bluuebunny/crossref_metadata_2025 huggingface dataset:
THE ACCUMULATION OF ADENOSINE IN RABBIT INTESTINAL MUSCLE
Authors: HULME MARILYN E. , WESTON A.H.
Published: July 2012

Strips of longitudinal muscle from rabbit intestine accumulated radioactivity when exposed to [3H]‐adenosine.

Accumulation of radioactivity was not sodium‐dependent or ouabain‐sensitive, but was reduced by cooling, zero glucose plus bubbling with N2, 2,4, dinitrophenol, dipyridamole, hexobendine and lidoflazine.

After 7 min exposure to [3H]‐adenosine, the tissue was found to contain radioactive adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and adenosine itself in the approximate ratio 13: 6: 4: 1.

In the presence of dipyridamole, hexobendine or lidoflazine (each 1 μm), the amounts of radioactive ATP, ADP, AMP and adenosine were reduced with the concentration of adenosine not significantly different from controls.

It is concluded that energy‐dependent uptake of adenosine does not occur in the longitudinal muscle of rabbit intestine. Adenosine enters the tissue by a passive process and rapidly becomes phosphorylated giving rise to apparently high tissue: medium ratios.

The drugs dipyridamole, hexobendine and lidoflazine appear to reduce the accumulation of radioactivity by preventing the formation of adenosine phosphate derivatives.
THE HYPOGLYCAEMIC EFFECT OF 5‐HYDROXYTRYPTOPHAN
Authors: FURMAN B.L.
Published: July 2012

In nialamide‐treated mice, L‐5‐hydroxytryptophan produced a dose‐dependent hypoglycaemic response which was independent of whether the animals had been fed or fasted.

This response was accompanied by a head‐twitching response which was also dose‐dependent.

The hypoglycaemic response was not accompanied by an elevation in plasma immunoreactive insulin levels and was fully manifest in alloxan diabetic animals.

5‐Hydroxytryptophan did not increase the in vitro glucose uptake of adipose tissue or skeletal muscle, either on incubation of the tissues in contact with the drug or on incubation of tissues removed from mice injected with the drug.

Both the hypoglycaemic and head‐twitching responses were prevented by pretreatment with methysergide or cyproheptadine and augmented by mepyramine treatment.
SOME SHORTCOMINGS OF DIRECT INTRAVENTRICULAR INJECTION IN MICE
Authors: SHAW G.G.
Published: July 2012

The use of X‐ray photography following injection of iophendylate to verify that intraventricular injections in mice have been satisfactorily accomplished is misleading since it fails to detect leakage into the periphery. Radioactive labelling reveals that a substantial proportion of the injected material is rapidly carried to the periphery in the bloodstream.
SOME EFFECTS OF DIPYRIDAMOLE, HEXOBENDINE AND LIDOFLAZINE ON INHIBITORY PROCESSES IN RABBIT DUODENUM
Authors: HULME MARILYN E. , WESTON A.H.
Published: July 2012

Some of the effects of dipyridamole, hexobendine and lidoflazine on mechanical responses in rabbit duodenum have been investigated. In concentrations known to inhibit tissue accumulation of adenosine and its metabolites, none of these agents potentiated inhibitory responses to intramural nerve stimulation or to application of adenosine, adenosine triphosphate or phenylephrine. These results neither support nor dispute the suggestion that adenosine or a related nucleotide is the intramural inhibitory transmitter but do show that tissue accumulation in rabbit duodenum is not an important feature in the termination of the action of adenosine.
THE CARDIOVASCULAR EFFECTS OF INTRAVENTRICULAR CLONIDINE AND BAY 1470 IN CONSCIOUS HYPERTENSIVE CATS
Authors: FINCH L.
Published: July 2012

Intraventricular administration of clonidine (5–30 μg) and an analogue, BAY 1470 (15–30 μg) to conscious renal hypertensive cats produced a fall in mean blood pressure lasting for approximately 3 hours. This fall in blood pressure was accompanied by a marked bradycardia.

Pretreatment with intraventricular phentolamine (100–200 μg), piperoxan (40–200 μg) or tolazoline (75–200 μg) abolished the cardiovascular effects of intraventricular clonidine (20 μg).

The cardiovascular effects of intraventricular clonidine (20 μg) were not modified by the pretreatment with either haloperidol (1 mg/kg i.p.) or desmethylimipramine (1 mg/kg i.p.).

Emesis was observed 1–2 min after the administration of either clonidine (5–20 μg) or BAY 1470 (30 μg). This preceded the cardiovascular actions and was still seen after pretreatment with haloperidol, desmethylimipramine, phentolamine, piperoxan or tolazoline.

It is concluded that the centrally mediated cardiovascular responses observed after intraventricular administration of small doses of clonidine are due to stimulation of central α‐adrenoceptors and are independent of central catecholamine uptake mechanisms and dopamine receptors.
EFFECTS OF IMIPRAMINE AND DESIPRAMINE ON RESPONSES OF SINGLE CORTICAL NEURONES TO NORADRENALINE AND 5‐HYDROXYTRYPTAMINE
Authors: BRADSHAW C.M. , ROBERTS M.H.T. , SZABADI E.
Published: July 2012

The technique of microelectrophoresis was used in order to study the effects of imipramine and desipramine on single neurones in the somatosensory cortex of the cat, anaesthetized with halothane.

Imipramine and desipramine, when applied for a brief period, did not affect the firing rate of the vast majority of the neurones tested.

Both potentiation and antagonism of excitatory responses to noradrenaline could be observed after a brief application of either of the antidepressants. Four drug‐interaction patterns could be distinguished: potentiation of immediate onset; potentiation reaching its maximum after a delay; antagonism followed by potentiation; antagonism followed by recovery.

When different doses of the same antidepressant were applied, it was found that the drug‐interaction patterns were related to the dose of antidepressant applied, a lower dose causing potentiation, and a higher dose antagonism of the response.

Both potentiation and antagonism of depressant responses to noradrenaline could be observed.

Both excitatory and depressant responses to 5‐hydroxytryptamine were modified by imipramine and desipramine: a smaller dose of the antidepressant potentiated, and a higher dose antagonized the responses.

