUMULATION BY ISOLATED SYMPATHETIC GANGLIA OF THE RAT
Authors: HIGGINS A.J. , NEAL M.J.
Published: July 2012

The effect of K‐depolarization on the uptake of low and high concentrations of [3H]‐choline by isolated superior sympathetic ganglia of the rat has been studied.

In unstimulated ganglia, the uptake of [3H]‐choline (0.1 μm) (‘high affinity uptake’) was unaffected by denervation or by hemicholinium‐3 (HC‐3), suggesting uptake by structures other than cholinergic nerve terminals.

K‐depolarization of the ganglia increased [3H]‐choline accumulation by the high affinity uptake process but in contrast the ‘low affinity’ accumulation of [3H]‐choline (100 μm) was decreased.

The K‐activated, ‘high affinity’ component of choline uptake was highly sodium‐dependent, inhibited by HC‐3, and was abolished by denervation.

In incubation conditions designed to prevent transmitter release (Ca‐free medium and high‐Mg medium), the K‐activated uptake of [3H]‐choline was abolished.

It is concluded that in unstimulated ganglia, there is little choline uptake by nerve terminals. However, when the terminals are depolarized, choline uptake is increased by the activation of a sodium‐dependent, HC‐3‐sensitive transport process. The activation of this uptake process is apparently associated with the release of acetylcholine from the terminals, or by changes in ionic fluxes, and not by the depolarization per se.
SELECTIVE α1‐AND α2‐ADRENOCEPTOR AGONIST‐INDUCED CONTRACTIONS AND 45Ca FLUXES IN THE RAT ISOLATED AORTA
Authors: GODFRAIND T. , MILLER R.C. , LIMA J. SOCRATES
Published: July 2012

Contractile responses produced by the α1‐adrenoceptor selective agonist, phenylephrine, and the α2‐adrenoceptor selective agonists, oxymetazoline and clonidine, have been compared to those produced by noradrenaline (non selective) in the rat aorta.

The relative order of potency of the agonists was noradrenaline > phenylephrine > clonidine > oxymetazoline. Noradrenaline and phenylephrine produced similar maximal responses. The maximal responses produced by oxymetazoline and clonidine were about 59% and 24% respectively of those produced by noradrenaline.

Concentrations of agonists producing maximal contractions exhibited different response‐time relationships. Responses to noradrenaline and phenylephrine were biphasic while responses induced by oxymetazoline and clonidine were monophasic.

In calcium‐free solution, contractions stimulated by oxymetazoline and clonidine were almost abolished while those stimulated by noradrenaline and phenylephrine were reduced by about 60–70%. The calcium entry blocker, cinnarizine, almost completely inhibited responses to oxymetazoline and clonidine and reduced noradrenaline‐ and phenylephrine‐stimulated responses by about 60%.

All the agonists stimulated the uptake of 45Ca into the La3+‐resistant Ca2+ fraction of the artery but only noradrenaline and phenylephrine stimulated the efflux of 45Ca into calcium‐free solution. The 45Ca uptake stimulated by oxymetazoline and clonidine was abolished by cinnarizine and that stimulated by noradrenaline and phenylephrine was reduced by about 85%.

It is concluded that clonidine and oxymetazoline stimulate contractions that are totally dependent on extracellular calcium. Noradrenaline and phenylephrine stimulate contractions that are partly dependent on extracellular calcium and partly dependent on intracellular calcium stores.
THE CONTRACTILE EFFECTS OF 5‐HYDROXYTRYPTAMINE ON THE RAT ISOLATED VAS DEFERENS
Authors: HAY D.W.P. , WADSWORTH R.M.
Published: July 2012

5‐Hydroxytryptamine (5‐HT) (5.16–1291 μm) produced a phasic contraction followed later by rhythmic contractions in the rat vas deferens, primarily in the epididymal half. 5‐HT (129 μm) produced no response in Ca2+‐free solution. Nifedipine (0.29 μm) or verapamil (2.04 μm) inhibited the initial phasic response to 5‐HT, but inhibition of the rhythmic contractions required concentrations 5 fold (nifedipine) or 30 fold (verapamil) higher.

