bluuebunny/crossref_metadata_2025 huggingface dataset:
THE ROLE OF β‐ADRENOCEPTORS IN THE RESPONSES OF THE HEPATIC ARTERIAL VASCULAR BED OF THE DOG TO PHENYLEPHRINE, ISOPRENALINE, NORADRENALINE AND ADRENALINE
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

The sympathetically‐innervated hepatic arterial vascular bed of the dog was perfused from a femoral artery. Hepatic arterial blood flow and perfusion pressure were recorded continuously, and the hepatic arterial vascular resistance (HAVR) calculated from these measurements.

Intra‐arterial injections of phenylephrine caused dose‐dependent rises in HAVR, indicating hepatic arterial vasoconstriction, at all doses above threshold. No secondary reductions in HAVR followed these responses.

Intra‐arterial injections of isoprenaline caused only dose‐dependent reductions in HAVR at doses above threshold.

Intra‐arterial injections of noradrenaline typically caused an initial increase in HAVR which was followed at all but the highest doses by a secondary, delayed, reduction in HAVR.

Intra‐arterial injections of adrenaline, like those of noradrenaline, resulted in hepatic arterial vasoconstriction followed by hepatic arterial vasodilatation.

On a molar basis, the most potent hepatic arterial vasoconstrictor was noradrenaline, followed by adrenaline and phenylephrine.

The maximum reductions in HAVR caused by adrenaline (mean reduction = 21.9%) and noradrenaline (16.9%) were significantly smaller than those due to isoprenaline (P < 0.001).

Propranolol attenuated the hepatic arterial vasodilator responses due to isoprenaline, and the secondary falls in HAVR following intra‐arterial adrenaline and noradrenaline.

Propranolol did not modify the vasoconstrictor responses to phenylephrine.

Both adrenaline and noradrenaline were more potent hepatic arterial vasoconstrictors after propranolol than in the absence of β‐adrenoceptor blockade. The potentiation of the vasoconstrictor effects of adrenaline was statistically significant.

After propranolol, adrenaline was a more potent hepatic arterial vasoconstrictor than noradrenaline.

Since the β‐adrenoceptors in the hepatic arterial vasculature were not blocked by atenolol, but were stimulated by salbutamol, it is concluded that they are predominantly of the β2‐type.

The vasoconstrictor actions of phenylephrine, noradrenaline and adrenaline were all antagonized by the systemic administration of phentolamine, all three dose‐response curves being shifted to the right.

The results are discussed with regard to the possible control of the hepatic arterial vasculature by naturally‐occurring catecholamines.
MODIFICATION, BY ASPIRIN AND INDOMETHACIN, OF THE HAEMODYNAMIC AND PROSTAGLANDIN RELEASING EFFECTS OF E. coli ENDOTOXIN IN THE DOG
Authors: FLETCHER J.R. , RAMWELL P.W.
Published: July 2012

Dogs treated with aspirin (10 mg/kg) or indomethacin (1.5 mg/kg) 45 min before, and 3 h after, an LD50 dose (1 mg/kg) of E. coli endotoxin were alive 72 h later.

Although all dogs in both treated groups survived, only those treated with indomethacin were protected against the fall in blood pressure 1–2 min following endotoxin.

Endotoxin increased the level of prostaglandin F2α in both the mixed venous and arterial blood. No increase was observed in the aspirin and indomethacin‐treated groups.

Aspirin and indomethacin treatment did not modify thrombocytopaenia or blood coagulation parameters following endotoxin.
EFFECTS OF 3‐METHYLINDOLE IN CATTLE
Authors: ATKINSON G. , BOGAN J.A. , BREEZE R.G. , SELMAN I.E.
Published: July 2012

Rapid intravenous injection of 3‐methylindole (3‐MI) was shown to induce an anaphylactoid‐like reaction in calves.

This was suggested by the reduction in response to a repeat dose of 3‐MI, by the reduction of effects in the presence of antagonists to the putative mediators of anaphylaxis in cattle and by the production of signs similar to those seen in experimentally induced bovine anaphylaxis.

The plasma half‐life of 3‐MI was short (14.4 min) and, since absorption of 3‐MI from the rumen is known to be slow, the extent of formation of 3‐MI from L‐tryptophan in the rumen would have to be substantial if 3‐MI is to be considered the causative agent of ‘fog fever’, an acute respiratory distress syndrome seen in cattle.
EFFECTS OF MIANSERIN, A NEW ANTIDEPRESSANT, ON THE in vitro AND in vivo UPTAKE OF MONOAMINES
Authors: GOODLET I. , MIREYLEES S.E. , SUGRUE M.F.
Published: July 2012

The effects of mianserin and of selected tricyclic antidepressants were compared in a number of monoamine uptake models.

The ability of mianserin to block the noradrenergic neurone membrane amine pump of rabbit brain stem slices was comparable to that of imipramine and amitriptyline and less than that of desipramine and nortriptyline. Both mianserin and desipramine were competitive inhibitors of noradrenaline uptake in vitro. The effect of mianserin on noradrenaline uptake in vivo was studied both peripherally and centrally. The ability of 6‐hydroxydopamine to lower rat heart noradrenaline levels was found to be very sensitive to inhibition by tricyclic antidepressants. Mianserin was active in this model. However, its ability to block the 6‐hydroxydopamine‐induced fall in rat heart noradrenaline concentration was appreciably less than that of the tricyclics studied.

Mianserin, like tricyclic antidepressants, was essentially devoid of effect on dopamine uptake both in vitro and in vivo.

The ability of mianserin to inhibit [3H]‐5‐hydroxytiyptamine uptake by rat hypothalamic synaptosomes was appreciably less than that of the tricyclic antidepressants studied. Mianserin was essentially devoid of effect on rat brain 5‐hydroxytryptamine uptake in vivo.

