bluuebunny/crossref_metadata_2025 huggingface dataset:
GLUTAMATE ANTAGONISTS IN RAT HIPPOCAMPUS
Authors: SEGAL M.
Published: July 2012

Hippocampal cellular responses to acidic amino acids and some of their antagonists were measured in the rat anaesthetized with urethane. The effects of these antagonists on the field responses of the rat hippocampus to afferent stimulation were measured in acute as well as chronically prepared rats.

Hippocampal pyramidal cells were excited by microiontophoretic application of glutamate and aspartate. These responses were antagonized by glutamic acid diethyl ester (GDEE), glutamic acid dimethyl ester (GDME) and by proline. Partial specificity could be seen as excitatory responses to acetylcholine were less susceptible to the antagonists.

Field responses of the hippocampus to commissural stimulation were reduced significantly in both an acutely prepared or the conscious rat following parenteral administration of GDEE and GDME but not proline. Responses to perforant path stimulation were not affected by these drugs.

It is suggested that an acidic amino acid may serve as a neurotransmitter in the commissural path to area CA1 of the dorsal hippocampus.
EFFECT OF INDOMETHACIN AND RELATED DRUGS ON THE CALCIUM ION‐DEPENDENT SECRETION OF LYSOSOMAL AND OTHER ENZYMES BY NEUTROPHIL POLYMORPHONUCLEAR LEUCOCYTES In vitro
Authors: NORTHOVER B.J.
Published: July 2012

1Rabbit isolated peritoneal neutrophil polymorphonuclear leucocytes were depleted of calcium by exposure for 1 h to calcium‐free bathing fluid at 4°C.

2Addition of calcium ions to the previously calcium‐depleted cells during incubation at 37°C stimulated the release of β‐glucuronidase and of lysozyme but not of lactate dehydrogenase.

3Low concentrations of indomethacin, flufenamate or salicylate, such as those which occur in the blood plasma after therapeutic doses of these drugs, selectively inhibited the calcium‐induced release of β‐glucuronidase. The slight release of this enzyme which occurred in the absence of added calcium ions was not altered by these drugs, neither was the release of lactate dehydrogenase.

4Release of lysozyme was inhibited by low concentrations of salicylate, amidopyrine or oxyphen‐butazone, independent of the presence or absence of calcium ions.

5Chloroquine, hydrocortisone or colchicine did not alter the release of leucocyte enzymes.
VASOCONSTRICTOR RESPONSE TO ARACHIDONIC ACID IN THE ISOLATED HIND LIMB OF THE DOG
Authors: FITZPATRICK T.M. , JOHNSON M. , KOT P.A. , RAMWELL P.W. , ROSE J.C.
Published: July 2012

1Arachidonic acid (AA) (25‐200 μg/kg) produced a dose‐related increase in perfusion pressure in dog isolated hind limbs perfused with either blood or a platelet‐free perfusate.

2Prostaglandin E2 produced vasodilatation while prostaglandin produced no vascular change at these administered doses.

3Phentolamine did not alter the arachidonic acid response, eliminating possible α‐adrenoceptor mediation.

4Aspirin and indomethacin blocked the vasoconstrictor response to AA.

5This study indicates that a vasoactive intermediate in prostaglandin synthesis can be elaborated in the absence of platelets.
DOPAMINE‐INDUCED NEUROGENIC VASODILATATION IN THE INTACT HINDLEG OF THE DOG
Authors: BOGAERT M.G. , DE SCHAEPDRYVER A.F. , WILLEMS J.L.
Published: July 2012

1The dopamine‐induced neurogenic vasodilatation, previously described in the isolated perfused hindleg of the dog, has been studied in anaesthetized dogs with intact circulation in the hindleg. Dopamine was administered intravenously and/or intra‐aortically, either as a bolus injection of 4 or 16 μg/kg, or as a continuous infusion of 4, 8, 16 or 32 μg kg−1 min−1.

2Dopamine, given as a bolus injection or by infusion, reversibly inhibited synaptic transmission in the paravertebral lumbar ganglia, studied with preganglionic stimulation at 1 Hz. The inhibitory effect decreased gradually when the frequency of stimulation was increased to 16 Hz. The inhibition by dopamine was also present when spontaneous postganglionic activity was recorded. These effects were more pronounced on intra‐aortic than on intravenous administration of dopamine.

3In about half of the animals studied, injection or infusion of dopamine elicited a decrease of vascular resistance in the innervated femoral artery, whereas systemic blood pressure either did not change or decreased. In the denervated femoral artery, an increase in vascular resistance was always observed.

4The decrease in femoral vascular resistance was considered to correspond with neurogenic vasodilatation caused by paravertebral ganglionic inhibition since (i) it only occurred in the innervated hindleg, (ii) blood pressure did not rise, (iii) this decrease was insensitive to atropine or propranolol and (iv) it was blocked by small doses of haloperidol. When hypovolemic shock was produced, the incidence of the neurogenic decrease of vascular resistance was smaller.

5Dopamine also increased renal blood flow. This increase was not reduced by the occurrence of the neurogenic vasodilatation in the innervated femoral artery.

6These results are consistent with the idea that the dopamine‐induced neurogenic vasodilatation, originally described in the isolated perfused hindleg of the dog, also occurs when the circulation to the hindleg is intact. This suggests that, in the dog, the inhibitory effect of dopamine on sympathetic ganglia modulates its peripheral vasoconstrictor effects. In hypovolemic shock, where sympathetic nervous activity is high, the inhibitory effect of dopamine on sympathetic ganglia disappears and its direct vasoconstrictor effect on the vessels dominates.
THE MODE OF ACTION AT THE MOUSE NEUROMUSCULAR JUNCTION OF THE PHOSPHOLIPASE A‐CROTAPOTIN COMPLEX ISOLATED FROM VENOM OF THE SOUTH AMERICAN RATTLESNAKE
Authors: HAWGOOD BARBARA J. , SMITH J.W.
Published: July 2012

Phospholipase A2‐crotapotin complex (P‐C complex) isolated from the venom of Crotalus durissus terrificus induced an irreversible blockade of neuromuscular transmission when twitch tension was measured in the mouse phrenic nerve‐hemidiaphragm preparation in vitro at 37°C.