Methysergide (2.13 μm) abolished the phasic and reduced the frequency of the rhythmic contractions. Phentolamine (2.65 μm) did not affect the phasic response but reduced the amplitude of the rhythmic contractions. The combination of phentolamine (2.65 μm) and methysergide (2.13 μm) completely abolished the response to 5‐HT (129 μm).

Desipramine (1.32 μm) had no effect on the phasic response to 5‐HT (129 μm), but the rhythmic contractions were reduced in amplitude with no effect on their frequency.

In vasa deferentia removed from reserpine‐treated or from guanethidine‐denervated rats, both phasic and rhythmic components of the 5‐HT (129 μm) contraction were augmented due to supersensitivity.

It is concluded that the phasic component of the 5‐HT contraction is mediated by post‐junctional 5‐HT receptors, while the rhythmic component is mediated by the combination of post‐junctional 5‐HT receptors and noradrenaline released from neuronal stores. Assuming that nifedipine and verapamil are acting solely by inhibition of calcium channels, the phasic and rhythmic components of the 5‐HT response may be mediated through separate Ca2+ channels. If this is correct, one channel might be a voltage‐dependent channel and the other could be similar to, but distinct from the channel mediating the response to methoxamine.
COMPARISON OF THE ACTIONS OF CENTRALLY AND PERIPHERALLY ADMINISTERED CLONIDINE AND GUANFACINE IN THE RABBIT: INVESTIGATION OF THE DIFFERENCES
Authors: BARBER N.D. , REID J.L.
Published: July 2012

Guanfacine was administered intravenously to rabbits and produced a dose‐dependent lowering of blood pressure.

Clonidine and guanfacine, administered to rabbits intravenously (30 μg/kg and 300 μg/kg respectively) and intracisternally (3 μg/kg and 12 μg/kg respectively) caused a similar degree of hypotension, apparently of central origin.

Saliva flow in vivo was estimated. Clonidine (30 μg/kg, i.v.) caused a significant decrease in salivation (P<0.05) for the first 50 min after injection. Guanfacine caused a significant fall (P<0.05) only at 50 and 180 min after injection.

Apparent partition coefficients for an octanol/buffer system at pH 7.4 for clonidine and guanfacine were 5.4 and 21.2 respectively.

Measurement of guanfacine levels concurrently in both plasma and brain showed that guanfacine had higher brain than plasma levels and that the brain levels were fairly constant over the 3 h measured. Brain:plasma ratios were 2.1:1, 5.3:1 and 13.6:1 after 15, 90 and 180 min respectively.

These results suggest that the long duration of action of guanfacine is due to its persistence at its central site of action.
THE BINDING PROPERTIES OF THE MUSCARINIC RECEPTORS OF THE CYNOMOLGUS MONKEY CILIARY BODY AND THE RESPONSE TO THE INDUCTION OF AGONIST SUBSENSITIVITY
Authors: BÁRÁNY E. , BERRIE C.P. , BIRDSALL N.J.M. , BURGEN A.S.V. , HULME E.C.
Published: July 2012

The binding properties of the muscarinic receptors in the ciliary muscle of cynomolgus monkeys have been evaluated.

The concentration of receptor binding sites is the highest yet reported. As found in many species and tissues, there are subclasses of agonist binding sites. Agonist binding is not affected by the non‐hydrolysable guanosine triphosphate (GTP) analogue, GppNHp, suggesting that these receptors are not linked to adenylate cyclase.