It is concluded that in certain situations large doses of mianserin may block noradrenaline uptake in vivo. However, in no way does mianserin rival tricyclic antidepressants in blocking monoamine uptake in vivo. The clinical efficacy of mianserin cannot be attributed to inhibition of monoamine uptake.
PLASMA NORTRIPTYLINE AND CARDIAC RESPONSES IN YOUNG AND OLD RATS
Authors: BONACCORSI AURORA , FRANCO R. , GARATTINI S. , MORSELLI P.L , PITA E.
Published: July 2012

The relationship between plasma concentrations and cardiac effects of nortriptyline was studied in anaesthetized young and old rats.

Nortriptyline was administered by two consecutive intravenous infusions which resulted in a peak plasma concentration followed by steady state values. Increasing infusion rates were followed by proportional increases in the drug plasma concentrations ranging from 0.15 to 6.0 μg/ml.

In young rats, nortriptyline induced an increase in the heart rate, a right rotation of the electrical axis and a prolongation of the PQ interval. Heart rate changes were not correlated with nortriptyline plasma concentrations, while significant correlations were found for the other two parameters. Plasma concentrations inducing 20% increase of the PQ interval and 40 degrees rotation of the electrical axis were 1.65 and 1.69 μg/ml respectively. Arrhythmias occurred at concentrations higher than 5.2 μg/ml.

Nortriptyline caused more severe cardiac effects in old than in young animals. However, plasma concentrations of nortriptyline in old rats were two to five times higher than those found in young rats at similar infusion rates. A higher concentration of the drug at its sites of action seems to be responsible for the more severe cardiac toxicity of nortriptyline observed in old rats.
INHIBITION BY Cd2+, VERAPAMIL AND PAPAVERINE OF Ca2+‐INDUCED CONTRACTIONS IN ISOLATED CEREBRAL AND PERIPHERAL ARTERIES OF THE DOG
Authors: HAYASHI S. , TODA N.
Published: July 2012

In helically cut strips of canine cerebral arteries exposed to Ca2+‐free media and depolarized by K+, the addition of Ca2+ caused biphasic (transient and sustained) contractions, while in coronary and mesenteric arteries, the addition of Ca2+ produced a sustained contraction sometimes preceded by a slight transient contraction.

These Ca2+‐induced contractions were attenuated by Cd2+ (5 to 100 μm) in a dose‐dependent manner, the attenuation being greater in cerebral than in coronary and mesenteric arteries. The inhibitory effect of Cd2+ was prevented and partially reversed by 1 mm cysteine.

Verapamil and papaverine were also effective in attenuating the Ca2+‐induced contractions in cerebral and peripheral arteries: susceptibility to verapamil was in the order, cerebral > coronary > mesenteric, while that to papaverine was in the order, cerebral = coronary > mesenteric.

It may be concluded that the agents that interfere with trans‐membrane influxes of Ca2+ cause a greater relaxation in cerebral than in peripheral arteries, as is seen with papaverine, a non‐specific vasodilator.
INTRARENAL STIMULATION OF RENIN SECRETION BY FRUSEMIDE IN THE ISOLATED KIDNEY OF THE RAT
Authors: VANDONGEN R.
Published: July 2012

Intrarenal infusion of frusemide markedly stimulated renin secretion in the isolated perfused kidney of the rat.

Renin values increased from 24 ± 6 to 195 ± 34 units of secretion rate (renin concentration (nmol angiotensin I/h per litre) × flow rate (ml/min)) following administration of frusemide for 8 min, compared with corresponding control values of 13 ±2 (P >0.05) and 47 ±18 (P < 0.001). This stimulatory effect was also observed when urine flow was interrupted by ligation of the ureters.

The changes in renal perfusion pressure and perfusate flow rate were not significantly different from the control values.

These findings indicate the existence of an intrarenal site of action for frusemide on renin secretion.

Since frusemide did not appear to alter perfusion pressure or flow rate, and was effective when urine flow was abolished, a dominant role for a vascular or macula densa receptor mechanism seems unlikely. A direct effect of frusemide on the renin secreting cell is therefore suggested.
SELECTIVITY OF BLOCKING AGENTS FOR PRE‐ AND POSTSYNAPTIC α‐ADRENOCEPTORS
Authors: DOXEY J.C. , SMITH C.F.C. , WALKER JULIE M.
Published: July 2012

Low frequency (0.1 Hz) electrical stimulation of the rat isolated vas deferens produced regular contractions that were inhibited by low concentrations of clonidine.

The inhibition of the vas deferens produced by clonidine was presynaptic in origin and involved α‐adrenoceptors.

Presynaptic α‐adrenoceptor antagonist activity was assessed by studying the effects of increasing concentrations of the antagonists on cumulative clonidine dose‐response curves on the stimulated vas deferens.

Postsynaptic α‐adrenoceptor antagonist activity was assessed by comparison of control cumulative noradrenaline dose‐response curves with those in the presence of increasing concentrations of antagonists in the rat anococcygeus muscle.

The results indicate that yohimbine and phentolamine are more potent in blocking presynaptic than postsynaptic α‐adrenoceptors. Phenoxybenzamine and prazosin block postsynaptic α‐adrenoceptors preferentially.

The findings support the view that presynaptic and postsynaptic α‐adrenoceptors differ in their sensitivity to α‐adrenoceptor antagonists.
RESPONSES OF THE CARDIOVASCULAR SYSTEM OF THE RAT TO NORADRENALINE INFUSIONS AND THEIR MODIFICATION BY ADRENOCEPTOR BLOCKING AGENTS
Authors: IMMS F.J. , NEAME R.L.B. , POWIS D.A.
Published: July 2012

The effects of noradrenaline upon the cardiovascular system of the rat, anaesthetized with pentobarbitone, have been investigated.

Noradrenaline produces a dose‐dependent increase in mean arterial blood pressure (MABP) which is due entirely to an increase in cardiac output; total peripheral vascular resistance (TPR) remains unchanged.

Following β‐adrenoceptor blockade the pressor response to infused noradrenaline is enhanced and is now due mainly to an increase in TPR; the increment in cardiac output is reduced.

After α‐adrenoceptor blockade the pressor response is greatly reduced; the residual increase in MABP is due solely to an increase in cardiac output.

