bluuebunny/crossref_metadata_2025 huggingface dataset:
TEMPERATURE COEFFICIENTS OF AFFINITY CONSTANTS FOR THE BINDING OF ANTAGONISTS TO MUSCARINIC RECEPTORS IN THE RAT CEREBRAL CORTEX
Authors: BARLOW R.B. , BIRDSALL N.J.M. , HULME E.C.
Published: July 2012

The temperature coefficients of binding of a series of muscarinic antagonists to their receptors in membrane preparations from the rat cerebral cortex has been examined.

At 37°C the affinity constants agree with those determined by antagonism of acetylcholine‐induced contractions of the guinea‐pig ileum.

The temperature‐dependence of the affinity constants is low; for the antagonists examined, the affinity constants at 0°C differ by less than a factor of 3 from those measured at 37°C.

There are qualitative similarities between the estimates of the temperature coefficient of binding of the antagonists to receptors in ileum strips and in the cerebral cortex.
EFFECTS OF METHOXYVERAPAMIL ON THE STIMULATION BY Ca2+, Sr2+ AND Ba2+ AND ON THE INHIBITION BY Mg2+ OF CATECHOLAMINE RELEASE FROM THE ADRENAL MEDULLA
Authors: AGUIRRE J. , FALUTZ J. , PINTO J.E.B. , TRIFARÓ J.M.
Published: July 2012

Bovine adrenal glands were perfused with Ca2+‐free Locke solution and catecholamine release was induced either by the introduction of Ca2+, Sr2+ or Ba2+ into the perfusion fluid or by the substitution of Na+ by an osmotically equivalent amount of sucrose.

Methoxyverapamil (D600) at a concentration of 3 × 10−4 m blocked the release of catecholamines in response to Ca2+, Sr2+ or Ba2+ stimulation but failed to block the release evoked by the omission of Na+.

Mg2+ (10 to 20 mm) blocked the release induced by Na+‐deprivation; however, this inhibitory effect of Mg2+ was not modified by D600.

D600 blocked the increase in the efflux of 45Ca from the perfused gland induced by the introduction of Ca2+ into the perfusion fluid and blocked the uptake of 45Ca into adrenal medullary slices induced by K+ depolarization.

The results suggest that Ca2+, Sr2+ and Ba2+ may enter the chromaffin cell through the same channel and that this channel is blocked by D600. Mg2+ may enter the cell through the same Ca2+ channel but with a high rate of permeation or it may enter through a channel which is resistant to D600. Alternatively, Mg2+ may exert its inhibitory effect at an extracellular site.
FUNCTIONAL ACTIVITY OF THE NORADRENERGIC INNERVATION OF LARGE CEREBRAL ARTERIES
Authors: DUCKLES SUE PIPER
Published: July 2012

The role of the sympathetic innervation of cerebral arteries remains controversial. Therefore, the functional activity of the adrenergic innervation of the rabbit basilar artery was characterized and compared to that of a peripheral artery, the ear artery.

Both the ear artery and basilar artery have similar endogenous noradrenaline (NA) contents but accumulation of [3H]‐NA was considerably greater in the basilar artery.

Studies of tritium efflux after loading with [3H]‐NA demonstrated a considerable non‐neuronal component since neither guanethidine nor tetrodotoxin completely blocked tritium efflux during nerve stimulation. Pretreatment with blockers of uptake2 did not eliminate this problem.

Comparison of methods for estimating the functional activity of adrenergic nerves showed that, for the vessels studied, NA content and [3H]‐NA accumulation gave markedly different answers. Fractional release of [3H]‐NA did not correspond to fractional release of endogenous NA.

Adrenergic nerves innervating cerebral arteries are shown to have a high activity relative to a peripheral artery. While cerebrovascular sympathetic innervation may not play an important role in normal circumstances, its influence may be seen in pathological conditions.
ANTICOAGULANT EFFECTS OF SULPHATED POLYSACCHARIDES IN NORMAL AND ANTITHROMBIN III‐DEFICIENT PLASMAS
Authors: KINDNESS G. , LONG W.F. , WILLIAMSON F.B.
Published: July 2012

Comparison of the effects of sulphated polysaccharides on thrombin‐induced clotting of normal and antithrombin III‐deficient plasmas suggests the involvement of antithrombin III (AT III) in the anticoagulant activities of cellulose, dextran and xylan sulphates.

AT III appears to play little or no role in the anticoagulant activity of carrageenans.
THE EFFECTS OF ACUTE AND CHRONIC ETHANOL ADMINISTRATION AND ITS WITHDRAWAL ON γ‐AMINOBUTYRIC ACID RECEPTOR BINDING IN RAT BRAIN
Authors: TICKU MAHARAJ K.
Published: July 2012

The effects of acute and chronic ethanol administration, and withdrawal on the binding of the inhibitory neurotransmitter, γ‐aminobutyric acid (GABA), was investigated in rat brain.

Acute ethanol (2 to 4 g/kg i.p. 30 min before removal of brain) produced an increase in the binding capacity of the low affinity GABA receptor binding site.

Following chronic ethanol administration (1 to 21 days), the GABA receptor binding characteristics were not altered. These results suggest a possible adaptation of GABA receptors to the continuous presence of ethanol at the GABA synapse.

During ethanol withdrawal, the affinity of the low affinity GABA receptor binding site was significantly lower than pair‐fed controls at 8 and 16 h withdrawal.

These results suggest that GABA receptor sensitivity may play a role in some of the neuropharmacological effects of ethanol and in its withdrawal symptoms.
EFFECTS OF VASODILATOR DRUGS, ALKALINE PHOSPHTASE, AND CYCLIC AMP‐DEPENDENT PROTEIN KINASE ON THE 45CALCIUM UPTAKE OF SARCOLEMMAL MICROSOMES FROM HUMAN UMBILICAL ARTERIES
Authors: KREYE VOLKER A.W. , SCHLICKER EBERHARD
Published: July 2012

A microsomal fraction was prepared from human umbilical arteries by differential centrifugation. The preparation was capable of an oxalate‐stimulated Ca2+ uptake at a mean rate of 0.74 nmol Ca2+ mg−1 protein min−1 which could be inhibited by a Ca2+ ionophore, A 23 187, and by Tween 80.