Ciliary muscles made subsensitive by treatment with muscarinic agonists have a decreased receptor concentration but no other changes in the binding properties of the receptors could be detected.
Studies on RX 781094: a selective, potent and specific antagonist of α2‐adrenoceptors
Authors: Doxey J.C. , Roach A.G. , Smith C.F.C.
Published: July 2012

The selectivity and specificity of RX 781094 [2‐(2‐(1,4 benzodioxanyl))2‐imidazoline HCl] for α‐adrenoceptors have been examined in peripheral tissues.

In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional α2‐adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea‐pig ileum (pA2 = 8.55).

Although RX 781094 was also a competitive antagonist at the postjunctional α1‐adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated α2/α1‐adrenoceptor selectivity ratio for RX 781094 was 288.

The rank order of α2/α1‐adrenoceptor selectivities for the antagonists studied was RX 781094 > RS 21361 > yohimbine > piperoxan > phentolamine > WB 4101 > prazosin.

RX 781094 had extremely low affinity for β‐adrenoceptors, histamine receptors, cholinoceptors, 5‐hydroxytryptamine and opiate receptors in vitro.

In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional α2‐adrenoceptor agonist effects of clonidine and guanabenz on electrically‐induced contractions of the vas deferens and anococcygeus muscle respectively.

In the vas deferens the rank order of α2‐adrenoceptor antagonist potencies was RX 781094 > phentolamine > piperoxan > yohimbine > RS 21361 > WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle.

In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional α2‐adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional α1‐adrenoceptors.

RX 781094 had little effect on the cardiovascular responses to 5‐hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone.

These results demonstrate that RX 781094 is a potent and selective α2‐adrenoceptor antagonist with a high degree of specificity for these receptors.
The evaluation of different types of anti‐convulsant drug activity against leptazol‐induced epileptogenic activity in the anaesthetized rat
Authors: Kent A.P. , Webster R.A.
Published: July 2012

The effects of various anticonvulsant drugs were evaluated quantitatively on the development of the epileptogenic EEG, induced by the intravenous infusion of leptazol in rats anaesthetized with urethane.

Leptazol alone produced five distinct phases of EEG activity developing from early wave and small spike and wave activity to larger spikes which later grouped and led to full body convulsion (FBC).

Drugs effective in petit mal such as clonazepam (0.1 and 0.25 mg kg−1) and ethosuximide (100 and 200 mg kg−1), significantly delayed the time to FBC by prolonging the early phases of the epileptogenic EEG and delaying the appearance of spiking.

Drugs effective in grand mal such as sodium valproate (60 mg kg−1) and phenytoin (5 mg kg−1) significantly prolonged the time to FBC by extending the later phases of the EEG and the development and grouping of spikes. Higher doses of these compounds were without effect. Carbamazepine and phenobarbitone produced mixed effects but were generally not markedly anticonvulsant.

The model is sensitive to drugs effective in both petit mal and grand mal, and appears able to differentiate usefully between them.
Neuronal influence on the mechanical activity of the ciliary muscle
Authors: Suzuki Ryo
Published: July 2012

Neuronal effects and the pharmacological properties of the bovine ciliary muscle were investigated in vitro. The bovine ciliary muscle exhibited no spontaneous activity.

Electrical stimulation of an isolated short ciliary nerve produced distinct contractions. The minimal stimulus duration required to evoke a contraction was 0.2 ms and amplitude of the contraction was maximal at 2 ms. Twitch or incomplete tetanus reached a complete tetanus with 4 Hz stimulation.

Raising the external potassium concentration from 5.9 to 158.8 mm produced a contracture which consisted of an initial phasic and then tonic components.

The contractions generated by either electrical stimulation (0.2–100 ms) or high K were potentiated by physostigmine and completely inhibited by atropine. Neither adrenoceptor agonists nor blockers influenced these contractions.

Application of tetraethylammonium (TEA), potentiated the electrically‐induced ciliary muscle contraction, and the effect of TEA was not completely inhibited by high concentrations of either atropine or tetrodotoxin. Thus, TEA presumably acts both pre‐junctionally and post‐junctionally to increase the contractile development of ciliary muscle.