After ganglion blockade resting cardiac output and TPR both fall, resulting in a reduction in MABP. The pressor response to noradrenaline is enhanced and is now due to increases in both TPR and in cardiac output.

The cardiovascular response of the anaesthetized rat to noradrenaline can be explained in terms of classical α‐ and β‐adrenoceptor stimulation by the amine; the unusual form of the response may be due to an effective predominance of β‐adrenoceptor‐mediated effects in this species.

It is suggested that the failure of exogenous noradrenaline to produce a rise in TPR results from a balance between the α‐adrenoceptor‐mediated increase and β‐adrenoceptor‐mediated decrease in this variable. However, this proposed balance is lost if resting vasoconstrictor tone is reduced by ganglion blockade.
STRUCTURE‐ACTIVITY RELATIONSHIPS FOR THE ANTICHOLINOCEPTOR ACTION OF TRICYCLIC ANTIDEPRESSANTS
Authors: SHEIN KIN , SMITH S.E.
Published: July 2012

The anticholinoceptor action of 15 tricyclic antidepressants and derivatives has been studied on the guinea‐pig ileum. At the muscarinic receptors the compounds were found to exert antagonism which was reversible and apparently competitive up to dose‐ratios of around 100 but non‐competitive above this level.

Log affinity constants were derived from log dose‐response curves at dose‐ratios <100, where parallel curves were obtained. Amitriptyline, the most potent compound, had 214 × the potency of the weakest, hydroxyimipramine, but was itself 20 × weaker than atropine.

Structure‐activity studies showed that dibenzocycloheptane derivatives were more potent than dibenzazepines and that S or O substitution for C‐11 or other major changes in the central ring of the tricyclic nucleus greatly reduced activity. Side‐chain N‐methylation increased potency markedly. This and other findings indicate that both tricyclic nucleus and side‐chain receptor attachments are largely non‐polar in type.
TOLMESOXIDE, A DRUG THAT LOWERS BLOOD PRESSURE BY A DIRECT RELAXANT EFFECT ON VASCULAR SMOOTH MUSCLE
Authors: DOXEY J.C.
Published: July 2012

The blood pressure of conscious normotensive, deoxycorticosterone acetate (DOCA) hypertensive and 1 kidney Goldblatt hypertensive rats and renal hypertensive and normotensive cats was reduced by tolmesoxide (4,5‐dimethoxy‐o‐tolyl methyl sulphoxide).

Tachycardia accompanied the hypotension. In rats the increase in heart rate was abolished by concurrent administration of propranolol. Tachycardia did not occur in pithed rats.

Vasoconstriction induced by sympathetic stimulation, noradrenaline, tyramine, angiotensin or vasopressin was antagonized by tolmesoxide.

The antagonism of vasoconstrictor responses produced by tolmesoxide was unaffected by β‐adrenoceptor, muscarinic or histamine antagonists.

It is concluded that the lowering of pressure produced by tolmesoxide results from a direct relaxant effect on vascular smooth muscle.
REGIONAL BRAIN ATROPHY AND REDUCTIONS IN GLUTAMATE RELEASE AND UPTAKE AFTER INTRASTRIATAL KAINIC ACID
Authors: FRIEDLE N.M. , KELLY P.H. , MOORE K.E.
Published: July 2012

Neurochemical changes and tissue weights were measured following intrastriatal injection of 2.5 μg of kainic acid in 2 μl of 0.9% w/v NaCl solution (saline) in the rat.

After kainic acid the striatum and neocortex on the injected side showed a progressive reduction in weight, the neocortex showing the greatest absolute weight loss and the striatum the greatest percentage change.

Large (80–90%) reductions in choline acetyltransferase (CAT) and l‐glutamate decarboxylase (GAD) activities in the striatum occurred within 2–4 days of the injection and persisted at least 10 weeks. At 10 weeks CAT and GAD activities were unaltered in the neocortex.

The absolute content of dopamine in the striatum was not different from control 5 days after the injection of kainic acid but was reduced at 2 and 10 weeks. At 2 weeks the concentration (μg/g wet weight) of dopamine also was reduced but at 10 weeks it was near normal due to atrophy of the striatum.

The high affinity glutamate uptake into a crude synaptosomal preparation of the striatum was reduced by 64% 5 days after kainic acid and was still reduced by 67% at 10 weeks.

The efflux of glutamate from slices of the striatum in the presence of 52 mm K+ was reduced by approximately 75% 5 days and 15 weeks after kainic acid.

In vitro kainic acid (10−4m) neither altered the high affinity uptake of radiolabelled glutamate into a homogenate of the striatum, nor released endogenous glutamate from slices of striatum.
INVOLVEMENT OF THE PERIAQUEDUCTAL GREY MATTER AND SPINAL 5‐HYDROXYTRYPTAMINERGIC PATHWAYS IN MORPHINE ANALGESIA: EFFECTS OF LESIONS AND 5‐HYDROXYTRYPTAMINE DEPLETION
Authors: DEAKIN J.F.W. , DOSTROVSKY J.O.
Published: July 2012

Electrolytic lesions of the periaqueductal grey matter (PAG) were made in rats. The analgesia produced by intraperitoneal injection of morphine (10 and 20mg/kg), tested by the tail flick and hot plate methods, was substantially reduced in the lesioned rats. Baseline pain thresholds were unaffected by the lesions.

The lesion effects were not due to damage to the dorsal raphe nucleus. The extent of histologically determined damage to the dorsal raphe and the resulting decrease in striatal 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations did not correlate with the reduction in morphine analgesia produced by the lesion. Furthermore, microinjections of 5, 6‐diHYDROXYTRYPTAMINE (5,6‐DHT) into the dorsal raphe nucleus produced a similar fall in 5‐HIAA levels but had no effect on morphine analgesia.

Selective destruction of the periventricular catecholamine system produced by microinjection of 6‐hydroxydopamine (6‐OHDA) caused a slight decrease in morphine analgesia, thus raising the possibility that catecholamines may be involved in the action of morphine in the PAG.