The rate of Ca2+ uptake in the fractions obtained by density gradient fractionation paralleled 5′‐nucleotidase activity suggesting that vesicles of predominantly sarcolemmal origin were responsible for the microsomal Ca2+ uptake.

Cyclic adenosine 3′,5′‐monophosphate‐dependent protein kinase enhanced membrane phosphorylation but did not affect Ca2+ uptake. Preincubation with alkaline phosphatase reduced membrane phosphorylation to a greater extent than Ca2+ uptake. These data are not in favour of a close correlation between Ca2+ uptake and phosphorylation.

None of 15 vasodilator drugs (bencyclane, carbocromen, diazoxide, dilazep, hydralazine, indapamide, isosorbide dinitrate, methyl‐isobutyl‐xanthine, minoxidil, naftidrofuryl, nitroglycerine, prenylamine, sodium nitroprusside, tetracaine, and verapamil) had any effect on Ca2+ uptake at 10−5 m. This suggests that vasodilator drugs do not act by a direct influence on the Ca2+ pumps of vascular smooth muscle cells.
SOME EFFECTS OF SODIUM NITROPRUSSIDE, METHOXYVERAPAMIL (D600) AND NIFEDIPINE ON RAT PORTAL VEIN
Authors: JETLEY MRIDULA , WESTON A.H.
Published: July 2012

The effects of methoxyverapamil (D600), nifedipine and sodium nitroprusside on noradrenaline‐induced electrical and mechanical activity in rat portal vein have been examined.

D600 and nifedipine produced a concentration‐dependent reduction in mechanical responses to noradrenaline whilst sodium nitroprusside had no effect. The effects of D600 and nifedipine were reversed by increasing the extracellular calcium concentration.

The mechano‐inhibitory effects of D600 were accompanied by a marked reduction in electrical activity with some evidence of electromechanical uncoupling.

The mechano‐inhibitory effects of nifedipine were associated with considerable electromechanical uncoupling.

It is concluded that in the concentrations used, D600 acts primarily by inhibiting calcium influx with some effect on electromechanical coupling whilst nifedipine interferes mainly with the coupling process. The inactivity of sodium nitroprusside suggests that the excitation‐contraction coupling process in rat portal vein is relatively simple and further studies with this tissue seem indicated.
INFLUENCE OF β‐ADRENOCEPTOR BLOCKING AGENTS ON THE TURNOVER RATE OF CARDIAC AND SPLENIC NORADRENALINE IN RATS
Authors: ALEXANDRE J.M. , CHEVILLARD C.
Published: July 2012

The effects of (+) and (±)‐propranolol, pindolol, alprenolol, practolol, acebutolol and bretylium were studied on the turnover rate of noradrenaline in heart and spleen of rats.

Bretylium (8 mg/kg) greatly reduced the turnover rate of noradrenaline in both organs.

(+)‐Propranolol (4 and 10 mg/kg) also diminished the turnover rate of noradrenaline, but its effects were smaller than those of (±)‐propranolol (4 and 10 mg/kg).

Pindolol (300 μg/kg) greatly increased the turnover rate of noradrenaline; this effect was especially important in the spleen.

Alprenolol (4 and 10 mg/kg) acebutolol (20 and 40 mg/kg) practolol (10 mg/kg) did not produce any significant change.

These effects are compatible with the view that β‐adrenoceptor blocking agents may affect noradrenaline release in different manners: anaesthetic properties of some of these drugs and blockade of β2prejunctional adrenoceptors produce a diminished release of transmitter, whereas the intrinsic sympathomimetic action of pindolol causes the opposite effect.
THE EFFECT OF SODIUM‐n‐DIPROPYL ACETATE ON γ‐AMINOBUTYRIC ACID‐DEPENDENT INHIBITION IN THE RAT CORTEX AND SUBSTANTIA NIGRA IN RELATION TO ITS ANTICONVULSANT ACTIVITY
Authors: KERWIN R.W. , OLPE H.‐R. , SCHMUTZ M.
Published: July 2012

We have examined the time course of the anticonvulsant property of valproate sodium on electroshock‐induced convulsions in rats and a comparison of this has been made with the action of the drug on single unit activity in the rat brain.

Intraperitoneal valproate sodium (100 to 400 mg/kg) protected rats from electroshock‐induced convulsion. This effect was dose‐dependent, the latency of the effect decreasing as a function of dose from 5 to 2 min.

The time course of this anticonvulsant property was paralleled by a pronounced inhibition of the spontaneous firing rate of cortical and nigral neurones, following intraperitoneal administration of valproate sodium (100 to 400 mg/kg).

The inhibitory action of microiontophoretically applied γ‐aminobutyric acid (GABA) and muscimol on the firing rate of cortical neurones was potentiated within 1 to 3 min of microiontophoretic application of valproate sodium. In contrast, the inhibitory action of glycine on cortical neurones was unaffected during the microiontophoretic application of valproate sodium.

Microiontophoretically applied valproate sodium also potentiated inhibitory responses to GABA in rats which had received 100 mg/kg of a GABA‐transaminase inhibitor, gabaculine, i.p. 16 h previously.

The duration of trans‐synaptic inhibitory responses recorded in the substantia nigra and cortex following submaximal electrical stimulation of the striatum and cortex respectively was, in general, unaffected by either intraperitoneal or local application of valproate sodium.

These observations are discussed in terms of the mechanisms underlying the rapid onset of the anticonvulsant properties of valproate sodium.
AN INCREASED CALCIUM SENSITIVITY OF MESENTERIC RESISTANCE VESSELS IN YOUNG AND ADULT SPONTANEOUSLY HYPERTENSIVE RATS
Authors: MULVANY M.J. , NYBORG N.
Published: July 2012

We have measured the calcium sensitivity in response to noradrenaline stimulation and potassium depolarization of isolated segments of 100 to 200 μm mesenteric resistance vessels from spontaneously hypertensive (SHR) and control Wistar‐Kyoto (WKY) rats. The rats were either young (4 wk) or adult (4 months), that is of ages before or after the SHRs had developed elevated blood pressure. Experiments were performed under conditions in which the effect of noradrenaline uptake by, and the potassium‐induced noradrenaline release from, the nerve terminals in the vessel walls was eliminated.