A similar concentration of the phospholipase A2 (10 μg/ml) alone did not affect neuromuscular transmission and no priming action was detected on later addition of crotapotin.

The rate of neuromuscular blockade induced by P‐C complex (15 μg/ml) was not altered by raising the frequency of nerve stimulation. Lower temperatures markedly increased the time of onset and reduced the rate of blockade (Q10 (27‐37°C) of 4.4) whilst replacement of Ca by Sr in the medium prevented this activity. These latter results suggest that enzymatic activity is important in the neurotoxicity of the complex.

A myotoxic action was shown by 30 μg/ml P‐C complex and 30 μg/ml phospholipase A2.

P‐C complex (150 μg) was injected into the tail vein of mice and the intoxicated hemidiaphragm preparation removed for intracellular recording at 25°C.

In fully intoxicated hemidiaphragms, resting membrane potentials were unaltered and endplate potentials (e.p.ps) varied in average amplitude from zero to less than 3 mV.

Miniature endplate potential (m.e.p.p.) frequency was lower at fully poisoned endplates than at controls; the frequency rose during a 50 Hz tetanus but was unaffected by either raising external K or the application of the Ca‐ionophore A23187.

E.p.ps were recorded in partially intoxicated hemidiaphragms with (+)‐tubocurarine (0.5‐1.0 μg/ml) added to prevent contraction. Evoked release was abnormal as 50 Hz tetanus elicited e.p.ps of very variable amplitude, no facilitation of response was shown to paired stimuli, and tetraethylammonium (0.5 mM) failed to increase e.p.p. amplitudes.

M.e.p.ps and e.p.ps were recorded at partially poisoned endplates in low Ca‐high Mg solution. A reduction in the quantal content of evoked transmitter release was observed in comparison with controls.

M.e.p.ps recorded at partially and at fully intoxicated endplates showed an altered amplitude distribution with a higher proportion of large potentials.

It is concluded that P‐C complex has a presynaptic site of action and may interfere with depolarization ‐ secretion coupling at the motor nerve terminals.
PATHWAYS OF PROSTAGLANDIN F2α METABOLISM IN MAMMALIAN KIDNEYS
Authors: HOULT J.R.S. , MOORE P.K.
Published: July 2012

High‐speed cytoplasmic supernatants of rat, rabbit, pig and guinea‐pig kidneys were prepared and the metabolism of 10 μg/ml prostaglandin F2α labelled with [3H1‐9β]‐prostaglandin F2α studied by thin layer radiochromatography and bioassay.

The metabolism of prostaglandin F2α measured by radiochromatography parallels biological inactivation in all species except the rabbit.

Kidneys metabolize prostaglandin F2α by two divergent pathways, yielding a mixture of prostaglandin E and F metabolites.

15‐Hydroxyprostaglandin dehydrogenase and prostaglandin Δ‐13 reductase are present in all species in characteristic proportions. Thus prostaglandin F2α is metabolized sequentially to 15‐keto prostaglandin F2α and 13,14‐dihydro‐15‐keto prostaglandin F2α. The rate and profile of formation of these metabolites is species‐dependent.

13,14‐Dihydro‐15‐keto prostaglandin F2α is the principal prostaglandin F series metabolite in all species.

Pig and guinea‐pig kidney contain an unidentified enzyme which converts 13,14‐dihydro‐15‐keto prostaglandin F2α to 13,14‐dihydro prostaglandin F2α.

Rat kidney contains a high concentration of a prostaglandin 9‐hydroxy dehydrogenase which converts 13,14‐dihydro‐15‐keto prostaglandin F2α to 13,14‐dihydro‐15‐keto prostaglandin E2.

Rabbit kidney contains a novel 9‐hydroxydehydrogenase which oxidises prostaglandin F2α directly to E2, thus producing a compound with more potent renal actions. The possible implications of this enzyme for kidney homeostasis are discussed.
THE DISTRIBUTION OF METHIONINE‐ENKEPHALIN AND LEUCINE‐ENKEPHALIN IN THE BRAIN AND PERIPHERAL TISSUES
Authors: HUGHES J. , KOSTERLITZ H.W. , SMITH T.W.
Published: July 2012

A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by adsorption of the extract onto Amberlite XAD‐2 resin. Elution with methanol separates the enkephalins and α‐endorphin from β‐endorphin.

Over 90% of the opioid peptide activity isolated from brain and gut of several species by our method was due to methionine‐ and leucine‐enkephalin. In contrast, the major opioid peptide activity recovered from the pituitary was due to peptides of much greater mol. wt. than the enkephalins.

An opioid peptide with properties unlike those of the known endorphins or enkephalins was present in brain extracts. This peptide, termed ∍‐endorphin, has an apparent mol. wt. of 700 to 1200; it constituted between 5 to 10% of the total opioid activity in our extracts.

A differential assay of methionine‐ and leucine‐enkephalin was made either by destroying methionine‐enkephalin activity with cyanogen bromide or by separating the peptides by thin layer chromatography.

The ratio of methionine‐enkephalin to leucine‐enkephalin varied greatly in different brain regions. The highest proportions of leucine‐enkephalin were found in the cerebral cortex and hippocampus.

Formaldehyde perfusion and fixation of the brain in vivo had no significant effect on the brain content of enkephalin, indicating that proteolytic breakdown is not a major problem in the extraction of these peptides.

It is suggested that the enkephalins may have a neurotransmitter role in both brain and peripheral tissues and that methionine‐ and leucine‐enkephalin may subserve separate neuronal functions.
THE SPECIFICITY OF OESTROGEN RECEPTOR IN BRAIN, PITUITARY AND UTERUS
Authors: GINSBURG M. , MACLUSKY N.J. , MORRIS I.D. , THOMAS P.J.
Published: July 2012

The specificity of oestrogen receptor in rat brain regions (hypothalamus, amygdala and cortex), pituitary and uterus was studied by measurement of the inhibition of 17β‐oestradiol high affinity binding in cytosol, in the presence of unlabelled putative inhibitors of binding.