The ciliary contractile response is primarily mediated by acetylcholine released from nerves, and this response is accompanied by a negligible contribution from the sympathetic nerves. Depolarization induced by electrical currents or by high K was ineffective in evoking contraction of the ciliary muscle.

The results suggest that excitation of the ciliary muscle is probably mediated via junction potentials or by a direct transmitter action without any very great change in the potential. Action potentials are probably generated in the presence of TEA.
Evidence against the temperature‐dependent interconversion of histamine H1‐ and H2‐receptors in the guinea‐pig ileum
Authors: Bertaccini G. , Zappia L.
Published: July 2012

The possible temperature‐dependent interconversion of histamine H1‐ and H2‐receptors in the guinea‐pig ileum suggested from previous studies was re‐investigated by use of new and selective H2‐receptor agonists and antagonists.

Chlorpheniramine, an H1‐blocker, caused a rightward shift of the cumulative histamine dose‐response curve at both 37°C and 12°C. Conversely cimetidine and tiotidine, two H2‐receptor blockers, were ineffective at both temperatures. Metiamide behaved as a non competitive antagonist at 12°C but only in very high concentrations.

Dimaprit and impromidine, two selective H2‐receptor agonists, were inactive at both 37°C and 12°C when given alone, whereas at both temperatures they elicited the already described relaxation of the contractions induced by histamine.

Similar results were obtained on the guinea‐pig whole ileum and on the longitudinal muscle strip: this indicates a lack of interference of the circular smooth muscle.

Our results allow us to conclude that no temperature‐dependent interconversion of histamine H1‐ and H2‐receptors occurs in the guinea‐pig ileum.
Comparison of the effects of bicuculline and strychnine on brain stem auditory evoked potentials in the cat
Authors: Martin M.R. , Penix L.P.
Published: July 2012

Experiments were performed to determine the effects of intravenously applied bicuculline and strychnine on the click‐evoked brain stem auditory evoked potentials (BAEP) of cats.

The BAEP was not affected by bicuculline (0.5 mg/kg, i.v.) administration. Strychnine (0.2 mg/kg, i.v.) administration caused a significant increase in the amplitude of peak 4, which is thought to be produced by potentials in the superior olive, lateral lemniscus and inferior colliculus.

These results suggest that strychnine blocks glycinergic inhibitory inputs to these auditory structures.
The effect of chronic antidepressant administration on β‐adrenoceptor function of the rat pineal
Authors: Cowen P.J. , Fraser Sheila , Grahame‐Smith D.G. , Green A.R. , Stanford Clare
Published: July 2012

The β‐adrenoceptor agonist, isoprenaline (1.5–3.0 mg kg−1 intravenously), produced a dose‐related increase in rat pineal melatonin content. This increase was prevented by pretreatment with the selective β1‐adrenoceptor antagonist, atenolol (2 mg kg−1), but not by the β2‐adrenoceptor antagonist, butoxamine (2 mg kg−1). The β2‐adrenoceptor agonist, terbutaline (5.0 mg kg−1), produced a moderate increase in pineal melatonin content.

Repeated daily administration of desmethylimipramine (10 mg kg−1 for 10 days) and map‐rotiline (10 mg kg−1 for 10 days), antidepressants predominantly inhibiting noradrenaline (NA) uptake, reduced the isoprenaline‐induced increase in pineal melatonin content. Amitriptyline (20 mg kg−1 for 14 days), a drug which inhibits both NA and 5‐hydroxytryptamine (5‐HT) uptake, had a similar effect. The β‐adrenoceptor agonist, clenbuterol (5 mg kg−1 for 14 days), also attenuated the increase in pineal melatonin produced by isoprenaline.