Excitatory responses to glutamate were not affected by imipramine and desipramine.
EFFECT OF CONVERTING ENZYME BLOCKADE ON ISOPRENALINE‐ AND ANGIOTENSIN I‐INDUCED DRINKING
Authors: HERTTING G. , MEYER D.K.
Published: July 2012

Intravenous infusion of 0.072 μmol kg−1 h−1 (1‐Asp, 5‐Ile) angiotensin I, 0.116 μmol kg−1 h−1 of (1‐Asp β‐amid, 5‐Val) angiotensin II or of (1‐Asp, 5‐Ile) angiotensin II, caused food‐deprived and water‐satiated rats to drink about 3.0 ml of water per animal. This indicates that angiotensin I has a 1.6 times stronger dipsogenic effect than the angiotensin II preparations when infused intravenously.

The converting‐enzyme‐inhibitor SQ 20881 (Pyr‐Trp‐Pro‐Arg‐Pro‐Gln‐Ile‐Pro‐Pro) (1.0 mg/kg i.v.) had no intrinsic dipsogenic effect.

SQ 20881 given in combination with angiotensin I or angiotensin II potentiated the dipsogenic effect of angiotensin I, but not that of the two angiotensin II preparations.

The drinking induced by isoprenaline (100 μg/kg, i.m.) was potentiated by SQ 20881 to the same extent as drinking produced by angiotensin I infusion.

Angiotensin I plasma levels were determined after angiotensin I infusion and isoprenaline application. Both were significantly raised by SQ 20881.

It is concluded that one of the mechanisms which mediate the dipsogenic effect of isoprenaline is stimulation of the renin‐angiotensin system and that increased plasma levels of angiotensin I may play a substantial role in this type of drinking.
CALCIUM EFFLUX AND SECRETION OF α‐AMYLASE FROM RAT PANCREAS
Authors: HEISLER S.
Published: July 2012

The efflux of 45Ca from rat pancreas was investigated in relation to the secretion of α‐amylase.

The 45Ca space in the pancreas was increased 1.6 times when pancreatic tissue was incubated in media in which the extracellular calcium concentration was reduced from 1.0 to 0.05 Mm.

Carbachol increased the rate of 45Ca efflux from the tissue and this effect was associated with an increase in the release of α‐amylase. Dibutyryl cyclic adenosine monophosphate (AMP) also evoked a secretory response, but did not alter the rate of 45Ca efflux. In combination with carbachol, the dibutyryl analogue of cyclic AMP reduced the carbachol‐stimulated increase in 45Ca efflux while enhancing the release of secretory protein.

The stimulatory effect of carbachol on 45Ca efflux was observed when pancreatic tissues were incubated in media containing a high concentration of ethyléneglycolbis (β‐aminoethyl)‐N,N′‐tetraacetic acid (EGTA).

Atropine blocked the effects of carbachol on both 45Ca efflux and secretion of α‐amylase.

It was concluded that intracellular calcium can and may sustain stimulus‐secretion coupling in the rat exocrine pancreas.
EFFECTS OF PROSTAGLANDIN INHIBITORS ON ANGIOTENSIN, OXYTOCIN AND PROSTAGLANDIN F2α CONTRACTILE EFFECTS ON THE RAT UTERUS DURING THE OESTROUS CYCLE
Authors: BAUDOUIN‐LEGROS MARYVONNE , MEYER P. , WORCEL M.
Published: July 2012

In the rat isolated uterus maximal spontaneous contractions and maximal sensitivity to angiotensin II, oxytocin and prostaglandin F2α were observed in di‐ and proestrus. Minimal sensitivity to the three agonists was observed in metoestrus. Maximal contractile effects of angiotensin II, oxytocin and prostaglandin F2α were thus observed when the ratio oestrogen/ progesterone levels was high.

The oestrogen‐dependent sensitivity of the rat uterus is partially mediated by endogenous prostaglandins. Indomethacin suppressed the increased sensitivity to angiotensin and oxytocin present in dioestrus and proestrus but did not affect that to prostaglandin F2α. Polyphloretin phosphate at a concentration of 10μg/ml resulted in complete identity of dioestrus and metoestrus dose‐response curves to angiotensin and oxytocin.

Spontaneous uterine contractions observed when oestrogen levels are high are also dependent on intramural prostaglandins as they were inhibited by indomethacin and polyphloretin phosphate. In the metoestrus uterus, prostaglandin F2α induced the reappearance of spontaneous contractions.

Prostaglandin F2α had a potentiating effect on angiotensin‐elicited contractions which persisted after washing out prostaglandin F2α.
FURTHER STUDIES ON THE MODE OF ACTION OF PSYCHOTOMIMETIC DRUGS: ANTAGONISM OF THE EXCITATORY ACTIONS OF 5‐HYDROXYTRYPTAMINE BY METHYLATED DERIVATIVES OF TRYPTAMINE
Authors: BRADLEY P.B. , BRIGGS I.
Published: July 2012

The actions of 5‐methoxytryptamine (5‐MeOT), N,N‐dimethyltryptamine (DMT), 5‐hydroxy‐N,N‐dimethyltryptamine (bufotenine, 5‐HODMT) and 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeODMT), and their interactions with 5‐hydroxytryptamine (5‐HT), acetylcholine, (–)‐noradrenaline, and glutamate were studied by microiontophoresis on single neurones in the brain stem of rats anaesthetized with urethane or decerebrate cats.

Like d‐lysergic acid diethylamide (LSD 25) the three psychotomimetic derivatives (DMT, 5‐HODMT, 5‐MeODMT) specifically antagonized 5‐HT excitations of single neurones, but the non‐psychotomimetic 5‐MeOT had no antagonistic effects.

In contrast to LSD 25, the psychotomimetic tryptamines only rarely antagonized glutamate effects, indicating that the excitatory 5‐HT receptors and the glutamate receptors on the same neurones may be closely related spatially, but are separate.

The methylated tryptamine derivatives were able to mimic the actions of 5‐HT on neurones. The non‐psychotomimetic 5‐MeOT was most potent in this respect, while the other three derivatives which are psychotomimetic, were less active.