Binding was inhibited only by those of the compounds tested that possessed oestrogen agonist or antagonist activity. The affinities were estimated and the ranking order of the compounds was the same in all tissue sources of cytosol and corresponded to the ranking order of agonist or antagonist potency.

There were some significant differences between some of the estimated affinities in different tissues, these being seen most commonly between pituitary and hypothalamus on one hand and uterus on the other.

The possibility of heterogeneity of oestrogen receptor is discussed.
THE EFFECT OF UPTAKE BY ADRENERGIC NERVE TERMINALS ON THE SENSITIVITY OF ARTERIAL VESSELS TO TOPICALLY APPLIED NORADRENALINE
Authors: MARSHALL JANICE M.
Published: July 2012

Direct observations were made of the rat mesenteric vasculature in vivo. They showed a gradual increase in the sensitivity to topically applied noradrenaline from the larger arteries to the precapillary arterioles which was paralleled by a gradual decrease in the density of the adrenergic innervation.

Both cocaine and chronic denervation increased the sensitivity to noradrenaline of the innervated arterial vessels, approximately in proportion to the density to their innervation. They did not affect the sensitivity of the non‐innervated precapillary arterioles.

It is concluded that the sensitivity gradient to topically applied noradrenaline results mainly from the uptake of the applied catecholamine by the perivascular nerve terminals.
ASSESSMENT OF THE SELECTIVITY OF OPC‐2009, A NEW β2‐ADRENOCEPTOR STIMULANT, BY THE USE OF THE BLOOD‐PERFUSED TRACHEA in situ AND OF THE ISOLATED BLOOD‐PERFUSED PAPILLARY MUSCLE OF THE DOG
Authors: HIMORI N. , TAIRA N.
Published: July 2012

The potency and selectivity of 5‐(1‐hydroxy‐2‐isopropylamino)butyl‐8‐hydroxy carbostyril hydrochloride hemihydrate (OPC‐2009), a new β2‐adrenoceptor stimulant, was compared with those of isoprenaline, trimetoquinol and salbutamol by the use of blood‐perfused tracheal preparations in situand of blood‐perfused papillary muscle preparations of the dog. All drugs were injected intra‐arterially.

All the four drugs decreased tracheal intraluminal pressure (tracheal relaxation) and increased tracheal blood flow in a dose‐dependent manner. The four drugs produced a dose‐dependent increase in developed tension of papillary muscles. In both preparations the duration of action of isoprenaline and salbutamol was short, whereas that of OPC‐2009 and trimetoquinol was long. These effects were antagonized by propranolol.

Dose‐response curves to the four drugs for tracheal relaxation were almost parallel. OPC‐2009 was 2.4 times more potent, and trimetoquinol and salbutamol were 2.2 and 6.2 times less potent than isoprenaline in causing tracheal relaxation.

Dose‐response curves to the four drugs for tracheal vasodilatation were also parallel. OPC‐2009, trimetoquinol and salbutamol were 3.9, 6.7 and 23 times less potent than isoprenaline.

Slopes of the dose‐response curves to the four drugs for increased developed tension were not parallel; that of OPC‐2009 was the least steep, whereas that of isoprenaline was the steepest. Trimetoquinol, salbutamol and OPC‐2009 were about 18, 570 and 2400 times less potent than isoprenaline.

Selectivity calculated from relative potencies indicate that OPC‐2009 was about 6000 times, salbutamol about 92 times and trimetoquinol about 8.2 times more selective than isoprenaline for tracheal smooth muscle as compared to ventricular muscle.

The high potency and selectivity of OPC‐2009 for tracheal smooth muscle and its long duration of action suggest its potential usefulness for treatment of bronchial asthma.

The present results are also compatible with the concept that β1‐adrenoceptors in cardiac muscle and β2‐adrenoceptors in tracheal and vascular smooth muscle can be distinguished. Furthermore, the results revealed that the β‐adrenoceptors mediating tracheal relaxation and vasodilatation may also be different.
THE INFLUENCE OF PROSTAGLANDINS ON NORADRENALINE‐INDUCED VASOCONSTRICTION IN ISOLATED PERFUSED MESENTERIC BLOOD VESSELS OF THE RAT
Authors: COUPAR I.M. , MCLENNAN P.L.
Published: July 2012

The report of the depression by indomethacin of vasoconstrictor responses to noradrenaline and their partial restoration by prostaglandin E2 (PGE2) and PGE1 in rat isolated perfused mesenteric blood vessels was investigated. The further suggestion that prostaglandins may be necessary for the combination of noradrenaline with the α‐adrenoceptor in this tissue was also studied.

The reported depression by indomethacin was confirmed and was further shown to be in the form of a concentration‐dependent flattening of the noradrenaline concentration‐effect curve.

A concentration‐dependent restorative effect was observed for all prostaglandins studied. The decreasing order of potency for the restoration towards normal of the indomethacin‐depressed responses to noradrenaline was: PGE2, PGE1, PGA1, PGF2α, PGA2.

The prostaglandins studied were not uniform in their restorative actions and could be separated into two groups. PGE2 and PGE1 restored responses towards the control level whereas PGA1, PGA2 and PGF2α increased responses to an above control level and did so over a smaller concentration range. The possibility of several prostaglandin receptors is discussed.

At concentrations equi‐effective in restoring depressed responses to control levels PGA1 but not PGE2, caused a parallel shift of the noradrenaline concentration‐effect curve to the left and a small, gradual rise in the basal perfusion pressure.

The reason for the differing effects remains obscure but does not seem to involve a change in the α‐adrenoceptor as indicated by the pA2 of phentolamine. Furthermore, the restorative and potentiating effect of PGA1 is not mediated by blockade of neuronal uptake of noradrenaline.