In contrast, chronic administration of the selective 5‐HT uptake inhibitor, fluoxetine (10 mg kg−1 for 10 days), or the antidepressants, iprindole and mianserin (both 20 mg kg−1 for 14 days), which do not inhibit monoamine uptake, failed to reduce the increase in pineal melatonin following isoprenaline. Repeated electroconvulsive shock was similarly without effect.

Ten hours after the final dose of desmethylimipramine (10 mg kg−1) once daily for 10 days there was no change in the usual dark phase increase in pineal melatonin.

The data suggest that repeated administration of certain antidepressant drugs results in reduced pineal β‐adrenoceptor sensitivity. However the lack of change in the dark phase increase in pineal melatonin following repeated desmethylimipramine, implies that the reduced β‐adrenoceptor sensitivity may be part of an adaptive process which maintains normal pineal function. Therefore the decrease in β‐adrenoceptor number in the brain reported after chronic antidepressant administration may not be associated with a change in overall synaptic function.
Seasonal variations in drug response and staircase phenomena in atrial muscle from a hibernating rodent (Spermophilus richardsonii)
Authors: Charnock John S. , Dryden William F. , Marshall Richard J.
Published: July 2012

Electrically driven atrial muscle from a hibernating rodent (Spermophilus richardsonii) showed marked seasonal variations in inotropic responsiveness to both the cardiac glycoside actodigin and to raised extracellular calcium concentration. In contrast, glycoside toxicity was apparent and comparable in all tissues.

These variations were accompanied by changes in force‐frequency (‘staircase’) characteristics of the tissues.

In contrast, no seasonal variation was observed in either positive inotropic responses to rubidium (a non‐glycoside inhibitor of Na+ + K+ ATP‐ase) or negative inotropic responses to methacholine.

In summer atria the calcium antagonist, verapamil (6 × 10−7 m) abolished the positive staircase phenomenon but did not modify the positive inotropic actions of actodigin.

These data do not support the hypothesis that ‘staircase’ and glycoside‐induced inotropism are mediated through a common mechanism.
An analysis of the effects of systemically administered clonidine on the food and water intake of rats
Authors: Sanger D.J.
Published: July 2012

It is known that intracerebral injections of clonidine can induce eating in rats but it has not been clear whether systemic administration can produce similar effects.

Subcutaneous injections of clonidine (0.01, 0.03, 0.1 mg/kg) increased food and water intake during the 6 h period following injection in non‐deprived male rats.

Pretreatment with a dose of yohimbine (1.0 mg/kg) shifted the clonidine dose‐response curves to the right, suggesting competitive antagonism.

A dose of naloxone (0.1 mg/kg) produced a lowering of the clonidine dose‐response curve but statistical analysis suggested that the opiate antagonist did not produce a competitive antagonism of the effect of clonidine.

The results are consistent with a role for α2‐adrenoceptors in appetite regulation.
Stimulation and inhibition of prostacyclin formation in the gastric mucosa and ileum in vitro by anti‐inflammatory agents
Authors: Boughton‐Smith N.K. , Whittle B.J.R.
Published: July 2012

Homogenates of rat gastric mucosa, forestomach and ileum and dog gastric mucosa reproducibly generated prostacyclin from endogenous substrate.

Prostacyclin formation was inhibited by pre‐incubation with indomethacin, flurbiprofen, naproxen, ketoprofen or meclofenamate (0.1–10 μm).

BW755C (3‐amino‐1[m‐(trifluoromethyl)‐phenyl]‐2‐pyrazoline) stimulated prostacyclin production in the rat gastric mucosa and ileum with inhibition occurring only at high concentrations (>200 μm). The stimulation of prostacyclin production by BW755C in rat forestomach homogenates was less pronounced, with inhibition at concentrations > 20 μm.

BW755C thus exhibits differential activity on prostacyclin production from different gastric tissues in vitro.

The antioxidant‐lipoxygenase inhibitor, nordihydroguiaretic acid (NDGA, 3–15 μm) likewise augmented rat mucosal prostacyclin formation.