5,7‐Dihydroxytryptamine‐induced lesions of the spinal cord 5‐hydroxytryptaminergic pathways reduced cord 5‐HT concentration by 70% and markedly attenuated morphine analgesia as determined by the tail flick test.

These experiments provide additional evidence that the PAG is a major site of action of opiates in producing analgesia. Furthermore, they have demonstrated the probable involvement of spinal 5‐hydroxytryptaminergic pathways in the mediation of opiate analgesic effects.
INTERACTION OF PENTOBARBITONE AND γ‐AMINOBUTYRIC ACID ON MAMMALIAN SYMPATHETIC GANGLION CELLS
Authors: BROWN D.A. , CONSTANTI A.
Published: July 2012

Interactions of bath‐applied pentobarbitone and γ‐aminobutyric acid (GABA) on neurones in isolated superior cervical ganglia of the rat have been examined with intracellular microelectrodes.

Pentobarbitone itself (30 μm‐1 mm) showed no clear or consistent GABA‐like effects: changes in resting input conductance and membrane potential were small and variable.

Pentobarbitone (100 μm) strikingly enhanced the conductance increases produced by GABA and 3‐aminopropanesulphonic acid, and reversed the depression of GABA‐evoked responses by bicucul‐line.

It is concluded that reversal of bicuculline action at the membrane conductance level might be explained by augmentation of GABA‐action. This augmentation cannot be attributed to ‘partial agonist’ properties of pentobarbitone or to interference with glial transport processes.
INHIBITION OF PRECURSOR INCORPORATION INTO NUCLEIC ACIDS OF MAMMALIAN TISSUES BY ANTIMALARIAL AMINOQUINOLINES
Authors: FIELD ROGER C. , GIBSON BETSY R. , HOLBROOK DAVID J. , MCCALL BARBARA M.
Published: July 2012

Chloroquine, primaquine and ethidium inhibited thymidine incorporation into deoxyribonucleic acid of rat tissues when administered concurrently with the labelled precursor.

Chloroquine and primaquine inhibited the incorporation of uridine and adenine, but not orotate, into various ribonucleic acid fractions of liver of rats and mice. These drugs had no effect on leucine incorporation into hepatic protein in rats or mice.

Although chloroquine and primaquine are active against different stages in the life cycle of the malarial parasites, the two aminoquinolines exert similar effects in rodent tissues.
AN in vitro COMPARISON OF β‐ADRENOCEPTOR STIMULANTS ON POTASSIUM‐DEPOLARIZED UTERINE PREPARATIONS FROM GUINEA‐PIGS
Authors: O'DONNELL STELLA R. , PERSSON C.G.A. , WANSTALL JANET C.
Published: July 2012

A comparison of six β‐adrenoceptor stimulants has been carried out on in vitro preparations of guinea‐pig uterus which were depolarized in K+‐Krebs solution. Results have also been obtained on uterine preparations in which contractions to acetylcholine were inhibited. The establishment of the conditions for the K+‐depolarized preparations are described.

There was no significant difference between potency values (mean neg log EC50 values) for any of the drugs on the two types of uterine preparation i.e. the preparations had the same sensitivity to the drugs.

There was a less than two‐fold difference between the relative potency values for the β‐adrenoceptor stimulants on the two types of uterine preparation. The relative potency values (isoprenaline = 100) on the K+‐depolarized preparation were fenoterol 74.1, salbutamol 15.1, rimiterol 13.5, terbutaline 8.2 and orciprenaline 5.6.

The relative potency values obtained on uterine preparations were less than three‐fold different from those previously found for guinea‐pig trachea (after inhibition of extraneuronal uptake).

The pA2 value for propranolol on the K+‐depolarized uterine preparations was 9.13.

It is concluded that the K+‐depolarized guinea‐pig uterine preparation can be used for quantitative studies on β‐adrenoceptor stimulant drugs. It lacks spontaneous activity, drugs can be added cumulatively and several drugs can be compared on a single preparation. In addition, the results obtained support the classification of the β‐adrenoceptors in guinea‐pig uterus and trachea in the same sub‐group (β2).
THE ANTIPYRETIC EFFECT OF TILORONE HYDROCHLORIDE IN THE CAT
Authors: CLARK WESLEY G. , ROBINS JEAN A.
Published: July 2012

The antipyretic activity of tilorone hydrochloride was studied in conscious, unrestrained cats provided with implanted jugular venous catheters, third cerebral ventricular (i.c.v.) cannulae and retroperitoneal thermocouples.

In afebrile animals, 10 mg/kg i.v. or 1 mg i.c.v. tilorone hydrochloride did not alter body temperature, but 20 mg/kg i.v. or 2 to 5 mg i.c.v. caused hypothermia and various behavioural responses.

Non‐hypothermogenic doses of tilorone (i.v. or i.c.v.) antagonized hyperthermic responses to leucocytic pyrogen (i.v. or i.c.v.), bacterial pyrogen (i.c.v.) and sodium arachidonate (i.c.v.) but did not antagonize prostaglandin E1 (i.c.v.).

These results indicate that tilorone has an antipyretic action within the central nervous system that is distinct from its hypothermogenic action. Although there is no published evidence to indicate that tilorone can inhibit prostaglandin synthesis peripherally, its ability to reduce hyperthermic responses to arachidonate suggests that it can inhibit prostaglandin synthesis within the brain.
COMPARISON OF THE EFFECTS OF ULTRAVIOLET LIGHT AND PURINERGIC NERVE STIMULATION ON THE GUINEA‐PIG TAENIA COLI
Authors: BURNSTOCK G. , WONG H.
Published: July 2012

The responses of the guinea‐pig taenia coli, urinary bladder and the rabbit portal vein to ultraviolet (u.v.) light were compared to those elicited by purinergic nerve stimulation and exogenous adenosine triphosphate (ATP).

In the presence of sodium nitrite, u.v. light between 340‐380 nm produced a maximum relaxation of the taenia coli. The relaxation was reversible and fast in onset. It was unaffected by atropine, guanethidine or low concentrations of phentolamine or propranolol. When the tone was low, the relaxation was usually followed by a ‘rebound contraction’ upon cessation of stimulation. Thus, the response to u.v. light closely resembles the responses to both purinergic nerve stimulation and exogenously applied ATP.