It appears that prostaglandins are required for the vasoconstrictor action of noradrenaline in rat mesenteric blood vessels and that this effect is distal to the drug‐receptor interaction. The possible involvement of prostaglandins with intracellular calcium ions is discussed.
α‐ADRENOCEPTORS IN THE MOUSE VAS DEFERENS AND THEIR EFFECTS ON ITS RESPONSE TO ELECTRICAL STIMULATION
Authors: MARSHALL I. , NASMYTH P.A. , NICHOLL CLAIRE G. , SHEPPERSON N.B.
Published: July 2012

Noradrenaline (ID50, 0.75 μM) and clonidine (ID50, 2.8 nM) produced a dose‐related inhibition of the twitch response of the isolated vas deferens of the mouse to electrical stimulation, their effectiveness decreasing as frequency of stimulation increased from 0.2 to 16 hertz.

Phenylephrine (1.0‐3.0 μM) produced a dose‐related contraction of the mouse isolated vas deferens and potentiated the responses to field stimulation.

Yohimbine (10 nM) antagonized the inhibitory effects of noradrenaline and clonidine, but had no effect on the motor activity of phenylephrine. At a concentration of 128 nM yohimbine potentiated the twitch response by 110% at 1 Hz, but its effectiveness decreased with increasing frequency of stimulation up to 16 hertz.

Thymoxamine (0.3 μM) antagonized the effects of phenylephrine, but not those of clonidine.

From a consideration of the known characteristics of pre‐ and postsynaptic α‐adrenoceptors, it is concluded that the inhibitory effect of noradrenaline is produced by stimulation of the former and the effects of phenylephrine by stimulation of the latter.
EVIDENCE FOR THE PARTICIPATION OF β1‐ADRENOCEPTORS IN ISOPRENALINE‐INDUCED RENIN RELEASE FROM RAT KIDNEY SLICES in vitro
Authors: DESAULLES E. , MIESCH F. , SCHWARTZ J.
Published: July 2012

The inhibitory effects were studied of 4 β‐adrenoceptor antagonists against renin release induced by isoprenaline (0.5 m̈mol/1) in rat kidney slices. Additionally the pA2 values of these 4 drugs were measured against isoprenaline in guinea‐pig isolated atria and trachea (against β1‐ and β2‐adrenoceptors respectively).

When employed at a concentration of 2 nmol/1 propranolol and atenolol significantly inhibited renin release (P < 0.001 and P < 0.01) whereas practolol and IPS 339 [t‐butyl‐amino‐3 ol‐2 propyl) oximino‐9 fluorene] had little effect.

A positive correlation was shown between the degree of inhibition of renin release and the pA2 of the antagonists at the β1‐adrenoceptors.

When practolol and IPS 339 were used in equipotent molar concentrations to propranolol for the β1‐adrenoceptors they inhibited renin release.

The results suggest that the adrenoceptor involved in the renin release induced by isoprenaline in the rat kidney is of the β1‐type.
EFFECTS OF DRUGS ON THE ACCUMULATION AND SPONTANEOUS RELEASE OF NORADRENALINE IN THE RAT ANOCOCCYGEUS MUSCLE
Authors: DOGGRELL S.A. , WOODRUFF G.N.
Published: July 2012

The ability of drugs to inhibit noradrenaline accumulation and to release noradrenaline was studied in the isolated anococcygeus muscle of the rat.

Noradrenaline, tyramine, 2‐amino, 6,7‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene (ADTN), 2‐amino, 6,7‐dimethoxy‐1,2,3,4‐tetrahydronaphthalene (dimethyl ADTN), and 5‐hydroxytryptamine were all potent inhibitors of noradrenaline accumulation and potent releasers of noradrenaline. ADTN was accumulated by the rat isolated anococcygeus muscle.

Amphetamine and desipramine were potent inhibitors of noradrenaline accumulation but poor releasers of noradrenaline.

Methoxamine, oxymetazoline, acetylcholine, and angiotensin were poor inhibitors of noradrenaline accumulation and did not release noradrenaline.

The mechanism of action of these drugs is discussed.
PROSTACYCLIN (PGI2) INHIBITS THE FORMATION OF PLATELET THROMBI IN ARTERIOLES AND VENULES OF THE HAMSTER CHEEK POUCH
Authors: HIGGS E.A. , HIGGS G.A. , MONCADA S. , VANE J.R.
Published: July 2012

Isolated rings of hamster aorta produced an unstable substance which inhibited platelet aggregation in vitro and had the same characteristics as prostacyclin.

Prostacyclin inhibited adenosine diphosphate (ADP)‐induced aggregation of hamster platelets in vitro.

The effects of prostacyclin on ADP‐induced platelet thrombi in the microcirculation of the hamster cheek pouch were studied with a television microscope.

Prostacyclin caused a dose‐dependent increase in the time of iontophoretic application of ADP which was required to induce platelet thrombi formation and embolization in venules (30 to 40 um diameter).

Prostacyclin caused a dose‐dependent reduction in the total time during which ADP‐induced thrombi were observed following local electrical damage to arterioles (40 to 80 um diameter).

Thrombus formation in venules and arterioles was abolished by 500 ng/ml prostacyclin in the Krebs solution superfusing the hamster cheek pouch.

Prostacyclin was approximately twenty times more potent than prostaglandin Ei in preventing thrombus formation in the microcirculation.
EFFECTS OF NICOTINE ON CARDIAC PROSTAGLANDIN AND PLATELET THROMBOXANE SYNTHESIS
Authors: WENNMALM AKE
Published: July 2012

Rabbit hearts were perfused with a solution containing [14C]‐arachidonic acid (AA) and various concentrations of nicotine (3 × 10−8 to 3 × 10−5m). The venous effluent was collected and extracted for lipid acid material, which was subsequently subjected to thin layer radiochromatography.