Paracetamol stimulated and, at higher concentrations, inhibited prostacyclin formation (> 1 mm), and had comparable activity in both rat gastric tissues.

The ability of NDGA and BW755C to enhance prostacyclin generation may reflect the removal of a modulating influence of lipoxygenase products on prostacyclin formation, the diversion of substrate to the cyclo‐oxygenase pathway, or free‐radical scavenging.
Stimulation‐evoked release of [3H]‐noradrenaline by 1, 10 or 100 pulses and its modification through presynaptic α2‐adrenoceptors
Authors: Marshall Ian
Published: July 2012

Mice isolated vasa deferentia were loaded with 1‐[7, 8‐3H]‐noradrenaline and subsequently field stimulated with 1, 10 or 100 pulses (2 ms pulse width, 1 Hz). The tritium overflow was separated into [3H]‐noradrenaline and its 3H‐metabolites.

The resting release of tritium contained about 7% [3H]‐noradrenaline, 33% [3H]‐3, 4‐dihydroxyphenylglycol ([3H]‐DOPEG) and 60% 3H‐non‐catechols with usually less than 1% [3H]‐dihydroxymandelic acid ([3H]‐DOMA). The proportion of the tritium as [3H]‐noradrenaline increased with stimulation train length to 35% with 100 pulses; this increase in [3H]‐noradrenaline was associated with falls in [3H]‐DOPEG and 3H‐non‐catechols. Generally the proportional increase in [3H]‐noradrenaline on stimulation was about 10 × total tritium when compared with the resting release.

The fractional release of [3H]‐noradrenaline per pulse was independent of train length, averaging about 6 × 10−6. This was reduced by the α2‐adrenoceptor agonist clonidine (0.3–30 nm) with an IC5o of 4.8 nm (10 pulses at 1 Hz).

The α2‐adrenoceptor antagonist, yohimbine (10–100 nm), did not alter the fractional release of [3H]‐noradrenaline elicited by 1 pulse. The antagonist did not change the amount or composition of the resting or evoked tritium overflow. However, yohimbine (l‐100 nm) increased the fractional release of [3H]‐noradrenaline per pulse for trains of 10 or 100 pulses (1 Hz) in a concentration‐dependent fashion. An increase above controls was significant only with 100 pulses and yohimbine, 30 nm.

The results show that the release of noradrenaline during trains of pulses in the mouse vas deferens can be regulated through presynaptic α2‐adrenoceptors. There was no evidence of inhibition by noradrenaline of its own release following a single pulse.
Twitch potentiation by organophosphate anticholinesterases in rat phrenic nerve diaphragm preparations
Authors: Clark Amanda L. , Hobbiger F.
Published: July 2012

Twitch potentiation produced by anticholinesterases has been variously attributed to the prolonged postjunctional action of acetylcholine (ACh), a prejunctional action of ACh involving the initiation of antidromic firing (ADF) in the nerve or a direct action of the anticholinesterases on nerve terminals initiating ADF.

The organophosphate anticholinesterases, paraoxon (diethyl‐4‐nitrophenylphosphate) and DFP (diisopropyl fluorophosphate), when applied to rat isolated diaphragm preparations for 30 min, produced twitch potentiation which subsequently declined.

The rates of onset and decline of twitch potentiation were directly related to the concentration of the organophosphates and the reversibility of their effects was in line with the reactivation of the phosphorylated enzymes formed by them, whether reactivation was spontaneous or induced by the oxime, N,N'‐trimethylene‐1, 3‐bis (pyridinium‐4‐aldoxime).

Reducing the output of ACh from nerve terminals (by reducing the ratio of calcium: magnesium ions in the bathing solution) or reducing the affinity of ACh for the nicotinic cholinoceptor (using the disulphide bond reducing agent, dithiothreitol) produced the same effects as did lowering the concentration of the organophosphates.