U.v. light did not initiate impulses in purinergic nerves since its action was unaffected by tetrodotoxin; nor did it release ATP from nerve terminals (in contrast to its release during purinergic nerve stimulation). The adenosine‐uptake inhibitor, dipyridamole, which potentiates the responses to purinergic nerve stimulation and ATP, did not affect the response to u.v. light.

Agents known to alter postjunctional responses to purinergic nerve stimulation and ATP also altered the response to u.v. light. High concentrations of the 2‐substituted imidazoline compounds, antazoline and phentolamine, which antagonize the responses to purinergic nerve stimulation and ATP, reduced the responses to u.v. irradiation. The prostaglandin synthesis inhibitor, indomethacin, which abolishes the ‘rebound contraction’ following stimulation of purinergic nerves, also blocks the ‘rebound ‘contraction’ following u.v. irradiation. Increases in the K+ concentration produced parallel changes in the inhibitory responses to u.v. light and purinergic nerve stimulation.

U.v. light produced relaxation and inhibition of spontaneous activity of the rabbit portal vein (relaxed by ATP), but had no effect on the guinea‐pig urinary bladder (contracted by ATP) and ureter (unaffected by ATP).

It is suggested that u.v. light is acting on some part of the purinergic receptor complex which is involved in the mediation of inhibitory responses to ATP and purinergic nerve stimulation, and may therefore provide a way of investigating the chemistry of inhibitory purinergic receptors.
THE EFFECTS OF A TOXIN ISOLATED FROM AUSTRALIAN TIGER SNAKE (Notechis scutatus scutatus) VENOM ON AUTONOMIC NEŮOMUSCULAR TRANSMISSION
Authors: HARRIS J.B. , ZAR M.A.
Published: July 2012

The effects on mammalian autonomic neuromuscular transmission of a purified toxin from the crude venom of the Australian tiger snake, Notechis scutatus scutatus, have been investigated.

The toxin had no measurable effect on transmission in either the rat anococcygeus, the rat vas deferens, or the longitudinal muscle of the guinea‐pig ileum.

The toxin induced a contraction of longitudinal smooth muscle of the ileum. The tissue relaxed in spite of the continued presence of the toxin, and remained insensitive to further doses. The contractile response was not mediated by either cholinergic or histaminergic mechanisms.

The toxin caused an inhibition of the response to field stimulation of the guinea‐pig vas deferens and the guinea‐pig seminal vesicle. The inhibition was spontaneously reversible, and the preparations remained insensitive to further doses of the toxin. The effects of the toxin were not mediated by either prostaglandins or by noradrenaline.

The inhibitory effects of a variety of compounds known to act at presynaptic sites were also blocked by exposure to the toxin; inhibition caused by postsynaptic activity was unaffected by the toxin.

It is suggested that the toxin inhibits transmission in the guinea‐pig vas deferens and seminal vesicle by a presynaptic mechanism.

The possibility that the mechanism involves phospholipase A2 activity is discussed.
THE DEVELOPMENT OF TOLERANCE TO KETAMINE IN RATS AND THE SIGNIFICANCE OF HEPATIC METABOLISM
Authors: LIVINGSTON A. , WATERMAN A.E.
Published: July 2012

A decrease in sleeping time in rats pretreated with ten daily doses of ketamine compared to controls is shown.

This decrease in sleeping time is associated with a more rapid decrease in circulating and brain levels of ketamine and its N‐demethylated metabolite and higher levels of the subsequent oxidation metabolite in the pretreated animals.

Metabolism of ketamine to its N‐demethylated metabolite by liver homogenates in vitro was more rapid when the livers were obtained from ketamine pretreated rats.

Microsomal preparations from rat liver were capable of metabolizing ketamine to its N‐demethylated metabolite and this metabolite to the subsequent oxidation metabolite in vitro. The Vmax and Km for the first reaction calculated from loss of substrate were 433 mol mg−1 protein h−1 and 0.133 mm respectively and 199 nmol mg−1 protein h−1 and 0.121 mm for the second reaction.

The results indicate that tolerance to ketamine in rats is associated with increased hepatic metabolism which can also be demonstrated in vitro in liver homogenates.
STIMULATION OF ACETYLCHOLINE OUTPUT FROM BRAIN SLICES CAUSED BY THE IONOPHORES BrX‐537A AND A 23187
Authors: CASAMENTI F. , MANTOVANI P. , PEPEU G.
Published: July 2012

The effect of two ionophores, BrX‐537A (Bromolasolacid) and A 23187, on acetylcholine (ACh) output from brain slices was studied.

The slices were prepared from rat cerebral cortex, incubated in Krebs solution containing physo‐stigmine and ACh output determined by bioassay.

Both ionophores enhanced ACh output. BrX‐537A exerted its maximal effect, a six fold increase, at a concentration of 1.8 μm, while A 23187 caused a three fold increase at a concentration of 58 um.

When the slices were incubated in a Ca‐free medium, the effect of A 23187 on ACh output was abolished while that of BrX‐537A was only reduced. BrX‐537A was also active when disodium edetate (EDTA) was added to the Ca‐free medium.

The activity of BrX‐537A was not affected by the presence of tetrodotoxin in the incubation medium.

The stimulation of ACh output elicited by KC1 (25 him) was increased further by hyoscine, but not by BrX‐537A. Hyoscine however had no effect when ACh output was stimulated by BrX‐537A.

The effect of BrX‐537A on ACh output was potentiated by the addition of Mg2+ (9.3 mm) to the incubation medium and was reduced in a Mg‐free medium.