Human platelets were incubated with nicotine (10−8 to 10−4m), in the absence or presence of unlabelled AA. The amount of smooth muscle stimulating activity resulting from 30 s of incubation was tested on a rabbit aortic strip.

In hearts perfused with [14C]‐AA; nicotine induced a dose‐related depression of the release of [14C]‐6‐keto‐prostaglandin F1a, and a parallel increase in the release of [14C]‐prostaglandin E2.

Nicotine neither induced synthesis of thromboxane in human platelets, nor affected the platelet synthesis of thromboxane induced by AA.

It is suggested that nicotine affects the metabolism of prostaglandin endoperoxides in the heart by inhibiting their conversion to prostacyclin and facilitating, directly or indirectly, the formation of prostaglandin E2.
MODULATION OF SYMPATHETIC TRANSMISSION BY NEURONALLY‐RELEASED DOPAMINE
Authors: HOPE W. , MAJEWSKI H. , McCULLOCH M.W. , RAND M.J. , STORY D.F.
Published: July 2012

When rabbits were pretreated with Fla‐63, there was a marked inhibition of dopamine‐β‐hydroxylase such that, after incubation of the ear arteries with [3H]‐dopamine, 47.2% of the tritium in the tissue was retained as unchanged dopamine.

[3H]‐dopamine was released by stimulation of the sympathetic nerves in ear arteries taken from rabbits pretreated with Fla‐63 and incubated with [3H]‐dopamine.

The dopamine antagonists metoclopramide (1.0 μm) and ergometrine (1.0 μm) enhanced the stimulation‐induced efflux of tritium in ear arteries taken from rabbits pretreated with Fla‐63 and incubated with [3H]‐dopamine, but not when the arteries were incubated with [3H]‐noradrenaline.

These results suggest that if dopamine is present in the transmitter stores, it can be released by stimulation of the sympathetic nerves, and if the amount is adequate, it can activate an inhibitory feedback loop where prejunctional dopamine receptors are present.
THEOPHYLLINE ANTAGONIZES SOME EFFECTS OF PURINES IN THE INTESTINE BUT NOT THOSE OF INTRAMURAL INHIBITORY NERVE STIMULATION
Authors: SMALL R.C. , WESTON A.H.
Published: July 2012

Hyoscine‐ and guanethidine‐treated preparations of longitudinal muscle of rabbit duodenum, guinea‐pig taenia caeci and fundic strip relaxed when exposed to noradrenaline, adenosine, adenosine triphosphate (ATP) or to field stimulation of their intramural nerves.

In guinea‐pig taenia caeci and fundus, theophylline 100 μmol/l had no effect on responses to noradrenaline, adenosine, ATP and intramural nerve stimulation.

In rabbit duodenum, theophylline 100 μmol/l antagonized some responses to adenosine but had no effect on responses to noradrenaline, ATP and intramural nerve stimulation.

Theophylline 1 mmol/l itself relaxed the intestinal tissues and in the fundic strip and taenia caeci, these relaxant effects were associated with abolition of spike activity and cellular hyperpolarization. In the taenia caeci, the amplitude of inhibitory post‐junctional potentials was reduced.

Theophylline 1 mmol/l antagonized the twitch suppression produced by adenosine and ATP in the transmurally‐stimulated guinea‐pig ileum but not that evoked by noradrenaline.

It is concluded that theophylline can selectively antagonize some actions of purines in the intestine but that it does not specifically antagonize the effects of intramural inhibitory nerve stimulation.
HYDROXY ANALOGUES OF OXYTOCIN AND OF LYSINE‐VASOPRESSIN
Authors: BISSET G.W. , CHOWDREY H.S. , HOPE D.B. , NILWISES N. , WÄLTI M.
Published: July 2012

Synthetic analogues of oxytocin and of lysine‐vasopressin with an hydroxyl group in either the l or d configuration replacing the primary amino group have been tested for biological activity.

[1‐l(‐2‐Hydroxy‐3‐mercaptopropanoic acid)] oxytocin ([l‐Hmp1]oxytocin) was 1.5 to 2 times more potent than oxytocin on the rat uterus in situ, the rat mammary strip and the rat mammary gland in situ and 3 times more potent on the rat isolated uterus.

The pressor activity of [1‐(l‐2‐hydroxy‐3‐mercaptopropanoic acid)‐8‐lysine]vasopressin ([l‐Hmp1, Lys8] vasopressin) was 2.2 and the antidiuretic activity 2.1 times that of lysine‐vasopressin.

The [d‐Hmp1] analogues of oxytocin and vasopressin were much less potent than the [l‐Hmp1] analogues.

The responses to oxytocin and its hydroxy analogues in vivo were qualitatively indistinguishable but the pressor and antidiuretic responses to the hydroxy analogues of lysine‐vasopressin were prolonged compared with those to the parent hormone.

The hydroxy analogues of oxytocin and lysine‐vasopressin were not inactivated by pregnancy plasma oxytocinase.

The results are discussed in relation to the importance of the primary amino group for the biological activity and metabolism of the neurohypophysial hormones.
THE EFFECTS OF DEPRIVATION OF PROSTAGLANDIN PRECURSORS ON VASCULAR SENSITIVITY TO ANGIOTENSIN II AND ON THE KIDNEY IN THE PREGNANT RABBIT
Authors: O'BRIEN P.M. SHAUGHN , PIPKIN FIONA BROUGHTON
Published: July 2012

Pregnant rabbits were deprived of essential fatty acids from day ten of pregnancy, and results compared with a control group on a normal diet.

At term, cannulation of jugular and carotid vessels was performed under anaesthesia, to study the vascular sensitivity to angiotensin II and basal blood pressure.

Plasma renin levels, urinary electrolytes and protein were measured.

Placental and renal tissue was examined histologically.