The 5‐HT mimicking actions of 5‐MeOT were the same in rats pretreated with p‐chlorophenylalanine or reserpine as in untreated rats. It therefore seems that the 5‐HT mimicking actions are unlikely to be due to release of 5‐HT, but are due to direct actions on 5‐HT receptors.

The evidence presented supports the hypothesis that LSD‐like psychotomimetics act by an antagonism of 5‐HT in the lower brain stem, and is not compatible with the suggestion that the psychotomimetic action of these drugs is related to 5‐HT receptor stimulation.
BIOASSAY OF OXYTOCIN ON THE SUPERFUSED MAMMARY GLAND OF THE MOUSE, USING AN AUTOMATIC APPARATUS
Authors: ROBINSON I.C.A.F. , WALKER J.M.
Published: July 2012

A sensitive method of assaying oxytocin using the superfused mouse mammary gland is described. The method is shown to be reliable, accurate and precise. Assays are performed automatically and the preparation is stable for at least 18 hours.

The preparation is relatively insensitive to bradykinin, histamine, 5‐hydroxytryptamine, angiotensin, prostaglandin F2α, adrenaline and noradrenaline. The contractions produced by acetylcholine can be abolished by atropine without the sensitivity to oxytocin being affected.

Vasopressin has a variable activity on the preparation; its potency can be as high as one‐fifth that of oxytocin.

It is concluded that this method compares favourably with other published methods.
ANTAGONISM BY FOLIC ACID OF PRESYNAPTIC INHIBITION IN THE RAT CUNEATE NUCLEUS
Authors: HILL R.G. , MILLER A.A.
Published: July 2012

Folic acid applied topically in solution to the rat cuneate nucleus reduced presynaptic inhibition produced by peripheral stimulation. This resembles the action of picrotoxin in the same animals and it is possible that these two convulsants are acting in a similar manner by blockade of the receptors for the presynaptic inhibitory transmitter.
ACUTE AND CHRONIC MORPHINE TREATMENT AND THE HYDROXYLATION OF [1‐14C]‐l‐TYROSINE IN THE MOUSE BRAIN
Authors: MARSHALL I. , SMITH C.B.
Published: July 2012

Tyrosine hydroxylase activity in slices of caudate nucleus was increased by morphine (100 mg/kg i.p.) administered to naive mice. During chronic treatment with morphine tolerance developed to this effect and 36 h after the final chronic morphine injection there was a decrease in enzyme activity in this area. There was no change in tyrosine hydroxylase activity in slices of diencephalon, brainstem or parietal cortex from either naive or morphine tolerant mice. Therefore, changes in tyrosine hydroxylase activity, measured in vitro, could account for the changes in dopamine synthesis, but not noradrenaline synthesis, produced by morphine in vivo.
ENHANCEMENT OF PENTAGASTRIN‐INDUCED GASTRIC ACID SECRETION BY CLONIDINE IN THE CONSCIOUS DOG
Authors: CURWAIN B.P. , ENDERSBY K.
Published: July 2012

The effect of intravenous clonidine on pentagastrin‐induced gastric acid secretion has been studied in conscious dogs with Heidenhain pouches. Dose‐dependent enhancement of secretion was found in response to clonidine (5–20 μg/kg). Clonidine (20 μg/kg) increased the maximal secretory rate to pentagastrin to a value not significantly different from the maximal response to histamine.
THE HAEMODYNAMIC EFFECTS OF PROLONGED ORAL ADMINISTRATION OF OXYFEDRINE, A PARTIAL AGONIST AT β‐ADRENOCEPTORS: COMPARISON WITH PROPRANOLOL
Authors: PARRATT J.R.
Published: July 2012

Haemodynamic changes have been studied in cats after the chronic oral administration of oxyfedrine (14 mg/kg for 3–4 weeks) or of placebo (lactose). The initial part of the study was carried out under double‐blind conditions. The arterial blood pressure was between 19 mmHg (diastolic) and 27 mmHg (systolic) higher in the oxyfedrine treated animals, but there were no differences between the two groups with regard to cardiac output, left ventricular dP/dt max, heart rate or systolic ejection time.

In cats similarly treated with propranolol (4 mg/kg) there was a slight (12%), but significant, reduction in cardiac output.

Isoprenaline dose‐response curves were shifted to the right in the cats administered oxyfedrine as well as in those administered propranolol. The degree of shift was five‐fold (positive chronotropic response) and 20‐fold (decrease in diastolic blood pressure) in the oxyfedrine group and 10‐ and 80‐fold, respectively, in the propranolol group.

In contrast to the partial blockade of the effects of isoprenaline, the haemodynamic response to oxyfedrine was largely unaltered, both in the cats pretreated with propranolol and in those pretreated with oxyfedrine. The pressor response to noradrenaline was potentiated in the cats pretreated with oxyfedrine.

These results provide an explanation for the anti‐anginal action of oxyfedrine. Some degree of β‐adrenoceptor blockade is achieved without a reduction in cardiac output or left ventricular dP/dt max. The relevance of these findings to the haemodynamic situation in angina is discussed.
THE EFFECTS OF A NEW β‐ADRENOCEPTOR BLOCKING COMPOUND, TOLAMOLOL, ON HAEMODYNAMICS AND MYOCARDIAL FUNCTION IN MAN
Authors: HILLIS W.S. , HUTTON I. , LAWRIE T.D.V. , LORIMER A.R. , REID J.M.
Published: July 2012

The effects of tolamolol on haemodynamics and myocardial contractility were investigated in two groups of six patients undergoing diagnostic cardiac catheterization.

The intravenous administration of tolamolol (0.15 mg/kg) produced a significant fall in heart rate from a control value (87 ± 7 to 62 ± 3 beats/min) 5 min after administration and a concomitant fall in cardiac output from 4.7 ± 0.9 to 3.5 ± 0.8 litres/minute. There was no significant change in systemic blood pressure, pulmonary artery blood pressure or stroke volume.

There was no change in left ventricular end diastolic pressure after tolamolol. There was a fall in the maximum rate of rise of the left ventricular pressure (LV dp/dtmax) and the derived index of the left ventricular contractile state (Vmax).