The response of the SHR and WKY vessels to noradrenaline under conditions where only the extracellular calcium appeared to have been removed was similar. When subsequently stimulated maximally by noradrenaline, the calcium‐sensitivity of the SHR vessels (Ca‐ED50 ≃ 0.1 mm) was greater than that of the WKY vessels (Ca‐ED50 ≃ 0.2 mm). When depolarized by potassium, all vessels were less sensitive to calcium and there was little difference in the calcium sensitivity of SHR and WKY vessels in either age group (Ca‐ED50 ≃ 0.8 mm).

The results suggest that whereas the potassium (potential)‐dependent calcium permeability of the SHR smooth muscle cell membrane is normal, the noradrenaline‐induced calcium permeability is abnormally high. The presence of this abnormality in the vessels from the young SHRs suggests that it may be a factor involved in the aetiology of hypertension in the SHR.
CHARACTERIZATION OF THE RECEPTOR MEDIATING THE ANTI‐ANAPHYLACTIC EFFECTS OF β‐ADRENOCEPTOR AGONISTS IN HUMAN LUNG TISSUE in vitro
Authors: BUTCHERS P.R. , SKIDMORE I.F. , VARDEY C.J. , WHEELDON A.
Published: July 2012

The rank order of potency of six β‐adrenoceptor agonists as inhibitors of the anaphylactic release of histamine from fragments of passively sensitized human lung in vitro was (‐)‐isoprenaline > (‐)‐adrenaline > (±)‐salbutamol > (‐)‐noradrenaline > R0363 > H133/22.

The β‐adrenoceptor antagonists, propranolol, atenolol and H35/25, blocked the response to both (‐)‐isoprenaline and (±)‐salbutamol competively. Each antagonist gave similar pA2 values with both agonists. pA2 values were consistenly at the high end of the range expected for interaction at a β2‐adrenoceptor.

Practolol did not antagonize isoprenaline in a competitive manner but was a competitive antagonist of salbutamol with a pA2 at the high end of the range expected for interaction at a β2‐adrenoceptor.

Data obtained with agonists are consistent with the receptor being of the β2‐subtype. Data obtained with antagonists indicate a consistently higher affinity for the receptor than observed for the β2‐subtype in other tissues but do not suggest a novel β‐adrenoceptor subtype on the mast cell of the human lung.
SOME DIRECT AND REFLEX CARDIOVASCULAR ACTIONS OF PROSTACYCLIN (PGI2) AND PROSTAGLANDIN E2 IN ANAESTHETIZED DOGS
Authors: CHAPPLE D.J. , DUSTING G.J. , HUGHES R. , VANE J.R.
Published: July 2012

The aim of the study was to determine the mechanism of the hypotension and bradycardia produced by prostacyclin (PGI2).

Haemodynamic studies were carried out in nineteen open‐chest beagle dogs anaesthetized with chloralose. PGI2 was infused intravenously or into the left atrium.

Infusions of PGI2 either intravenously or into the left atrium equally reduced arterial pressure and total peripheral resistance but bradycardia was greater after infusion into the left atrium.

Comparison of effects of PGI2 with those of prostaglandin E2 (PGE2) showed that although left atrial infusions both reduced aortic pressure and total peripheral resistance, PGE2 always increased heart rate, cardiac output and maximum acceleration.

Similar effects were observed with sodium nitroprusside except that it always caused tachycardia and reduced stroke volume.

Atropine (0.05 or 1 mg/kg i.v.) reduced or reversed the bradycardia induced by PGI2 but its hypotensive effects were reduced only after 1 mg/kg atropine. After vagotomy changes in cardiac output, stroke volume and maximum acceleration were increased, the hypotensive effects of PGI2 were reduced and the bradycardia was reversed; effects induced by PGE2 were not significantly altered.

The hypotension induced by prostacyclin is due to two components, a direct relaxation of vascular smooth muscle and a reflex, non‐cholinergic vasodilatation. The bradycardia is reflex in nature and is partially mediated by the vagus pathway.
BLOCKADE OF ADRENALINE‐INDUCED HYPERGLYCAEMIA IN THE ANAESTHETIZED CAT BY CONTINUOUS INFUSION OF PHENTOLAMINE AND PROPRANOLOL
Authors: AL‐JIBOURI LAYLA M. , FURMAN B.L. , PARRATT J.R.
Published: July 2012

The effects of adrenoceptor blocking drugs on the metabolic responses to adrenaline infusion (1 μg kg−1 min−1) have been studied in the anaesthetized, fasted cat.

Propranolol, in doses (0.25 or 1 mg/kg) which prevented completely adrenaline‐induced tachycardia, reduced but did not abolish adrenaline‐induced hyperglycaemia.

Phentolamine infusion, at a rate (15 μg kg−1 min−1 after a priming dose of 2.5 mg/kg) which reversed the pressor effect of adrenaline, reduced but did not abolish adrenaline‐induced hyperglycaemia.

The continuous infusion of a combination of phentolamine (15 μg kg−1 min−1 after a priming dose of 2.5 mg/kg) and propranolol (5 μg kg−1 min−1 after a priming dose of 0.25 mg/kg) prevented completely the hyperglycaemia response to adrenaline infusion over a 6 h period.

The increase in blood lactate concentration produced by adrenaline was prevented completely by the combined infusion of propranolol and phentolamine but was not modified by phentolamine alone.
ATROPINE INHIBITS THROMBOXANE A2 GENERATION IN ISOLATED LUNGS OF THE GUINEA‐PIG
Authors: BERTI F. , FOLCO G.C. , GIACHETTI A. , MALANDRINO S. , OMINI G. , VIGANÒ T.
Published: July 2012

Histamine (0.5 to 5 μg) and slow reacting substance of anaphylaxis (SRS‐A, 0.05 to 0.3 u), injected in the isolated, perfused lungs of normal and ovalbumin‐sensitized guinea‐pigs, promote formation and release of thromboxane A2(TXA2) and other arachidonate metabolites, the effect being more pronounced in sensitized lungs.