Though no changes were found in tissues, blood or urine, a markedly significant increase in response to angiotensin II was found in the group deprived of essential fatty acids. This parallels the findings in vascular response in human pre‐eclampsia.
EFFECTS OF MODULATORS OF ARACHIDONIC ACID METABOLISM ON THE SYNTHESIS AND RELEASE OF SLOW‐REACTING SUBSTANCE OF ANAPHYLAXIS
Authors: BURKA J.F. , FLOWER R.J.
Published: July 2012

Slow‐reacting substance of anaphylaxis (SRS‐A) was released in the peritoneum of passively sensitized rats challenged with ovalbumin and from rat isolated peritoneal cells stimulated with calcium ionophore A23187.

Both monocytes (macrophages) and mast cells appear to be involved in the synthesis and release of SRS‐A.

The immunological release of SRS‐A in vivo is enhanced by indomethacin and inhibited by dexamethasone, mepacrine, 1‐phenyl‐3‐pyrazolidone (1‐P‐3‐P), and methylimidazole.

SRS‐A release induced by A23187 in vitro is inhibited by dexamethasone, indomethacin, 1‐P‐3‐P, eicosatetraynoic acid (ETA) and 15‐hydroperoxy arachidonic acid. The inhibition induced by dexamethasone, indomethacin and 1‐P‐3‐P is reduced by an increase in the calcium concentration from 1 mm to 5 mm, whereas the inhibition induced by ETA is increased.

The results suggest that a lipoxygenase is important in the synthesis and release by SRS‐A.
LOCALIZATION OF SENSITIVE SITES TO TAURINE, γ‐AMINOBUTYRIC ACID, GLYCINE AND β‐ALANINE IN THE MOLECULAR LAYER OF GUINEA‐PIG CEREBELLAR SLICES
Authors: OKAMOTO KOICHI , SAKAI YUTAKA
Published: July 2012

The localization, in the molecular layer of guinea‐pig cerebellar slices, of the sites most sensitive to iontophoretically applied taurine, γ‐aminobutyric acid (GABA), glycine and β‐alanine was investigated.

The most sensitive sites were located (expressed as the distance from the Purkinje cell body to the pial surface): 0 μm, 60 μm and 220 μm for taurine; 0 μm and 180 μm for GABA; 80 μm and 200 μm for glycine, and 80 μm, 180 μm and 300 μm for β‐alanine.

The sensitive site (at 0 μm) to GABA was considered to represent the basket synapses on the Purkinje cell soma, while the sites (60 to 80 μm and 200 to 300 μm) for taurine, glycine and β‐alanine were tentatively assigned to the synapses of the stellate neurones on the Purkinje cell dendrites.

Inhibitory actions of all four amino acids tested at the most sensitive sites were antagonized by both picrotoxin and strychnine.

The possibility that taurine might be the neurotransmitter of the stellate neurones in guinea‐pig cerebellum is discussed.
AN in vitro STUDY OF VARIOUS DRUGS ON CENTRAL AND PERIPHERAL AIRWAYS OF THE RAT: A COMPARISON WITH HUMAN AIRWAYS
Authors: LULICH K.M. , PATERSON J.W.
Published: July 2012

The effect of histamine and other drugs on the central and peripheral airways of the rat was studied by applying them directly to isolated tracheal and lung strip preparations. These effects were then compared with those observed on human isolated bronchial muscle preparations.

Acetylcholine and 5‐hydroxytryptamine (5‐HT) both contracted the lung strip and trachea of the rat, and both were more potent on the trachea than the lung strip.

Histamine and prostaglandins E2 (PGE2) or F2γ (PGF2γ) produced no effect on either the lung strip or trachea of the rat.

On the human isolated bronchial preparation, in contrast to the rat airways, both histamine and PGF2γ produced marked concentration‐dependent contractions and 5‐HT either produced no response or a slight relaxation.

In view of these results, the use of anaphylactic bronchoconstriction in the rat as a model for the study of asthma in man is questioned.
INHIBITION OF VASOPRESSIN RELEASE TO CAROTID OCCLUSION BY γ‐AMINOBUTYRIC ACID AND GLYCINE
Authors: FELDBERG W. , SILVA M. ROCHA E
Published: July 2012

In cats anaesthetized with pentobarbitone sodium or chloralose, the amino acids, γ‐aminobutyric acid (GABA) and glycine, were applied to the ventral surface of the brain stem through paired Perspex rings placed across the medulla.

Applied to a region situated at the transition between medulla and cord, both amino acids greatly attenuated and even abolished the vasopressin release in response to carotid occlusion. Glycine was about 100 times more potent than GABA and effective in a concentration of 0.1 mg/ml. The pressor response to carotid occlusion was not affected.

Applied to a region situated 5 to 6 mm more rostrally, the amino acids did not affect vasopressin release but in strong concentrations, greatly attenuated the pressor response to carotid occlusion.

The two responses to carotid occlusion, vasopressin release and the pressor response, can thus be influenced independently.

It is concluded that the pathways carrying afferent impulses from the baroreceptors in the carotid sinus reach the ventral surface of the brain stem at two regions. At both, synaptic transmission can be blocked by the application of an inhibitory amino acid and thus prevent either the release of vasopressin at the caudal site, or the increase of vasomotor tone at the rostral site.
ANTAGONISM OF VASODEPRESSOR AND GASTRIC SECRETORY RESPONSES TO HISTAMINE BY THE H2‐RECEPTOR ANTAGONISTS, RANITIDINE AND CIMETIDINE, IN THE ANAESTHETIZED DOG
Authors: DALY M.J. , HUMPHRAY JANET M. , STABLES R.
Published: July 2012

The new H2‐receptor antagonist, ranitidine, has been compared with cimetidine as an inhibitor of gastric acid secretion in the anaesthetized dog.

Both ranitidine and cimetidine given intravenously inhibited histamine‐induced gastric secretion in a dose‐related manner. Ranitidine was 4.2 times more potent than cimetidine when given as an intravenous infusion and 9.6 times more potent as an intravenous bolus dose.

In a separate series of experiments, ranitidine was compared with cimetidine as an antagonist of vasodepressor responses to histamine. Mepyramine alone displaced the histamine dose‐response curve to the right. After a maximally effective dose of mepyramine, further displacement could be achieved with ranitidine and cimetidine, ranitidine being 19.2 times more potent than cimetidine.