These results suggest that tolamolol has a predominantly negative chronotropic but also a lesser negative inotropic action on the heart.
THE ACTION OF 5‐HYDROXYTRYPTAMINE AND RELATED COMPOUNDS ON THE ACTIVITY OF RETZIUS CELLS OF THE LEECH Hirudo medicinalis
Authors: SMITH P.A. , WALKER R.J.
Published: July 2012

The equipotent molar ratios of a range of tryptamine analogues, as compared with 5‐hydroxytryptamine (5‐HT), have been determined on the basis of their ability to hyperpolarize the membrane potential of the Retzius cell of the leech, Hirudo medicinalis.

The substitution of methyl, fluoro, chloro, methoxy or acetyl groups onto the 5‐HT molecule progressively reduced the potency.

5‐Methoxylation or terminal N‐methylation of tryptamine considerably increased the potency of tryptamine but these compounds tended to depolarize cells rather than cause hyperpolarization. In some experiments they were ineffective on preparations pretreated with 5‐HT.

It is suggested that these compounds may act by a different mechanism from the 5‐hydroxylated indoles, perhaps involving a different receptor.
ROLE OF ENDOGENOUS CATECHOLAMINES IN THE ANTI‐INFLAMMATORY ACTIVITY OF α‐ADRENOCEPTOR BLOCKING AGENTS
Authors: GREEN K.L.
Published: July 2012

Drugs which release or modify the response to catecholamines were examined for their effect on the permeability of the mouse peritoneal vascular bed to circulating plasma albumin, labelled with Evans blue.

Phenoxybenzamine, phentolamine, piperoxane, yohimbine or cocaine reduced the extravasation of Evans blue into the peritoneum, an effect which was antagonized by β‐adrenoceptor blocking drugs. The inhibitory effect of desipramine on the extravasation of Evans blue was less completely antagonized by β‐adrenoceptor blockade.

Inhibition of catecholamine biosynthesis, ganglion blockade or adrenergic neurone blockade antagonized the reduction in dye extravasation by α‐adrenoceptor blocking agents and cocaine, but had no significant effect on the response to desipramine. The inhibitory effects of α‐adrenoceptor blocking agents on dye extravasation were not prevented by bilateral adrenalectomy.

Mice subjected to the procedure for estimation of vascular permeability excreted increased amounts of adrenaline and noradrenaline. Pretreatment with phenoxybenzamine, piperoxane or cocaine further increased catecholamine excretion, but desipramine caused only a small increase in catecholamine excretion which did not correlate with its effect on dye extravasation.

It is suggested that phenoxybenzamine, phentolamine, piperoxane and cocaine reduce vascular permeability in the mouse peritoneum by releasing and/or potentiating the effects of endogenous catecholamines on β‐adrenoceptors. Endogenous catecholamines do not appear to be involved in the anti‐inflammatory activity of desipramine.
THE PHARMACOKINETICS OF [14C]‐EDROPHONIUM IN NORMAL WISTAR RATS AND HOMOZYGOUS GUNN RATS WITH LIGATED RENAL PEDICLES
Authors: BACK D.J. , CALVEY T.N.
Published: July 2012

The distribution kinetics of [14C]‐edrophonium were studied in both normal Wistar and homozygous Gunn rats with ligated renal pedicles.

After intravenous injection the plasma concentration‐time curve of [14C]‐edrophonium was adequately fitted by a triexponential function in both species of rat and interpreted in terms of a three compartment model.

The influence of the route of administration (i.e., systemic venous versus hepatic portal) of [14C]‐edrophonium on its concentration in plasma was studied in normal Wistar rats with ligated renal pedicles. There was a marked difference in the area under the plasma concentration‐time curve depending on the route of administration.

The parameters of the model were determined and compared.

The value of the metabolism rate constant was approximately the same in both species of rat. This suggests that the rate of conjugation of [14C]‐edrophonium is unaltered in the homozygous Gunn rat despite the genetic lesion in UDP‐glucuronyltransferase.
ANTAGONISM OF THE SPINAL ACTION OF DIAZEPAM BY SEMICARBAZIDE
Authors: BANNA N.R. , JABBUR S.J. , SAADÉ N.E.
Published: July 2012

In spinal unanaesthetized cats, pretreatment with semicarbazide (200 mg/kg) 2–4.5 h prior to the administration of diazepam (1–4 mg/kg) completely blocked the enhancement of the segmental dorsal root reflex by the latter compound. Pyridoxine hydrochloride (200 mg/kg), given 3.5 h after semicarbazide, restored the spinal effect of diazepam administered 1 h later. The possibility of a link between diazepam and spinal γ‐aminobutyric acid is suggested and discussed.
THE EFFECTS OF MICROIONTOPHORETICALLY APPLIED MORPHINE AND TRANSMITTER SUBSTANCES IN RATS DURING CHRONIC TREATMENT AND AFTER WITHDRAWAL FROM MORPHINE
Authors: BRADLEY P.B. , DRAY A.
Published: July 2012

The effects of microiontophoretically applied acetylcholine, noradrenaline, 5‐hydroxytryptamine and morphine were studied on single brain stem neurones of rats during chronic morphine pretreatment and 24 h after its withdrawal. No significant changes were observed in the initial spontaneous neuronal firing rate or in the qualitative or quantitative effects of acetylcholine, noradrenaline or 5‐hydroxytryptamine. However, in chronically treated animals there was a significant decrease in the number of neurones excited by morphine or showing tachyphylaxis to morphine on repeated microiontophoretic applications.