Carbachol injected (1 to 10 μg) or perfused (1 μg ml−1 min−1) through normal or sensitized lungs does not elicit formation of TXA2 and prostaglandins. Furthermore the increased generation of arachidonate metabolites due to histamine is not altered by carbachol.

Atropine and ipratropium bromide (1 μg ml−1 min−1) reduce significantly the increased rate of production of TXA2 caused by histamine and SRS‐A both in normal and sensitized lungs, whereas hexamethonium (10 to 25 μg ml−1 min−1) is ineffective.

The mechanism of action of atropine in inhibiting the increased generation of TXA2 is clearly not related to its antimuscarinic or antihistaminic properties. The drug might act at the early events, involved in the activation of arachidonic acid metabolism. The results suggest new sites of action for atropine which, besides the control of the vagal bronchomotor tone, interferes directly with the primary mediators of anaphylaxis.
RESPONSIVENESS TO VASOACTIVE AGENTS OF CEREBRAL AND MESENTERIC ARTERIES ISOLATED FROM CONTROL AND RESERPINE‐TREATED DOGS
Authors: HAYASHI SHIGEHIRO , MIYAZAKI MIZUO , TODA NOBORU
Published: July 2012

Pretreatment of dogs for 20 to 24 h before the start of experiments with reserpine (0.5 mg/kg) depleted noradrenaline from cerebral and mesenteric arteries, the diminution being greater in the latter arteries.

Contractile responses of helically‐cut strips of cerebral and mesenteric arteries to noradrenaline were unaffected by pretreatment with reserpine. Tyramine‐induced contractions of mesenteric arteries were markedly attenuated by reserpine‐pretreatment, whereas the contraction of cerebral arteries was not influenced. The contractile response of mesenteric arteries to transmural nerve stimulation or nicotine was abolished by reserpine‐pretreatment, but the relaxation induced by nicotine of cerebral arteries contracted with prostaglandin F2α was not affected Pretreatment with reserpine attenuated the contractions of mesenteric arteries induced by angiotensin II, but did not alter the response of cerebral arteries to 5‐hydroxytryptamine.

In prostaglandin‐contracted cerebral and mesenteric arterial strips, relaxant effects of acetylcholine, isoprenaline and K+ were not significantly influenced by reserpine‐pretreatment.

It appears that tyramine and nicotine do not release noradrenaline from dog cerebral arteries in amounts sufficient to cause significant contractions. Attenuation of the response to angiotensin II by pretreatment with reserpine is not the result of depletion of noradrenaline from the mesenteric arterial wall but may be due to interference with the mechanism specific to actions of angiotensin II.
METABOLISM OF [3H]‐(±)‐ISOPRENALINE BY ISOLATED ATRIA AND CORONARY ARTERIES OF THE KITTEN
Authors: CORNISH E.J. , GOLDIE R.G.
Published: July 2012

Isolated coronary arteries of the kitten accumulated more unchanged isoprenaline and metabolized more amine than atria following incubation for 1 to 20 min with [3H]‐(±)‐isoprenaline (25 ng/ml or 5 μg/ml).

Cortisol (10 or 80 μm), U‐0521 (120 μm) and oxytetracycline (100 μm) all reduced metabolite formation.

Cortisol inhibited ‘Iso InfluxMin’ (cellular isoprenaline accumulation plus total metabolite production). In contrast, it increased, decreased or did not alter accumulation of unmetabolized isoprenaline, depending upon the experimental conditions.

Isoprenaline accumulation was increased in atria and reduced in coronary arteries by U‐0521, while oxytetracycline reduced accumulation in coronary arteries at the high amine concentration.

It is concluded that in atria, cortisol inhibits metabolism and has differential effects on a number of extraneuronal compartments which accumulate isoprenaline. Both cortisol and U‐0521 appear to be extraneuronal uptake inhibitors and inhibitors of catechol‐O‐methyltransferase in coronary arteries. Oxytetracycline may have effects additional to inhibition of isoprenaline binding to connective tissue fibres.
COMPARATIVE STUDIES ON THE EFFECTS OF TOLMESOXIDE (Rx71107), A TOLMESOXIDE METABOLITE (Rx71112) AND NIFEDIPINE IN ISOLATED BLOOD VESSELS
Authors: MIKKELSEN ERICH , PEDERSEN OLE LEDERBALLE
Published: July 2012

The effect was studied of tolmesoxide (Rx71107), a tolmesoxide metabolite (Rx71112) and nifedipine on active tension in human isolated crural veins and in rat thoracic aorta. The effects of tolmesoxide and nifedipine on 22Na and 45Ca net influx in noradrenaline‐induced contractions were investigated in rat thoracic aorta.

Tolmesoxide, Rx71112 and nifedipine caused a concentration‐related inhibition of noradrenaline (NA)‐ and potassium (K+)‐induced contractions in human veins. Nifedipine was by far the most potent drug in these respects. Tolmesoxide (4.7μm‐4700 μm) and Rx71112 (22 μm‐220 μm) inhibited the NA‐induced contraction more effectively than the K+‐induced concentration. The reverse was true for nifedipine (0.0023‐3 μm).

Nifedipine had a similar potency in inhibiting the NA‐induced contraction in rat aorta and human veins, whereas the inhibitory effect of tolmesoxide was more pronounced in rat aorta than in human veins.

Tolmesoxide was a weak antagonist of the contractile effects of the cumulative addition of calcium on human veins. In concentrations up to 470 μm, tolmesoxide was completely devoid of inhibitory effects on 22Na and 45Ca net influx in rat aorta. Rx71112 (220 μm) had an inhibitory effect on 22Na net influx but no significant effect on 45Ca net influx.

Nifedipine was an effective antagonist of the contractile effects of cumulative addition of calcium in human veins and had a concentration‐related inhibitory effect on both 22Na and 45Ca uptake in rat aorta.