Ranitidine alone had no effect on vasodepressor response curves to histamine, acetylcholine or (−)‐isoprenaline or on vasopressor response curves to phenylephrine.

These results indicate that displacement of the histamine dose‐response curve after mepyramine blockade by ranitidine and cimetidine is due to selective H2‐receptor antagonism.
FURTHER EVIDENCE FOR THE INVOLVEMENT OF Na+CHANNELS IN THE RELEASE OF ADRENAL CATECHOLAMINE: THE EFFECT OF SCORPION VENOM AND GRAYANOTOXIN I
Authors: ITO S. , NAKAZATO Y. , OHGA A.
Published: July 2012

The effects of venom from the scorpion, Leiurus quinquestriatus, and grayanotoxin I on catecholamine secretion were studied in the perfused adrenal glands of guinea‐pig.

Scorpion venom (0.1 to 10 μg/ml) caused a dose‐dependent increase in catecholamine output. The response to the venom was partially inhibited by atropine (0.5 mm) plus hexamethonium (1 mm). The dose‐response curve was shifted to the right in the presence of these blocking agents.

Grayanotoxin I (0.1 to 0.5 mm) caused a dose‐dependent increase in catecholamine output which was significantly reduced by atropine (0.5 mm) plus hexamethonium (1 mm). However, when grayanotoxin I (0.1 mm) was applied together with scorpion venom (0.1 μg/ml, a concentration which alone, was almost ineffective) the maximum catecholamine output was reached even in the presence of atropine plus hexamethonium.

Tetrodotoxin (0.1 or 0.2 μm) reversibly inhibited the secretory responses induced by scorpion venom (10 μg/ml) and grayanotoxin I (0.1 mm) plus scorpion venom (0.1 μg/ml).

Scorpion venom and grayanotoxin I plus scorpion venom did not cause catecholamine secretion in the absence of extracellular Na+or Ca2+ions. However, the secretory response was restored by reintroduction of Na+or Ca2+ions.

It is suggested that both scorpion venom and grayanotoxin I activate Na+channels on the chromaffin cell and result in catecholamine secretion.
EFFECTS OF NERVE STIMULATION AND OF ADMINISTRATION OF NORADRENALINE OR POTASSIUM CHLORIDE UPON THE RELEASE OF PROSTAGLANDINS I2, E2 AND F2α FROM THE PERFUSED MESENTERIC ARTERIAL BED OF THE RABBIT
Authors: PIPILI EVA , POYSER N.L.
Published: July 2012

The release of prostaglandin I2 (PGI2), PGE2 and PGF2α from the perfused mesenteric arterial bed of the rabbit was examined at rest, following nerve stimulation and following noradrenaline (NA) or potassium chloride (KCl) administration.

Stimulation of adrenergic nerves at 10 Hz caused a significant increase in the release of both PGI2, (assayed in terms of 6‐oxo‐PGF1α) and PGE2 but a significant decrease in the release of PGF2α.

Exogenous Na (2 μg) increased the output of PGI2 and PGE2 but left the output of PGF2α unaffected.

KCl (15 mg) significantly increased the output of PGF2α but left the output of PGI2 unaffected.

It is concluded that PGI2 and PGE2 output from the mesenteric arterial bed of the rabbit increases following stimulation of adrenoceptors. The sympathetic nervous system may therefore modulate PGI2/platelet interaction.

Prostaglandins released from the blood vessels by sympathetic nerve stimulation may also modulate adrenergic transmission to the blood vessels.
ASPIRIN INHIBITS THE EARLY MYOCARDIAL RELEASE OF THROMBOXANE B2 AND VENTRICULAR ECTOPIC ACTIVITY FOLLOWING ACUTE CORONARY ARTERY OCCLUSION IN DOGS
Authors: COKER SUSAN J. , LEDINGHAM I. McA. , PARRATT J.R. , ZEITLIN I.J.
Published: July 2012

Acute coronary artery occlusion in anaesthetized open‐chest greyhounds led to early release of thromboxane B2 (TxB2) into venous blood draining the ischaemic region. No release occurred from the remainder of the left ventricular wall (coronary sinus sampling). TxB2 release and ventricular ectopic activity were positively correlated (r = 0.863) 2 min post‐occlusion. Aspirin (3 mg/kg i.v.) suppressed both local TxB2 release and ectopic activity and prevented ventricular fibrillation. It is suggested that TxB2 release is a factor contributing to early post‐infarction arrhythmias.
ALTERATION OF SMOOTH MUSCLE CONTRACTILITY AFTER MUSCARINIC AGONIST‐INDUCED K+ LOSS
Authors: JAMES‐KRACKE MARILYN R. , ROUFOGALIS BASIL D.
Published: July 2012

After stimulation of the longitudinal smooth muscle of the guinea‐pig ileum by an optimal dose (2times10−7 m) of a muscarinic agent, cis‐2‐methyl‐4‐dimethylaminomethyl‐1,3‐dioxolane methiodide (CD), the muscles failed to regain their normal spontaneous activity for 20 to 30 min. During the recovery period, subsequent contractions induced by either CD or 60 mm KCl were altered, particularly when only short times (15 min or less) were allowed between exposures.

Altered responses to CD had depressed phasic but increased tonic tensions and were characteristic of responses induced by lower doses of CD. The altered responsiveness probably represented an early phase of muscle ‘desensitization’.

In contrast to muscarinic stimulation, the smooth muscles gave identical responses after repeated stimulation by 60 mm KCl, even when only 2 min were allowed between exposures.

Whereas K+ levels increased in muscles exposed to 60 mm KCl, they decreased during contractions to CD. The K+ levels remained low until the muscles recoverd their normal responsiveness.