We suggest that some of the cellular central nervous system changes which occur during chronic morphine treatment are reflected by the decrease in sensitivity of neurones to morphine excitation.
EFFECT OF PHARMACOLOGICAL BLOCKADE ON LITHIUM‐INDUCED WATER DRINKING
Authors: PERUMAL T.A. , RAO J. PRAKASA
Published: July 2012

Administration of lithium chloride (40 mg/kg i.p.) led to a significant increase in 24 h water intake of rats. Prior administration of propranolol and haloperidol blocked the effect of lithium while atropine failed to show such an effect. The dipsogenic effect of lithium is probably exerted through β‐adrenergic and dopaminergic pathways.
EFFECTS OF CATECHOLAMINE SYNTHESIS INHIBITION ON ETHANOL‐INDUCED WITHDRAWAL SYMPTOMS IN MICE
Authors: BLUM K. , WALLACE J.E.
Published: July 2012

α‐Methyl‐p‐tyrosine, a catecholamine synthesis inhibitor, was studied to determine its effects against ethanol‐induced withdrawal symptoms in mice. Significant (P < 0.001) potentiation of the withdrawal convulsion score induced by ethanol vapour exposure for three days was observed in mice. The synergistic effect was not due to alteration of ethanol metabolism. These results indicate that reductions in catecholamines (dopamine and noradrenaline) augment seizure activity induced by subchronic exposure to ethanol.
STUDIES ON THE METABOLISM OF CATECHOLAMINES IN THE CENTRAL NERVOUS SYSTEM OF THE MOUSE
Authors: CEASAR P.M. , HAGUE P. , SHARMAN D.F. , WERDINIUS B.
Published: July 2012

The distribution of the metabolites of noradrenaline, 1‐(3,4‐dihydroxyphenyl)ethane‐1,2‐diol (DOPEG) and 1‐(4‐hydroxy‐3‐methoxyphenyl)ethane‐1,2‐diol (MOPEG), in the brain of the mouse has been investigated.

The rate of disappearance of the metabolites after inhibition of the enzyme monoamine oxidase has been used to estimate their turnover rates in the mouse hypothalamus. It was concluded that the turnover of DOPEG was much faster than that of MOPEG.

When mice were treated with reserpine dissolved in 5% ascorbic acid solution there was an increase in the hypothalamic concentration of both MOPEG and DOPEG. However, similar increases in the concentrations of the two metabolites were seen when the animals were treated with 5% ascorbic acid solution alone.

The administration of tropolone, an inhibitor of the enzyme catechol‐O‐methyl transferase, resulted in an increase in the concentration of DOPEG.

Mice, exposed to a temperature of −15° C showed increased hypothalamic concentrations of both DOPEG and MOPEG.

The rates of formation in the mouse striatum of 3,4‐dihydroxyphenylacetic acid (DOPAC) and 4‐hydroxy‐3‐methoxyphenylacetic acid (HVA), acidic metabolites of dopamine, were compared with the turnover rate of dopamine, estimated from the rate at which this catecholamine disappears after treatment with α‐methyl‐p‐tyrosine. It was concluded that the estimate of dopamine turnover obtained by this method is likely to be too large because of the compensatory feedback mechanism which is thought to play a role in the metabolism of dopamine in the brain.
THE RELATION BETWEEN THE ADRENERGIC NEURONE‐BLOCKING AND NORADRENALINE‐DEPLETING ACTIONS OF SOME GUANIDINE DERIVATIVES
Authors: ABBS E.T. , DODD M.G.
Published: July 2012

The effects of some guanidine derivatives, (—)‐N‐(1‐phenylethyl) guanidine (PEG), guanethidine and debrisoquine have been investigated on the content and subcellular distribution of noradrenaline in cat spleen and on the overflow of noradrenaline from this organ during stimulation of the splenic nerve.

PEG and guanethidine, at a dose of 5 mg/kg, produced adrenergic neurone blockade within 15 min and the same dose of debrisoquine produced blockade within 30 minutes.

All three compounds produced a decrease of similar magnitude in the noradrenaline content of the high‐speed particulate (P2) and supernatant (S) fractions of splenic homogenates; these actions were temporally correlated with the adrenergic neurone‐blocking action of the compounds.

PEG did not produce any further decrease in the noradrenaline content of the subcellular fractions at times up to 18 h after its administration; adrenergic neurone blockade was maintained throughout this period but had disappeared after 7 days when the noradrenaline content of the subcellular fractions was restored to control levels.

Guanethidine, in contrast, caused a marked progressive loss of the transmitter from all subcellular fractions‐an effect which was maximal 18 h after its administration but continued, as did the adrenergic neurone‐blocking action, for at least 72 hours. This additional loss of noradrenaline, over and above that seen after 15 min, is unlikely to be connected with the adrenergic neurone‐blocking action of the drug.

Dexamphetamine both prevented and antagonized the neurone blockade and the subcellular noradrenaline‐depleting action of PEG and guanethidine. The restoration of nerve function after administration of dexamphetamine to animals pretreated with 5 mg/kg of either of these compounds was temporally correlated with a selective repletion of the noradrenaline content of the supernatant fraction of the spleen.

Larger doses (15 mg/kg) of PEG or guanethidine produced a selective depletion of noradrenaline in only the supernatant fraction of the spleen. This depletion was temporally correlated with the adrenergic neurone‐blocking action of these compounds. The lack of effect of the compounds at this dose level on the noradrenaline contained in the P2 fraction may be due to ‘stabilization’ of the store of noradrenaline in vivo which gives rise to this fraction on homogenization.

It is suggested that the guanidine‐type adrenergic neurone‐blocking agents displace the noradrenaline which is readily available for release by nerve impulses, and that it is this action that may account for their sympathomimetic properties.

The ability of these guanidines to impair the release of noradrenaline by nerve impulses could occur because whilst they are present within the neurone the ‘nerve‐releasable store’, which may in these experiments appear in the supernatant fraction after homogenization, may be unable to refill with transmitter.
LACK OF COPULATORY BEHAVIOUR IN MALE CASTRATED RATS AFTER p‐CHLOROPHENYLALANINE
Authors: DEL FIACCO M. , FRATTA W. , GESSA G.L. , TAGLIAMONTE A.
Published: July 2012

The effect of p‐chlorophenylalanine (PCPA) on the copulatory behaviour of normal and castrated male rats with females in oestrus was studied.

Castration 2 months before the experiment completely prevented the increased copulatory behaviour produced by PCPA in normal rats.

The administration of testosterone restored the copulatory behaviour in the castrated rats indicating that testosterone is essential for this behaviour.
ON THE SIMULTANEOUS ACTION OF TWO COMPETITIVE ANTAGONISTS
Authors: GINSBORG B.L. , STEPHENSON R.P.
Published: July 2012

A hypothesis is outlined predicting the conditions in which the addition of a second competitive antagonist will increase rather than reduce the response to an agonist.