The results indicate that tolmesoxide and Rx71112 cause dilatation of human crural veins in vitro at concentrations that do not interfere with the net transmembranal movements of Ca and are thus clearly different from the effects of nifedipine.
BTS 39 542, A DIHYDROPHTHALAZIN‐1‐YLACETIC ACID WITH HIGH EFFICACY DIURETIC ACTIVITY
Authors: COOLING M.J. , SIM M.F.
Published: July 2012

BTS 39 542, a novel dihydrophthalazin‐1 ‐ylacetic acid, has high efficacy diuretic activity in mice, rats, rabbits and dogs. It is twice as potent as frusemide in mice and dogs, ten times as potent in rats and twenty times as potent in rabbits

BTS 39 542, like frusemide, exerts its major effects in the loop of Henle and increases renal blood flow but does not affect glomerular filtration rate in dogs

The ratio of the excretion of the major cations (sodium plus potassium) to that of the major anion (chloride) after either BTS 39 542 or frusemide varied with species. In rats and rabbits the ratio was approximately unity but in mice and dogs the ratio consistently exceeded unity

A method for evaluating diuretics based on potency and relative potassium excretion is described.
EFFECTS OF OXOLINIC ACID ON THE SLEEP‐WAKEFULNESS CYCLE OF THE RAT
Authors: D'ANGELO L. , MONTI J.M.
Published: July 2012

A study was carried out in rats (prepared for chronic sleep recording) of the effects of oxolinic acid on the sleep‐wakefulness cycle

In addition, the actions of oxolinic acid on the sleep‐wake cycle were assessed after pretreatment with drugs interfering with central catecholamine mechanisms or facilitating central γ‐aminobutyric acid (GABA) activity

Oxolinic acid (8–32 mg/kg) induced a significant and dose‐related increase of waking EEG, while slow wave and REM sleep were decreased

The effects of oxolinic acid on waking, slow wave and REM sleep were antagonized by α‐methyl‐p‐tyrosine (50–100 mg/kg) which interferes with the synthesis of catecholamines

FLA‐63 (25 mg/kg) which is a specific inhibitor of noradrenaline synthesis, was effective in blocking oxolinic acid‐related increase of waking and decrease of slow wave sleep

Haloperidol (0.4‐0.6 mg/kg) which blocks central dopamine and noradrenaline receptors, reversed oxolinic acid‐induced actions on waking and slow wave sleep. Spiroperidol (2–4 mg/kg) which interferes with dopamine and 5‐hydroxytryptamine mechanisms, only antagonized the effect of oxolinic acid on light slow wave sleep. REM sleep was further decreased by both neuroleptic agents

γ‐Hydroxybutyrate (25–50 mg/kg), which acts as a GABA agonist and amino‐oxyacetic acid (20 mg/kg), which considerably increases central GABA levels, were ineffective in blocking oxolinic acid‐related disruption of the sleep‐wake cycle

Our results suggest that the catecholamines are involved in the arousing effect of oxolinic acid.
DISSIMILAR EFFECTS ON BODY TEMPERATURE IN THE CAT PRODUCED BY GUANOSINE 3‘, 5’‐MONOPHOSPHATE, ACETYLCHOLINE AND BACTERIAL ENDOTOXIN
Authors: DASCOMBE M.J. , MILTON A.S.
Published: July 2012

Guanosine 3′, 5′‐monophosphate (cyclic GMP) and N2‐2′‐O‐dibutyryl guanosine 3′, 5′‐monophosphate (db cyclic GMP) have been injected into the third cerebral ventricle (i.c.v.) of the unanaesthetized cat and the effects on rectal temperature and on behavioural and autonomic activities observed and compared with those of acetylcholine and physostigmine

Acetylcholine (100 nmol) and physostigmine (100 nmol) injected together i.c.v. produced a rise in body temperature in cats at an environmental temperature of 20–24°C, which was abolished by pretreatment i.c.v. with atropine (200 nmol)

Cyclic GMP and db cyclic GMP (10–1250 nmol) had no effect on body temperature in cats at an environmental temperature of 20–24°C but produced hypothermia (1250 nmol) in cats at an environmental temperature of 9–11°C

The O‐somatic antigen of Shigella dysenteriae (20 μg/kg i.v.) produced fever in cats which was not potentiated by caffeine (25 mg/kg i.p.). Levels of endogenous cyclic GMP in c.s.f. taken from the cisterna magna during fever induced by bacterial endotoxin in the presence or absence of paracetamol (50 mg/kg i.p.) and/or caffeine were similar to values for afebrile cats

It is concluded that exogenous cyclic GMP and db cyclic GMP can inhibit central events mediating autonomic and behavioural thermoregulation stimulated in cats by exposure to cold environments.
THE ACTION OF LOPERAMIDE IN INHIBITING PROSTAGLANDIN‐INDUCED INTESTINAL SECRETION IN THE RAT
Authors: HARDCASTLE JACQUELINE , HARDCASTLE P.T. , READ N.W. , REDFERN J.S.
Published: July 2012

The mechanisms by which loperamide inhibits the intestinal secretion induced by prostaglandin E2 were investigated in rat jejunum.

In vivo loperamide prevented prostaglandin‐induced fluid secretion but did not reduce the associated rise in the transintestinal potential difference.

In intestinal sheets the electrical response to prostaglandin E2 was enhanced in the presence of loperamide.

The ionic basis of these changes was determined by measuring Na+ and Cl− fluxes across intestinal sheets. Loperamide did not reduce the prostaglandin‐induced increase in net Cl− secretion, although it prevented the inhibition of mucosal‐to‐serosal Na+ movement.

Loperamide does not alter cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels by a direct action at the enterocyte, since in isolated enterocytes neither basal nor prostaglandin‐stimulated cyclic AMP levels were affected by the drug.
MECHANISM OF DECLINE IN RAT BRAIN 5‐HYDROXYTRYPTAMINE AFTER INDUCTION OF LIVER TRYPTOPHAN PYRROLASE BY HYDROCORTISONE: ROLES OF TRYPTOPHAN CATABOLISM AND KYNURENINE SYNTHESIS
Authors: YOUNG SIMON N.
Published: July 2012

Two mechanisms have been proposed to explain the decline in brain tryptophan and 5‐hydroxytryptamine (5‐HT) after administration of hydrocortisone and the subsequent induction of liver pyrrolase. These are depletion of tryptophan by high rates of tryptophan catabolism and inhibition of tryptophan uptake by elevated levels of the tryptophan catabolite, kynurenine.