It is concluded that A 23187 stimulates ACh output by transporting extracellular Ca2+ into cholinergic nerve endings. The effect of BrX‐537A does not depend only on Ca2+ but also on other mechanisms.
ANTAGONISM OF THE EFFECTS ON THERMOREGULATION OF Δ9‐TETRAHYDROCANNABINOL BY CLOMIPRAMINE IN THE RAT
Authors: FENNESSY M.R. , TAYLOR D.A.
Published: July 2012

The effect of pretreatment with clomipramine hydrochloride (15 mg/kg, i.p.) on the (‐)‐trans‐A9‐tetrahydrocannabinol (A9‐THC)‐induced changes in body temperature and brain amines of the rat was investigated.

A dose of 0.05 mg/kg of A9‐THC produced hyperthermia and a decrease in whole brain concentration of 5‐hydroxyindoleacetic acid (5‐HIAA). Doses of 2 and 5 mg/kg produced hypothermia and increases in brain 5‐HIAA whereas 0.5 mg/kg did not affect either parameter. A9‐THC, at any of the doses, did not affect the whole brain concentrations of dopamine, noradrenaline or 5‐hydroxytryptamine.

Clomipramine modified these responses of A9‐THC in that the dose‐response curves appeared to be shifted to the right.

It is concluded that clomipramine acts as an antagonist to these actions of A9‐THC by interfering with entry of A9‐THC into tryptaminergic neurones.
THE EFFECTS OF METHOTREXATE AND MELPHALAN IN SHEEP
Authors: GREENWOOD B. , KERRY P.J.
Published: July 2012

Sheep were injected with either methotrexate or melphalan in an attempt to lower the numbers of neutrophil granulocytes in peripheral blood.

Methotrexate, 5.0 mg/kg intravenously, on three consecutive days, produced no noticeable clinical or haematological changes.

A single dose of melphalan, 1.0 mg/kg intravenously, depleted lymphocytes and granulocytes, but the numbers of the latter then rose to values exceeding the levels before melphalan treatment. Doubling the dose of melphalan proved fatal.

The failure of methotrexate to produce changes can be explained in terms of ruminant metabolism.
ACETYLCHOLINE AND SOMATICALLY EVOKED INHIBITION ON PERIGENICULATE NEURONES IN THE CAT
Authors: GODFRAIND J.M.
Published: July 2012

Perigenicuiate neurones in cats were found to be inhibited by iontophoretically applied acetylcholine (ACh) and some of them by somatic sensory stimulation under certain experimental conditions.

Under chloralose anaesthesia, perigenicuiate neurones could be divided into two groups with regard to their spontaneous activity, sensitivity to glutamate and reaction to sensory inputs. Somatic sensory stimulation clearly inhibited the glutamate discharges of those perigenicuiate neurones which were characterized by a high sensitivity to glutamate and the absence of spontaneous activity. ACh had no clear inhibitory effect.

Under fluothane and urethane anaesthesia, no somatic sensory influence was noticed but ACh depressed almost all perigenicuiate neurones.

In an unanaesthetized midpontine pretrigeminal preparation, the inhibitory effect of ACh was confirmed.

No conditions were found under which the inhibitory influences of ACh and those of somatic sensory stimulation could be observed simultaneously on the same neurone. Therefore, it could not be established whether ACh mediates the somatic sensory influences on perigenicuiate cells.
ACUTE MYOCARDIAL ISCHAEMIA IN ANAESTHETIZED CATS: EFFECTS OF PAPAVERINE
Authors: KISIN I.
Published: July 2012

The effects of papaverine on coronary blood flow, myocardial oxygen consumption, myocardial oxygen tension and the ischaemic ECG pattern were studied in anaesthetized open‐chest cats representing three models of acute coronary insufficiency: ligation, spasm, and perfusion of the coronary artery at a stabilized insufficient level.

Despite the increase in myocardial oxygen consumption reflecting elevation of oxygen demand, papaverine improved the signs of myocardial ischaemia (the myocardial oxygen tension and ECG pattern), as long as there was a possibility of an increase in blood supply to the affected zone. Where this was excluded, the symptoms were actually aggravated.

The results suggest that there is no basis for dividing coronary dilators into ‘benign’ and ‘malignant’ according to their ability to increase myocardial oxygen requirements. A coronary dilator enhancing oxygen demand may prove beneficial even following complete coronary artery occlusion.
E. col/ ENDOTOXIN SHOCK IN THE DOG; TREATMENT WITH LIDOCAINE OR INDOMETHACIN
Authors: FLETCHER J.R. , RAMWELL P.W.
Published: July 2012

Dogs treated with lidocaine (1 mg kg−1 h−1) or indomethacin (1.5 mg/kg) before and after an LD60 dose (1 mg/kg) of E. coli endotoxin survived for at least 72 h.

Although all dogs in both treated groups survived, only those treated with indomethacin were significantly protected against the fall in the arterial blood pressure 1 to 2 min following endotoxin administration.

Endotoxin increased the plasma prostaglandin F2α (PGF2α) concentration in the control and lidocaine‐treated groups, however, no increase was observed with indomethacin treatment.

Neither lidocaine nor indomethacin alone had any significant effect on the parameters measured in this model.

Following the administration of endotoxin, lidocaine‐treated animals had significantly decreased plasma fibrinogen concentrations when compared to the other groups.

This study suggests that lidocaine, a local anaesthetic and a drug widely used for cardiac arrhythmias, might offer protection in endotoxin shock.
THE EFFECTS OF PUTATIVE 5‐HYDROXYTRYPTAMINE ANTAGONISTS ON THE BEHAVIOUR PRODUCED BY ADMINISTRATION OF TRANYLCYPROMINE AND L‐TRYPTOPHAN OR TRANYLCYPROMINE AND L‐DOPA TO RATS
Authors: DEAKIN J.F.W. , GREEN A.R.
Published: July 2012

The putative 5‐hydroxytryptamine (5‐HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L‐tryptophan (100 mg/kg). Hyperactivity and hyper‐reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (—)‐propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p‐chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg).

Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and l‐DOPA (50 mg/kg) whereas propranolol was without effect.

None of the putative 5‐HT receptor antagonists affected brain 5‐HT turnover as assessed by rate of accumulation of 5‐HT following monoamine oxidase inhibition with tranylcypromine.