Experiments were performed with the guinea‐pig ileum as the test tissue, hexyltrimethyl ammonium as the agonist, benzilyltropine methiodide as the ‘slow’ antagonist and pentyltriethyl ammonium as the ‘fast’ antagonist.

The results are consistent with the hypothesis, if the affinity constant for hexyltrimethyl ammonium is between 2.7 and 3.7 × 104 m−1, if the dissociation time constant for the slow antagonist is greater than 10 min and if that for the fast antagonist is less than 10 seconds.
DIRECT ESTIMATES OF CHLORIDE ACTIVITY IN MUSCLE FIBRES DEPOLARIZED BY CARBACHOL
Authors: FELTZ ANNE , JAOUL ANNE
Published: July 2012

Intracellular chloride activities have been measured in muscle fibres with chloride‐sensitive electrodes. It was found that the depolarization induced by carbachol produces an influx of chloride ions, the accumulation of which leads to further sustained depolarization. The present study thus confirms the evidence put forward by Jenkinson & Terrar (1973) of an influence of chloride ions on the membrane potential after a prolonged application of carbachol.
EFFECT OF P‐CHLOROPHENYLALANINE ON BRAIN MONOAMINES AND BEHAVIOUR DURING ETHANOL WITHDRAWAL IN MICE
Authors: GRIFFITHS P.J. , LITTLETON J.M. , ORTIZ A.
Published: July 2012

The administration of p‐chlorophenylalanine to mice prevents the rise in brain 5‐hydroxytryptamine concentration associated with ethanol withdrawal but does not affect the increase in brain catecholamines which occurs at the same time. The locomotor excitement, piloerection, tremor and handling convulsions which occur during ethanol withdrawal were not affected. These results suggest that the increase in brain 5‐hydroxytryptamine which occurs in ethanol withdrawal is a consequence of increased 5‐hydroxytryptamine synthesis and that it is probably not involved in the above behavioural changes of ethanol withdrawal.
THE LONG‐TERM REGULATION OF TYROSINE HYDROXYLASE ACTIVITY IN CULTURED SYMPATHETIC GANGLIA: ROLE OF GANGLIONIC NORADRENALINE CONTENT
Authors: MACKAY A.V.P.
Published: July 2012

An organ culture system is described for the in vitro maintenance of superior cervical sympathetic ganglia taken from mice of any age. The relation of tyrosine hydroxylase (T‐OH) activity to ganglionic noradrenaline (NA) content has been investigated under various culture conditions.

Depolarizing stimuli such as raised extracellular potassium and ouabain evoked increases of approximately 70% in the T‐OH activity of cultured ganglia over a 48 h period. Exposure to a high concentration of potassium (high K+) for 30 min at the start of a 48 h culture was sufficient to elicit significant increases in T‐OH activity.

Depolarization‐induced rises in T‐OH activity were observed after culture in the presence or absence of nerve growth factor.

The NA content of ganglia, cultured for 48 h in the presence of high K+, ouabain, reserpine, clorgyline and α‐methyl‐p‐tyrosine, showed no constant relation to their T‐OH activity.

Dibutyryl cyclic adenosine 3′‐5′‐monophosphate (dibutyryl cyclic AMP) mimicked high K+ in its effect on ganglionic T‐OH activity and NA content. Theophylline enhanced the potassium effects.

Rises in the T‐OH activity of ganglia cultured in the presence of high K+ and dibutyryl cyclic AMP were abolished if the protein synthesis inhibitors cycloheximide or actinomycin D were present in the culture medium.

It is concluded that the link between prolonged depolarization and rises in T‐OH activity does not seem to depend upon changes in ganglionic NA content. In the intact animals, trans‐synaptic modulation may take the form of a depolarization‐induced rise in the cyclic AMP content of sympathetic ganglionic neurones leading to nuclear mediated synthesis of T‐OH.
EFFECT OF PREGANGLIONIC NERVE STIMULATION ON SENSITIVITY OF THE SUPERIOR CERVICAL GANGLION TO NICOTINIC BLOCKING AGENTS
Authors: ALKADHI K.A. , McISAAC R.J.
Published: July 2012

Periodic stimulation (every 10 min) of the cervical sympathetic nerve increased the ganglionic block by low concentrations of chlorisondamine (CHL) in the superior cervical ganglion of the cat when compared to the contralateral unstimulated side.

Periodic stimulation of the postganglionic nerve was ineffective in increasing the block.

Ganglionic block by low concentrations of mecamylamine had the same stimulus dependency, but ganglionic block by any dose of hexamethonium was not influenced by nerve stimulation.

Physostigmine infused together with CHL increased the rate of onset of block produced by CHL. Atropine had no apparent effect on the development of ganglionic block by CHL.

Repeated intra‐arterial injections of 1,1‐dimethyl‐4‐phenylpiperazinium into the circulation of the superior cervical ganglion increased the magnitude of block produced by CHL. Similar injections of methacholine had no effect on ganglionic block produced by CHL.

The results are interpreted to indicate that activation of ganglionic nicotinic receptors increased the affinity of receptors for CHL and mecamylamine.
THE ROLE OF BRAIN 5‐HYDROXYTRYPTAMINE IN THE HYPERACTIVITY PRODUCED IN RATS BY LITHIUM AND MONOAMINE OXIDASE INHIBITION
Authors: GRAHAME‐SMITH D.G. , GREEN A.R.
Published: July 2012

Administration to rats of LiCl (3 mEq/kg) subcutaneously twice daily for 3 days followed by monoamine oxidase inhibition with either tranylcypromine (TCP; 20 mg/kg) or pargyline (75 mg/kg) on the fourth day produces a syndrome of hyperactivity indistinguishable from that produced by monoamine oxidase inhibition and l‐tryptophan administration.

At least 3 injections of LiCl (3 mEq/kg) are necessary before hyperactivity is seen but one dose of LiCl (10 mEq/kg) 5 h before TCP also caused hyperactivity. The hyperactivity is blocked by prior administration of p‐chlorophenylalanine, a tryptophan hydroxylase inhibitor.