The increase in plasma kynurenine after hydrocortisone injection (25 mg/kg) was small, and kynurenine, at a concentration ten fold greater, did not inhibit tryptophan uptake by brain as measured by the Oldendorf technique. Thus, inhibition of tryptophan uptake by kynurenine is not an important mechanism in the control of brain tryptophan and 5‐HT.

The decline in brain tryptophan after hydrocortisone was comparable to that seen in other tissues, which comprise more than half of the body weight of a rat.

The total decline in free tryptophan stores in whole animals treated with hydrocortisone was estimated to be about 450 μg. This amount of tryptophan would be catabolized by tryptophan pyrrolase in about 20 min, when the enzyme is induced, according to an earlier estimate of the rate of tryptophan catabolism in vivo.

Tryptophan pyrrolase activity remains high for much longer than 20 min, suggesting that there is net protein catabolism, which releases tryptophan and prevents non‐protein tryptophan levels falling very far.

These results demonstrate that the decline in brain tryptophan and 5‐HT after hydrocortisone is caused by depletion of tryptophan stores due to the high activity of tryptophan pyrrolase. However, our data suggest that this effect is diminished by release of tryptophan from proteins. Thus, peripheral protein metabolism may be an important factor in the control of brain tryptophan levels and 5‐HT synthesis.
THE EFFECT OF THE CONVULSANT AGENT, CATECHOL, ON NEUROTRANSMITTER UPTAKE AND RELEASE IN RAT BRAIN SLICES
Authors: MINCHIN M.C.W. , PEARSON G.
Published: July 2012

The effect of catechol on uptake and K+‐stimulated release of γ‐aminobutyric acid (GABA), D‐aspartate, noradrenaline and acetylcholine has been studied in slices of cerebral cortex and thalamus.

Low concentrations of catechol did not influence the uptake of any of the neurotransmitters in either brain area.

Noradrenaline release was unaffected by catechol.

Acetylcholine release from both cortical and thalamic slices was inhibited by high concentrations of catechol. This phenomenon is unlikely to be related to catechol‐induced convulsions.

Catechol (100 μm) inhibited GABA release from cortical slices by 28%. However, at a concentration of 10 μm catechol enhanced the release of D‐aspartate from thalamic slices by over 100%.

Potentiated release of excitatory amino acid transmitters may contribute to the enhanced excitability of thalamic cells which occurs during sensory myoclonus induced by low doses of catechol.
EFFECTS OF GLYCERYL TRINITRATE AND SIN‐1A ON MUSCULATURE AND VASCULATURE OF THE DOG TRACHEA in situ
Authors: MARUYAMA M. , SATOH K. , TAIRA N.
Published: July 2012

In dog trachea in situ, perfused arterially with blood, isoprenaline, glyceryl trinitrate and N‐nitroso‐N‐morpholinoamino‐acetonitrile (SIN‐1 A) given intra‐arterially, decreased tracheal tone which had been elevated by neostigmine and increased tracheal blood flow. Glyceryl trinitrate and SIN‐1 A were more effective on the tracheal musculature than on the tracheal vasculature whereas isoprenaline was equally effective on both.
BINDING OF [3H]‐PRAZOSIN AND [3H]‐DIHYDROERGOCRYPTINE TO RAT CARDIAC α‐ADRENOCEPTORS
Authors: GUICHENEY PASCALE , MEYER PHILIPPE
Published: July 2012

[3H]‐prazosin binds specifically to a single class of α‐adrenoceptors in rat cardiac membranes (KD25°C = 0.2 nM).

That these receptors are of the α1‐type was indicated by competition studies, i.e. α1‐antagonists such as prazosin and (2‐(2, 6‐dimethoxyphenoxyethyl) aminomethyl‐1, 4‐benzodioxane (WB 4101) were more potent than the α2‐antagonists, yohimbine and piperoxan in inhibiting [3H]‐prazosin binding.

A comparative study of [3H]‐prazosin binding and [3H]‐dihydroergocryptine binding to cardiac membranes showed that both [3H]‐prazosin and [3H]‐dihydroergocryptine (at low concentrations) bind to α1‐adrenoceptors, while [3H]‐dihydroergocryptine (at higher concentrations) also binds to another class of sites.
ACCUMULATION OF [3H]‐OUABAIN IN FUNCTIONALLY DIFFERENT CANINE CARDIAC TISSUES: DIFFERENTIAL Rb+ UPTAKE
Authors: RHEE H.M.
Published: July 2012

In order to understand tissue‐specific differences in sensitivity to ouabain, the distribution of [3H]‐ouabain was investigated in seven functionally different, canine cardiac tissues.

Specialized cardiac tissues (e.g., pacemaker or conducting tissues) accumulate much less ouabain than do the contractile tissues such as the left ventricule or the papillary muscle.

This study confirms a greater Rb+ uptake in the Purkinje fibre than in the contractile tissue.

The results disprove the hypothesis that a high accumulation of ouabain in the Purkinje fibre is responsible for the well‐known sensitivity to ouabain in this tissue.
THE RESPONSE OF THE RABBIT RECTOCOCCYGEUS MUSCLE TO STIMULATION OF EXTRINSIC rNHIBITORY NERVES AND TO SYMPATHOMIMETIC DRUGS
Authors: KING B.F. , MUIR T.C.
Published: July 2012

The effects of stimulating sympathetic or non‐adrenergic non‐cholinergic (NANC) nerves or of the addition of noradrenaline (NA) or isoprenaline (Iso) were investigated on carbachol‐induced tone and on contractions produced by acetylcholine (ACh) and by pelvic nerve stimulation, in the rabbit rectococcygeus muscle.

Each procedure reduced carbachol‐induced tone; sympathetic and NANC nerve stimulation were equipotent but both were less effective than sympathomimetic drugs, of which Iso was the better. Both Iso and NA, but not sympathetic nerve stimulation, inhibited the contractions produced by pelvic nerve stimulation in a concentration‐dependent manner. Against ACh‐induced contractions, only Iso was effective. The effects of NANC nerve stimulation on the motor responses to pelvic nerve stimulation or to ACh were not investigated.

The inhibitory effects of sympathetic nerve stimulation, of Iso and of NA were reduced by propranolol (3 × 10−6m) but unaffected by phentolamine (3 × 10−5m).