Microinjections of 5,7‐dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5‐HT concentrations without an effect on brain 5‐HT concentrations. The behavioural response to the putative 5‐HT receptor agonist, 5‐methoxy JV, N‐dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5‐HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5‐HT receptors.

Pretreatment with α‐methyl p‐tyrosine (2 × 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L‐tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome.

p‐Chloroamphetamine‐induced 5‐HT depletion had no effect on any component of the tranylcypromine‐L‐DOPA behaviour.
ADRENOCORTICOTROPHIC HORMONE FRAGMENTS MIMIC THE EFFECT OF MORPHINE in vitro
Authors: PLOMP GERDA J.J. , VAN REE JAN M.
Published: July 2012

Fragments of the N terminal part of adrenocorticotrophic hormone (ACTH) inhibited the electrically evoked contractions of the mouse vas deferens. This inhibition could be antagonized by naloxone.

The same fragments displaced radiolabelled morphine from morphine antiserum.

Structure‐activity relationship studies showed that in both assay systems the active core is located within the sequence ACTH 7–10.

It is postulated that the Trp9 residue and the peptide bond between Trp9 and Gly10 are particularly important for interaction of ACTH fragments with morphine receptors.
CHANGES IN PLASMA NORADRENALINE CONCENTRATION AS A MEASURE OF RELEASE RATE
Authors: BENEDICT C.R. , FILLENZ M. , STANFORD CLARE
Published: July 2012

A method is described for repeated sampling of plasma noradrenaline (NA) in freely moving rats. Na concentration does not change during the day or after adrenalectomy.

Exogenous NA has a half‐life of 1.5 min; drugs which block neuronal and extra‐neuronal uptake lengthen this to 6.3 min.

Swim‐stress leads to a steep rise followed by a rapid decline in plasma NA concentration.

This method of plasma NA sampling can serve as a measure of both steady and rapid changes in release rate over long periods of time.
EFFECTS OF CIGARETTE SMOKE ON THE METABOLISM OF VASOACTIVE HORMONES IN RAT ISOLATED LUNGS
Authors: BAKHLE Y.S. , HARTIALA J. , TOIVONEN H. , UOTILA P.
Published: July 2012

The effects of exposure of rats to cigarette smoke have been studied on the metabolism of vasoactive hormones in isolated lungs from these animals.

Rats were exposed for 1 h per day to cigarette smoke for 1 day or for 10 days.

Angiotensin I conversion was increased after 1 day's exposure but after 10 days' exposure conversion returned to normal.

Inactivation of prostaglandin E2 was decreased after 1 day's exposure. After 10 days' exposure there was a further decrease which could not be attributed to smoke alone.

The inactivation of 5‐hydroxytryptamine and bradykinin remained unchanged after both short and longer exposures to smoke.

The metabolic activity of the lung towards some vasoactive hormones in the pulmonary circulation is affected by exposure of the animal to cigarette smoke and such changes may be relevant to the initiation of cardiovascular changes consequent upon cigarette smoking.
EFFECTS OF MORPHINE, PHYSOSTIGMINE AND RAPHE NUCLEI STIMULATION ON 5‐HYDROXYTRYPTAMINE RELEASE FROM THE CEREBRAL CORTEX OF THE CAT
Authors: AIELLO‐MALMBERG PETRA , BARTOLINI A. , BARTOLINI ROSALIA , GALLI A.
Published: July 2012

The release of 5‐hydroxytryptamine (5‐HT) from the cerebral cortex and caudate nucleus of brainstem‐transected cats and from the cerebral cortex of rats anaesthetized with urethane was determined by radioenzymatic and biological assay.

The stimulation of nucleus linearis intermedius of raphe doubles the basal 5‐HT release in the caudate nucleus and increases it 3 fold in the cerebral cortex. The effects of the electrical stimulation of the raphe are potentiated by chlorimipramine.

Brain 5‐HT release is greatly increased by morphine hydrochloride (6 mg/kg i.v.) and by physostigmine (100 μg/kg i.v.), but not by dl‐DOPA (50 mg/kg i.v.).

It is suggested that the 5‐HT releasing action of physostigmine can contribute to some of its pharmacological effects such as the analgesic effect so far attributed exclusively to its indirect cholinomimetic activity.

The 5‐HT releasing action of physostigmine seems unrelated to its anticholinesterase activity.
THE ROLE OF HISTAMINE Hr AND H2‐RECEPTORS IN THE GENERATION OF THROMBOXANE A2 IN PERFUSED GUINEA‐PIG LUNGS
Authors: BERTI F. , FOLCO G. C. , NICOSIA SIMONETTA , OMINI C. , PASARGIKLIAN R.
Published: July 2012

When isolated perfused lungs from normal and ovalbumin sensitized guinea‐pigs were challenged with histamine and 2‐methylhistamine (agonists for Hj‐receptor), a release of thromboxane A2‐like substance was observed. The effect of histamine on production of thromboxane A2 (TXA2) in sensitized lungs, was more pronounced than in normal lungs (P < 0.01).

Specific activation of histamine H2‐receptors in normal lungs with large doses (100 jag) of dimaprit and 4‐methylhistamine, does not produce thromboxane‐like or prostaglandin‐like substances.

Perfusion of the lungs with pyrilamine (10 μg/ml) inhibited the release of arachidonate metabolites induced by histamine H1‐receptor stimulation, whereas cimetidine (5 μg/ml) was ineffective.

It is concluded that only the stimulation of histamine H1‐receptors appears to be responsible for generation of thromboxane A2 and other prostaglandin‐like substances in normal guinea‐pig lungs. In sensitized lungs, an increased ability of histamine to release TXA2 could be due to a possible interconversion of H2 into Hj‐receptors.
CONTENT AND SUBCELLULAR LOCALIZATION OF CATECHOLAMINES AND 5‐HYDROXYTRYPTAMINE IN HUMAN AND ANIMAL BLOOD PLATELETS: MONOAMINE DISTRIBUTION BETWEEN PLATELETS AND PLASMA
Authors: DA PRADA M. , PICOTTI G.B.
Published: July 2012

The content of adrenaline (Ad), noradrenaline (NA) and dopamine was measured in human, guinea‐pig, cat, rabbit and rat blood platelets by a highly sensitive and specific radioenzymatic method.