LiCl pretreatment does not alter the concentration of l‐tryptophan in the brain. However after monoamine oxidase inhibition the 5‐hydroxytryptamine (5‐HT) accumulation was significantly greater in animals given lithium indicating an increase in 5‐HT synthesis of 70%. This was confirmed by measuring 5‐hydroxyindoleacetic acid accumulation after probenecid (200 mg/kg).

The hyperactivity produced by the 5‐HT analogue, 5‐methoxy N,N‐dimethyltryptamine was not potentiated by lithium pretreatment but one injection of LiCl (3 mEq/kg) which did not alter the rate of 5‐HT synthesis, did potentiate the hyperactivity following TCP (20 mg/kg) and l‐tryptophan (50 mg/kg).

These results suggest that lithium administration may cause an initial alteration of the 5‐HT available for release at the nerve ending, which is followed after subsequent treatment by an increase in the rate of 5‐HT synthesis. The possible clinical significance of these findings is discussed.
THE EFFECTS OF CERTAIN ANAESTHETIC AND ANTI‐CONVULSANT DRUGS ON THE CSF POTASSIUM FLUXES OF THE DOG
Authors: HALLIDAY J. , MOIR A.T.B.
Published: July 2012

A technique has been developed for open‐ended perfusion of the cerebroventricular system of the unanaesthetized dog.

Perfusion with an artificial CSF solution containing inulin and 42K allowed the potassium fluxes out of and into the CSF to be monitored over a period of 2 to 3 hours.

Sodium thiopentone and sodium pentobarbitone, in doses producing light anaesthesia, caused varying degrees of depression (up to 50%) in the CSF potassium fluxes, influx being consistently more affected than efflux. These effects are attributed to a decrease in the potassium exchange between extracellular and intracellular compartments in the brain.

Diazepam depressed both potassium fluxes by up to 10% while there was some evidence that diphenylhydantoin depressed only potassium influx.

Paraldehyde, in contrast to the other drugs, when given at a dose level sufficient to produce light anaesthesia, stimulated CSF potassium fluxes, particularly efflux.
THE EFFECTS OF ANTICHOLINESTERASES ON SYNAPTIC TRANSMISSION THROUGH NICOTINIC AND MUSCARINIC RECEPTORS IN RAT SYMPATHETIC GANGLIA in vivo
Authors: DREW G.M. , LEACH G.D.H.
Published: July 2012

Stimulation of the entire spinal sympathetic outflow at supramaximal voltage and 25–100 Hz, in the chlorisondamine‐treated, pithed, adrenalectomized rat produced a delayed pressor response (late pressor response; LPR).

The LPR was abolished by phenoxybenzamine, bretylium or a small dose of atropine (25–50 μg/kg), suggesting the involvement of ganglionic muscarinic receptors.

In the presence of atropine at a dose level (15 μg/kg) which did not influence the LPR, the anticholinesterases physostigmine, neostigmine and Ro 02–0683 but not BW 284C51 markedly enhanced and prolonged the LPR, whereas all of them reduced the pressor responses to AHR‐602.

After blockade of the ganglionic muscarinic receptors with a large dose of atropine (250 μg/kg) the four anticholinesterases did not influence responses to DMPP or noradrenaline and only slightly enhanced responses to preganglionic nerve stimulation at 6 Hz in the absence of chlorisondamine.

It is concluded that inhibition of butyrylcholinesterase accounts for the enhancement and prolongation of the LPR by anticholinesterases.
IMPLICATION OF GASTRIC MUCOSAL HISTAMINE IN INHIBITION BY ISOPRENALINE OF PENTAGASTRIN‐INDUCED GASTRIC SECRETION
Authors: LUNDELL L. , SVENSSON S.E.
Published: July 2012

The effect of isoprenaline on pentagastrin‐induced gastric secretion was studied in conscious rats with Heidenhain pouches. The influence of isoprenaline on pentagastrin‐induced release and formation of gastric mucosal histamine was also examined.

Isoprenaline strongly inhibited pentagastrin‐induced acid secretion, an inhibition which could not be overcome by increasing the dose of pentagastrin.

Propranolol blocked the inhibitory effect of isoprenaline on pentagastrin‐induced acid secretion.

Isoprenaline enhanced pepsin secretion induced by pentagastrin, an effect which was blocked by propranolol.

Isoprenaline reduced the increase in formation and release of gastric mucosal histamine following pentagastrin infusion, an inhibitory influence which was almost completely blocked by propranolol.

The inhibition by isoprenaline of pentagastrin‐induced acid secretion is tentatively related to alterations in gastric mucosal histamine occurring simultaneously.
ANTAGONISM OF THE EFFECT OF ISOPRENALINE ON HEART RATE BY PILOCARPINE
Authors: SADAVONGVIVAD C. , SATAYAVIVAD JUTAMAAD
Published: July 2012

The interaction of pilocarpine and isoprenaline on heart rate was investigated in the spontaneously beating, right isolated atrium of the rat.

The log dose‐effect curve of isoprenaline, measured in the presence of various concentrations of pilocarpine, was not modified when the concentration of the latter did not exceed 10−6 m even though significant slowing of the heart had occurred. At concentrations higher than 10−6 m a rapid but graded shift to the right of isoprenaline response curves occurred so that at pilocarpine 10−5 m the pD2 of isoprenaline was reduced from 11 to 3.3; cocaine slightly reduced this antagonism.

It is concluded that pilocarpine antagonizes isoprenaline by some mechanism which is not of the simple competitive type.
ANTAGONISM OF INHIBITORY AMINO ACID ACTION BY TUBOCURARINE
Authors: CURTIS D.R. , GAME C.J.A. , McCULLOCH R.M.
Published: July 2012

A comparison has been made of the antagonism by microelectrophoretically administered (+)‐tubocurarine, bicuculline methochloride and strychnine of the inhibition of spinal interneurones and Renshaw cells in the cat by glycine and γ‐aminobutyric acid. The results indicate that (+)‐tubocurarine would be of little use in assessing which of these amino acids was the transmitter at central inhibitory synapses.
ON THE MECHANISM OF ACTION OF CLONIDINE: EFFECTS ON SINGLE CENTRAL NEURONES
Authors: ANDERSON CAROLINE , STONE T.W.
Published: July 2012

Noradrenaline and clonidine were applied by microiontophoresis to single neurones in the cerebral cortex and medullary reticular formation of anaesthetized rats.