In the presence of high (45 mm) concentrations of KCI, Iso and NA produced a concentration‐dependent inhibition of tone that was antagonized by propranolol (3 × 10−6m).

Methoxamine (4 × 10−7 to 4 × 10−5m) and phenylephrine (5 × 10−7 to 5 × 10−5m) which interact mainly with α1 ‐adrenoceptors, produced only small, transient reductions in carbachol‐induced tone which were subject to tachyphylaxis, unlike those produced by Iso and NA. These inhibitory effects were antagonized by phentolamine (3 × 10−6m) or azapetine (3 × 10−6m).

Phenylephrine (5 × 10−4 m) and high doses (3 × 10−5m or greater) of NA enhanced the contractile response to pelvic nerve stimulation and, on occasion, produced muscle contraction. These effects were antagonized by phentolamine (3 × 10−6m).

These results suggest that inhibition of the rectococcygeus, a muscle which has no intramural nerve plexus, can be inhibited by stimulation of extrinsic NANC nerves, the transmitter for which is unknown and by sympathetic nerve stimulation via a‐ and β‐adrenoceptors located postsynaptically on the muscle. Excitatory α‐adrenoceptors may also be present.
EFFECTS OF A POTENT AND SPECIFIC β2‐ADRENOCEPTOR ANTAGONIST ON INTRAOCULAR PRESSURE
Authors: NATHANSON JAMES A.
Published: July 2012

Physiological studies support the possibility of adrenergic regulation of aqueous humor secretion from the ciliary process, a tissue which has recently been shown to contain a predominance of β2‐adrenoceptors.

The present experiments examine the effects of a potent and highly specific β2‐antagonist (IPS 339) on intraocular pressure in the normal rabbit eye.

The observed decrease in pressure caused by IPS 339 suggests that highly specific β2‐antagonists may be useful in decreasing elevated intraocular pressure.
UPTAKE OF 5‐HYDROXYTRYPTAMINE IN THE CATECHOLAMINE CONTAINING AREAS OF THE HYPOTHALAMUS OF THE RAT AFTER TREATMENT WITH PHENELZINE AND TRYPTOPHAN
Authors: ARBUTHNOTT G.W. , ECCLESTON D. , LASZLO I. , NICOLAOU N.
Published: July 2012

Uptake of 5‐hydroxytryptamine in the catecholamine containing nerve endings of the hypothalamus in the rat brain was found after intraperitoneal injection of phenelzine sulphate (25 mg/kg) and tryptophan (100 and 400 mg/kg).

The results were obtained by fluorescence microscopy and microspectrofluorimetry.
ANGIOTENSIN INHIBITS ACTION OF VAGUS NERVE AT THE HEART
Authors: POTTER ERICA K.
Published: July 2012

The effects of angiotensin II and angiotensin III (Des‐Asp angiotensin II) on cardiac vagal nerve endings were studied in intact dogs and in isolated guinea‐pig atria. Decreases in heart rate evoked by electrical stimulation of the peripheral end of the cut vagus were attenuated in the presence of angiotensin II and angiotensin III.
COMPARISON OF THE EFFECTS OF ETHYLENEDIAMINE ANALOGUES AND γ‐AMINOBUTYRIC ACID ON CORTICAL AND PALLIDAL NEURONES
Authors: PERKINS M.N. , STONE T.W.
Published: July 2012

The actions of ethylenediamine (EDA) and structurally related compounds were investigated by microiontophoresis in Wistar rats.

EDA inhibited, via a bicuculline‐sensitive mechanism, the spontaneous firing rate of all cortical and pallidal cells tested.

The results with the analogues suggest that two amine groups are required for this neuronal depressant action whereas a carboxyl grouping is not. N‐substitution reduces the depressant effect. The length of the molecule is also critical, more than 3 methylene components seriously reducing its effectiveness. A rigid analogue of EDA, piperazine, was also active. In addition the apparent transport numbers of EDA and γ‐aminobutyric acid (GABA) were calculated, showing a close similarity between the two.

The results are discussed with respect to the possibility that EDA may represent a new class of GABA‐mimetics, or may indicate the existence of a novel diamine receptor mediating bicuculline‐sensitive inhibition in the rat CNS.
THE ASSOCIATION BETWEEN THE MELANOCYTE‐STIMULATING HORMONE RECEPTOR AND THE α2‐ADRENOCEPTOR ON THE Anolis MELANOPHORE
Authors: CARTER R.J. , SHUSTER S.
Published: July 2012

The primary effect of catecholamines was to lighten Anolis skin previously darkened by α‐melanocyte‐stimulating hormone (α‐MSH). In concentrations above 10−7 m noradrenaline, 10−6 m adrenaline and 10−5 m dopamine, darkening of subpopulations of melanophores occurred. Subsequent experiments were concerned with the effect of low catecholamine concentrations on α‐MSH action.

The relationship between MSH receptors and α‐adrenoceptors on the Anolis melanophore was studied by a kinetic approach using the rate bioassay method and by use of α‐adrenoceptor agonists and antagonists.

α‐MSH dose‐response curves were shifted, in parallel, to the right in the presence of the catecholamines, noradrenaline, adrenaline and dopamine, and Lineweaver‐Burke plots and Arunlakshana‐Schild plots indicated that the catecholamines antagonized MSH action by a competitive mechanism.

Phentolamine had an inhibitory effect on the action of adrenaline but not on the action of MSH. Therefore MSH and catecholamine actions were mediated by separate receptors.

The classical kinetics of competition are not confined to competition at a single receptor.

The α‐adrenoceptor was defined as the α2‐subtype since (a) the α2‐selective agonist, clonidine, was found to mimic catecholamine action. (b) The α2‐selective antagonist, yohimbine, blocked the actions of clonidine and adrenaline. (c) The α1‐selective antagonist, prazosin, had negligible blocking effects on adrenaline and clonidine.