In all platelet specimens analyzed, the content of the three catecholamines (CA) was several thousand times lower than that of 5‐hydroxytryptamine (5‐HT).

In basal conditions, the NA concentration in platelets and plasma always exceeded that of Ad and dopamine.

In rat and rabbit platelets, Ad, NA and dopamine were present only in the free (unconjugated) form.

Platelets of rats with storage pool deficiency (Fawn‐hooded) contained much less 5‐HT and CA than normal rat platelets.

Following restraint stress, platelets of Fawn‐hooded rats, in contrast to normal rat platelets, did not accumulate CA in spite of a dramatic rise in plasma CA.

Reserpine, a monoamine depletor, released CA as well as 5‐HT from rabbit platelets in vivo.

Subcellular fractionation experiments with rabbit platelets indicate that both CA and 5‐HT are most concentrated in the fraction consisting of pure 5‐HT organelles.

Both in humans and rabbits the concentration gradient between platelets and plasma was much lower for CA than for 5‐HT, indicating that a high affinity transport mechanism operates in vivo for 5‐HT but not for CA.

In conclusion, the present data show that both human and animal platelets contain Ad, NA and dopamine. The bulk of the CA seems to be stored as unconjugated amines together with 5‐HT, histamine and p‐octopamine in a multitransmitter storage site, namely the 5‐HT organelle.
THE INHIBITORY MATERIAL IN EXTRACTS FROM THE BOVINE RETRACTOR PENIS MUSCLE IS NOT AN ADENINE NUCLEOTIDE
Authors: BOWMAN ANN , GILLESPIE J.S. , MARTIN W.
Published: July 2012

Methods are described for the removal of adenosine or purine nucleotides from extracts of bovine retractor penis muscle (BRP). These methods did not interfere with the biological test preparations. Removal of adenosine and purine nucleotides by these methods did not modify the inhibitory action of the extract on the BRP. The effect of the extract on the BRP resembles that of inhibitory nerve stimulation. If the inhibitory substance present in the extract is the inhibitory transmitter, then the results indicate that, in this tissue, the transmitter is neither adenosine nor a purine nucleotide.
CONCOMITANT DEVELOPMENT OF [3H]‐DOPAMINE AND [3H]‐5‐HYDROXYTRYPTAMINE UPTAKE SYSTEMS IN RAT BRAIN REGIONS
Authors: KIRKSEY D.F. , SLOTKIN T.A.
Published: July 2012

Synaptosomal uptake mechanisms of 5‐hydroxytryptamine and dopamine were examined in cerebral cortex, corpus striatum and midbrain plus brainstem of developing rats.

In all regions, there was generally a parallel biphasic development of both uptake systems; the most rapid increases occurred in the first two weeks postpartum, followed by a slower rate of increase.

Kinetic studies with dopamine indicated that the maturation involved increases in maximal uptake without a change in the substrate Km, suggesting that there is a change in the number of terminals but not in the uptake system per se.
GLUTAMATE AS THE NEUROTRANSMITTER OF CEREBELLAR GRANULE CELLS IN THE RAT: ELECTROPHYSIOLOGICAL EVIDENCE
Authors: STONE TREVOR W.
Published: July 2012

Glutamate and the excitatory aminoacid antagonist, α‐aminoadipic acid (αAA), have been applied by microiontophoresis to Purkinje cells in the rat cerebellum.

Glutamate produced excitation of Purkinje cells and αAA selectively reduced that excitation without affecting responses to acetylcholine or hydrogen ions.

Monosynaptic spikes were evoked in Purkinje cells by stimulating the parallel fibres. αAA had little effect on these spikes when applied alone.

When the Purkinje cell excitability was reduced by the iontophoresis of γ‐aminobutyric acid, αAA then produced failure of the monosynaptic spike on 10 of 13 Purkinje cells, in doses shown to be selectively antagonistic towards aminoacids.

These results support neurochemical evidence that glutamic acid may be the neurotransmitter released by granule cell parallel fibres.
A STUDY OF THE MUSCARINIC RECEPTOR BY GEL ELECTROPHORESIS
Authors: BIRDSALL N.J.M. , BURGEN A.S.V. , HULME E.C.
Published: July 2012

Muscarinic receptors from the brain of rat, guinea‐pig and frog have been labelled with tritiated propylbenzilylcholine mustard ([3H]‐PrBCM).

After solubilisation and sodium dodecyl sulphate (SDS)‐polyacrylamide gel electrophoresis a single radiolabeled peak was seen which was completely suppressed when labelling was carried out in the presence of 10−6 m atropine. The results suggest the presence of a single polypeptide chain with a molecular weight of ∼80,000.

In the case of intestinal smooth muscle multiple labelled peaks were found. Precautions against proteolysis led to the identification of a major peak with a molecular weight in the region of 80,000.
SINGLE PULSE STIMULATION OF GUINEA‐PIG VAS DEFERENS AND THE PRESYNAPTIC RECEPTOR HYPOTHESIS
Authors: KALSNER STANLEY
Published: July 2012

The effect of phenoxybenzamine on the efflux of [3H]‐noradrenaline and the mechanical response to single pulse excitation of superfused guinea‐pig vas deferens was determined to examine the validity of the currently accepted hypothesis of a presynaptic negative feedback system on adrenergic nerve terminals.

The adrenoceptor antagonist enhanced both the outflow of tritium and the mechanical response to single pulse stimulation. The efflux of labelled material and the responses to 4 pulses were also enhanced, as expected.

Blockade of neuronal and extraneuronal uptake did not by itself increase nerve‐induced outflow or the mechanical response nor did it prevent phenoxybenzamine from doing so.

The present observations cannot be accommodated within the framework of a hypothesis that proposes that the enhancement of response and tritium efflux by phenoxybenzamine results from blockade of a feedback system whereby noradrenaline released by previous impulses inhibits its own subsequent release.