It is concluded that the twitch potentiation produced by paraoxon and DFP, and its failure to be maintained when the higher concentrations of the organophosphates were used, were the direct result of the excess of ACh in the synaptic cleft, following inhibition of acetylcholinesterase.
Opiate activation of potassium conductance inhibits calcium action potentials in rat locus coeruleus neurones
Authors: North R. A. , Williams J.T.
Published: July 2012

Opiates act on μ‐receptors to increase the potassium conductance of rat locus coeruleus neurones. Opiates also depress the rate of rise and peak amplitude of calcium action potentials in these cells. The action of opiates on calcium action potentials was prevented by two procedures which blocked the opiate‐induced potassium current, intracellular caesium and extracellular barium. This indicates that the opiate reduction in calcium entry is secondary to an increased potassium current.
Central nervous system effects of arachidonic acid, PGE2, PGF2α, PGD2 and PGI2 on gastric secretion in the rat
Authors: Puurunen Juhani
Published: July 2012

The effects of arachidonic acid, prostaglandin E2 (PGE2), PGF2α, PGD2 and PGI2 on gastric secretion (acid, pepsin and volume) after intracerebroventricular administration were investigated in conscious, pylorus‐ligated rats.

Arachidonic acid 30–1000 μg had no effect on gastric secretion.

PGE2 3 and 10 μg, reduced gastric secretion as measured 1 hour after injection, although the inhibition induced by 3 μg disappeared by 2 h.

PGF2α 10 and 30 μg, inhibited gastric secretion as measured after 1 h, whereas no change was observed in the gastric contents collected 2 h after 10 μg of PGF2α. Intramuscular injection of 30 μg of PGF2α had no effect on gastric secretion.

Intracerebroventricular administration of 1–30 μg of PGD2 or PGI2 had no effect on gastric secretion.

The results indicate that PGE2 and PGF2α have a potent central antisecretory action in conscious, pylorus‐ligated rats, whereas arachidonic acid, PGD2 and PGI2 do not have any central effects on gastric secretion. It is suggested that PGE2 and PGF2α may be involved in the central nervous system control of gastric secretion.
The selectivity of β‐adrenoceptor antagonists on isoprenaline‐induced changes in heart rate, blood pressure, soleus muscle contractility and airways function in anaesthetized cats
Authors: Letts L.G. , Richardson D.P. , Temple Diana M. , Williams L.R.
Published: July 2012

The β‐adrenoceptor antagonist activity of propranolol, metoprolol, atenolol and butoxamine in anaesthetized cats has been measured and compared with the activity of four synthetic phenylethanolamine derivatives.

The effects of isoprenaline on four parameters in the anaesthetized cat: heart rate, blood pressure, soleus muscle contractility and airway reactance, were measured and the modification of the isoprenaline dose‐response relation by each of the antagonist drugs assessed.

Parallel shifts in log dose‐response curves for isoprenaline were caused by propranolol for all parameters, by metoprolol and atenolol for each parameter except blood pressure, and butoxamine for each except soleus muscle and heart rate.

Selectivity of action of the antagonists between different organs was measured by comparing DR 10 values, computed from isoprenaline dose‐ratios.

Propranolol was the most potent antagonist and showed slight selectivity of action on soleus muscle compared with heart. Atenolol and metoprolol were approximately equipotent and were cardioselective at low doses only. Butoxamine was the least potent antagonist and possessed non‐β‐adrenoceptor effects on the parameters measured.

Each of the new compounds, 4′‐bromo‐2′‐methyoxy‐N‐isopropyl phenylethanolamine, the 4′‐chloro‐ and 4′‐methyl analogues, and 4′‐methoxy‐N‐t‐butyl phenylethanolamine, was a potent antagonist but did not exhibit any selectivity of action.

The results suggest no clear separation of β‐adrenoceptors into β1‐ and β2‐ subclasses in organs of the cat. There is no apparent separation of β‐adrenoceptor‐mediated effects on skeletal muscle and airways.