We conclude that a close association exists between the separate MSH receptor and α2‐adrenoceptor on the Anolis melanophore. The competition that takes place between MSH and catecholamines must occur after hormone‐receptor interaction, possibly through a common adenylate cyclase moiety oppositely controlled by the two receptors involved.
CHANGES IN BODY TEMPERATURE AND OXYGEN CONSUMPTION RATE OF CONSCIOUS MICE PRODUCED BY INTRAHYPOTHALAMIC AND INTRACEREBROVENTRICULAR INJECTIONS OF Δ9‐TETRAHYDROCANNABINOL
Authors: FITTON A.G. , PERTWEE R.G.
Published: July 2012

Δ9‐Tetrahydrocannabinol (Δ9‐THC) was injected into the preoptic area of the anterior hypothalamus or into the third or fourth cerebral ventricle of the conscious mouse through a chronically implanted cannula and the effects on body temperature and oxygen consumption rate were measured.

At an ambient temperature of 22°C, injections of Δ9‐THC into the fourth ventricle (5 and 10 μg) produced dose‐dependent falls in rectal temperature. Hypothermia was also observed after injections of the drug into the hypothalamus (5 and 10 μg) or into the third ventricle (10 μg).

The hypothermia produced by Δ9‐THC was associated with a fall in oxygen consumption rate. Falls in rectal temperature and in oxygen consumption rate were significantly greater after injection of Δ9‐THC than after injection of the drug vehicle, Tween 80.

The falls in rectal temperature and oxygen consumption rate produced by injection of Δ9‐THC into the fourth ventricle were abolished by elevation of the ambient temperature from 22 to 32°C.

A pretreatment that consisted of subcutaneous injections of Δ9‐THC (20 mg/kg) given once daily for three days produced tolerance to the hypothermic effect of the drug when injected on day 4 either into the fourth ventricle (10 μg) or into a lateral tail vein (2.0 mg/kg).

The results suggest that Δ9‐THC acts centrally to alter thermoregulation in mice not only when it is injected directly into the hypothalamus or cerebral ventricles but also when it is given intravenously. After intraventricular or intravenous administration the drug may act at extrahypothalamic as well as at hypothalamic sites. The data also support the hypothesis that in mice, tolerance to the hypothermic effect of Δ9‐THC is pharmacodynamic and does not depend on changes in metabolism or distribution of the drug.
MYOTOXIC ACTIVITY OF THE CRUDE VENOM AND THE PRINCIPAL NEUROTOXIN, TAIPOXIN, OF THE AUSTRALIAN TAIPAN, Oxyuranus scutellatus
Authors: HARRIS J.B. , MALTIN C.A.
Published: July 2012

The crude venom of the Australian taipan, Oxyuranus scutellatus and its principal neurotoxin, taipoxin, were injected into the anterolateral aspect of one hind limb of the rat.

The effects of the venom and toxin on the morphology and physiology on the underlying soleus muscles were examined.

Both the crude venom and the toxin caused necrosis and degeneration of the muscle. Damage to the peripheral muscle fibres could be seen at the light microscopic level as early as 3 h after injection of the toxic compounds.

The necrotic response was accompanied by an infiltration of phagocytic cells and an extensive oedema. The wet weight of the damaged muscles was almost doubled by 6 h.

In individual muscle fibres, necrosis was associated with the disruption of the plasma membrane and the disorganization of the myofibrils. The basal lamina of the muscle fibres was left intact.

Denervated mammalian muscles and innervated avian muscles were also destroyed by taipoxin, but immature avian muscle growing in tissue culture was resistant.

Of the 3 subunits of taipoxin, only the basic α‐taipoxin was itself myotoxic. However, its potency was enhanced by the presence of the acid γ‐subunit. The role of the neutral β‐subunit is unclear.

The period of necrosis and degeneration lasted for approximately 48 h, after which the muscle fibres began to regenerate. Regeneration took place within the surviving basal lamina, with the formation of myotubes by three days, and small, immature muscle fibres by five days. Regeneration was virtually complete by 21 days.
MEMBRANE PROPERTIES AND EXCITATORY NEUROMUSCULAR TRANSMISSION IN THE SMOOTH MUSCLE OF DOG CEREBRAL ARTERIES
Authors: FUJIWARA SHIGERU , ITOH TAKEO , SUZUKI HIKARU
Published: July 2012

Drug actions on electrical and mechanical properties of smooth muscle cells and neuromuscular transmission in the canine cerebral arteries were investigated by use of microelectrode and isometric tension recording methods.

In the basilar and middle cerebral arteries, the resting membrane potentials were — 49.4 mV and — 51.7 mV, respectively, the length constants 0.57 mm and 0.45 mm, respectively and the time constants 142 ms and 118 ms, respectively.

Outward current pulses did not evoke the spike in either artery but did evoke the spike under conditions of pretreatment with 10 mm tetraethylammonium (TEA).

The maximum slope of depolarization produced by a ten fold increase in [K]o plotted on a log scale was 40.1 mV in the basilar artery and 42.2 mV in the middle cerebral artery. 2‐Nicotinamidoethyl nitrate, the K‐permeability accelerator, had no effect on the membrane potential.

K‐free or ouabain [10−5m] treatment slightly depolarized the membrane. Re‐addition of K [5.9 mm] hyperpolarized the membrane by several mV. Thus, the contribution of an active Na‐K pump in the membrane potential seems to be small.

In both arteries, acetylcholine, adenosine, noradrenaline and isoprenaline in concentrations up to 10−5 m did not modify the membrane potential and resistance, while 5‐hydroxytryptamine (over 10−8 m) and ATP (over 10−5 m) depolarized the membrane, decreased the membrane resistance and produced a dose‐dependent contraction. Adenosine suppressed the contraction evoked by excess [K]o(39.8 mm).

Perivascular nerve stimulation produced excitatory junction potentials (e.j.ps). Often e.j.ps were followed by a hyperpolarization. Repetitive stimulation produced facilitation after several stimuli and depression followed. In some cells, this depression appeared without facilitation.

The e.j.ps ceased with pretreatment with guanethidine (10−6 m) or tetrodotoxin (3 × 10−7 m), while phentolamine (10−7m) and yohimbine (10−7m) enhanced the amplitude of e.j.ps. ATP (10−5 m) and noradrenaline (10−6 m) supressed and prazosin had little effect on the e.j.ps. Atropine (10−6 m) also had no effect on the e.j.ps.

Specific features of the cerebral artery and systemic vascular beds were compared, and the features of adrenoceptors on the smooth muscle membrane were compared with findings in other vascular beds.