Of a total of 247 neurones studied, 79% of medullary units and 60% of cortical units responded in the same manner to both noradrenaline and clonidine. The usual response was a depression of neuronal firing rate.

It proved possible to antagonize some responses to both substances by the microiontophoresis of bulbocapnine, whilst leaving unaffected similar responses to 5‐hydroxytryptamine.

On 13% of the cells, clonidine produced an increase of firing rate. This effect could not be attributed to a post‐synaptic antagonism of tonically released endogenous noradrenaline, but may indicate a presynaptic action of clonidine, reducing noradrenaline release.

These observations are thought to support the idea that clonidine may have an agonist action on noradrenaline receptors in the brain.
PHYSICOCHEMICAL PROPERTIES AND BIOLOGICAL ACTIVITY: THERMODYNAMIC PROPERTIES OF COMPOUNDS RELATED TO ACETYLCHOLINE ASSESSED FROM DEPRESSION OF FREEZING‐POINT AND ENTHALPIES OF DILUTION
Authors: BARLOW R.B.
Published: July 2012

Measurements have been made of the osmotic coefficients and enthalpies of dilution of acetylcholine and of compounds related to it in which the carbonyl and ether groups have been replaced by methylene and the trimethylammonium group by triethylammonium. All were iodides. Measurements were also made with tetraethylammonium iodide and agree with published values.

Where necessary the affinities of the compounds for acetylcholine receptors in the guinea‐pig ileum and frog rectus, or their activities relative to acetylcholine, have been measured.

The osmotic coefficients were used to calculate activity coefficients and excess free energies, which have been used with the excess enthalpies to calculate the excess entropies of the solutions. These indicate that the ester and carbonyl groups have a marked ordering effect on the ions in water compared with methylene groups; the ether group has an intermediate effect.

When the results are interpreted in terms of ion‐pair formation they can be used to calculate the ion‐association constants and enthalpies and entropies of formation of ion‐pairs, and lead to similar conclusions: that the order associated with ion‐pair formation is greater with the esters and ketones. There appears to be extensive ion‐association in the concentrations (0.5 to 1 m) usually used in n.m.r. studies.

There is no obvious correlation between the effects of groups on water and their activity or affinity at muscarine‐sensitive acetylcholine receptors but it is possible that ability to activate nicotine‐sensitive receptors may be associated with an increase in order, though it would be necessary to study entropy changes in systems actually involving receptors in order to prove this. It is also necessary to suppose that ability to activate these receptors is limited to compounds with small onium groups.
A NEW APPROACH TO THE MEASUREMENT AND CLASSIFICATION OF FORMS OF SUPERSENSITIVITY OF AUTONOMIC EFFECTOR RESPONSES
Authors: KALSNER S.
Published: July 2012

It is proposed that sensitizations of autonomic effectors to agonists by drugs or procedures be considered in two main categories: those involving changes in the effective concentration of agonist at receptors (type I) and those involving changes in the responding tissue beyond the initial combination of agonist and receptors (type II). Type I sensitizations are appropriately described by determining the dose‐ratio (horizontal shift of the dose‐response curve) and type II sensitizations by assessing the change in the magnitude of the response.

The inadequacy of the dose‐ratio in assessing sensitizations related to an altered physiology of the responding tissue is illustrated by means of hypothetical examples with particular reference to the slopes of dose‐response curves and altered maximal responses.

An evaluation of the enhancement of responses of rabbit aortic strips to agonists by reserpine indicates that it is a type II sensitization. The shifts of dose‐response curves to noradrenaline, isoprenaline, normetanephrine and 5‐hydroxytryptamine after reserpine‐treatment, were described both by the dose‐ratio and by the increment in the magnitude of the response at various contraction amplitudes. The dose‐ratio varied unpredictably for each agonist depending on the response level selected for comparison and also varied between agonists. However, the mm increment in response magnitude after reserpine approximated a constant value. Responses to potassium which by horizontal procedures were assessed among the least increased, were found to be enhanced the most when considered as a type II sensitization.

It is concluded that both type I and type II procedures should be applied when dealing with an unidentified sensitization and that the data be critically assessed. The appropriate use of these procedures can aid in identifying and clarifying sensitizations, as well as in elucidating the sequence of steps between receptor activation and response in an effector.
SPECIFIC SUPERSENSITIVITY OF SMOOTH MUSCLE TO ANGIOTENSIN II AFTER NEPHRECTOMY
Authors: MEYER P. , PAPADIMITRIOU A. , WORCEL M.
Published: July 2012

The dose‐response curves for angiotensin, 5‐hydroxytryptamine and carbachol were obtained on rat uterus and colon excised 24 h after a bilateral nephrectomy or a sham operation.

There was a shift to the left in the dose‐response curves to angiotensin of organs from nephrectomized animals. Dose‐response curves to 5‐hydroxytryptamine and carbachol were not affected by nephrectomy.

The interaction of the two competitive antagonists (1‐Asn, 5‐Ileu, 8‐Ala)‐angiotensin II and (1‐Asn, 5‐Ileu, 8‐Ileu)‐angiotensin II with angiotensin II receptors was tested in control and nephrectomized organs. There was a decrease of the KI values in colon muscle after nephrectomy.

In conclusion, nephrectomy produces a specific supersensitivity to angiotensin that seems to be due to a change in the structure of angiotensin receptors, at least in colon smooth muscle. This increase in sensitivity may be the result of the elimination of a tropic factor that acts on angiotensin receptor sites.
SENSITIZATION OF NORADRENALINE RESPONSES BY INHIBITORS OF EXTRANEURONAL UPTAKE IN A CORONARY ARTERY PREPARATION
Authors: KALSNER S.
Published: July 2012

Inhibition of neuronal uptake with cocaine had no significant effect on the dose‐response curve to noradrenaline in strips of beef coronary artery. However, responses were enhanced about 3‐fold by 17β‐oestradiol and the haloalkylamine GD‐131, two known inhibitors of extraneuronal uptake.