Increasing the extracellular K+ concentration (5 to 13 mm) hastened the recovery of the muscle responsiveness after CD, whereas lowering external K+ concentration to 1.35 mm or the addition of ouabain (5times10−7 m) delayed the recovery. The results suggested that the Na+,K+‐pump is rate‐limiting in the recovery of the normal ionic balance of the muscles after stimulation by muscarinic agonists.
THE EFFECT OF FENFLURAMINE ON THE MICROSTRUCTURE OF FEEDING AND DRINKING IN THE RAT
Authors: BURTON M.J. , COOPER S.J. , POPPLEWELL D.A.
Published: July 2012

The effects of three doses of fenfluramine on feeding and drinking in the rat were examined.

Feeding and drinking were subdivided into meals and bouts, and the changes in feeding/drinking were expressed in terms of meal/bout frequency, meal/bout size, meal/bout length, and eating/drinking rate.

The changes in these parameters were examined over different time periods after the injection.

Significant changes in the distribution of inter‐response intervals within meals were found in time period 1 with 5 mg/kg and 10 mg/kg doses of fenfluramine. Videotape and computer analysis showed that the changes in inter‐response interval histograms differed significantly from those seen in normal animals approaching satiety. Drinking parameters also changed.

Compensatory increases in feeding were observed in time period 4 with the 10 mg/kg dose.

The difficulties in designing and interpreting experiments in feeding are discussed, and the action of fenfluramine as an anorectic drug is considered.
MECHANICAL AND ELECTROPHYSIOLOGICAL EFFECTS OF SEA ANEMONE (Anemonia sulcata) TOXINS ON RAT INNERVATED AND DENERVATED SKELETAL MUSCLE
Authors: ALSEN C. , HARRIS J.B. , TESSERAUX I.
Published: July 2012

Some effects of the sea‐anemone toxin ATX‐II on mammalian nerve‐muscle preparations have been described

When ATX‐II (10−8‐10−6 m) was applied to rat hemidiaphragm preparations, both directly and indirectly generated twitch responses were potentiated and prolonged. At the same time the resting tension of the preparations increased

The increase in resting tension caused by ATX‐II in innervated muscles was not prevented by curarization, but was reversed by exposure to tetrodotoxin. The increase in denervated muscles was not completely reversed by tetrodotoxin

At concentrations exceeding 1 × 10−7 M, ATX‐II caused a sodium‐dependent depolarization of both normal and denervated muscles. The depolarization of the denervated muscles was only partially reversed by tetrodotoxin

In the presence of ATX‐II repetitive endplate potentials (e.p.ps) were evoked by single shocks to the motor nerves in many fibres, and in those in which a single e.p.p. was still observed, the quantum content (m) was increased. Miniature e.p.p. frequency was not increased by ATX‐II, even when muscle fibres were depolarized by 30 mV

The indirectly and directly elicited action potentials of normal and denervated muscle fibres were much prolonged by ATX‐II. The action potentials remained sodium‐dependent. The sodium‐dependent tetrodotoxin‐resistant action potential of the denervated muscle fibre was also prolonged by ATX‐II. 7 It is concluded that ATX‐II both activates, and delays inactivation of, sodium channels in mammalian skeletal muscle fibres, probably by interacting with the channel ‘gate’.
THE ACQUISITION OF RESPONDING WITH CONDITIONED REINFORCEMENT: EFFECTS OF COCAINE, (+)‐AMPHETAMINE AND PIPRADROL
Authors: BENINGER RICHARD J. , HANSON DALE R. , PHILLIPS ANTHONY G.
Published: July 2012

A procedure for examining the acquisition of a lever‐pressing operant with conditioned reinforcement was used to compare the effects of three psychomotor stimulants

Hungry rats were trained to associate an auditory tone (i.e., conditioned reinforcer) with food. Preference for the tone was then measured after treatment with pipradol (5, 10, 15 mg/kg), cocaine (1, 5, 10mg/kg)or(+)‐amphetamine(0.5, 1.5, 5.0 mg/kg)

In agreement with previous data, 10 mg/kg of pipradrol enhanced the effect of conditioned reinforcement whereas animals treated with any of the doses of (+)‐amphetamine showed no effect

Rats treated with cocaine (1 or 5 mg/kg) showed an effect of conditioned reinforcement but the effect was not significantly greater than in controls

The present data suggest important differences in enhancement of responding for conditioned reinforcement by various drugs in the psychomotor stimulant class. These differences in turn may be related to the pharmacological actions of these compounds on release of catecholamines from different storage pools.
In vivo AND in vitro EFFECTS OF ENDOTOXIN ON PROSTAGLANDIN RELEASE FROM RAT LUNG
Authors: FEUERSTEIN NILI , RAMWELL PETER W.
Published: July 2012

The release of prostaglandins (PGE2, PGF2α, PGI2) and thromboxane A2 (T×A2) from rat lung exposed to E. coli endotoxin, in vivo ox in vitro has been studied.

Lung strips of endotoxin‐treated rats demonstrated a preferential increase of T×A2 and PGF2α and a decrease in the ratio PGI2/T×A2.

These data suggest that changes in the proportions of arachidonic acid metabolites might play a role in the pulmonary pathophysiology during endotoxin shock.

Incubation of lung strips with endotoxin in vitro failed to stimulate prostaglandin release; paradoxically, it suppressed both the spontaneous and the ionophore‐induced prostaglandin release.

These findings suggest that the increase in prostaglandin release by the lung following endotoxin administration in vivo is probably mediated by factor(s) generated in endotoxaemia and is not due to a direct action of endotoxin on the lung tissue.
INVOLVEMENT OF THE ADRENAL GLANDS IN THE HYPOTENSIVE RESPONSE TO BROMOCRIPTINE IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: HAMILTON T.C.
Published: July 2012

The dopamine agonist, bromocriptine, produced a hypotensive response following oral administration to conscious normotensive and spontaneously hypertensive (SH‐) rats.

In SH‐rats the dose‐related falls in blood pressure to bromocriptine, 3 to 30 mg/kg orally or intraperitoneally, were biphasic, an initial fall at 1 h being followed by some recovery at 2 h and a subsequent fall in blood pressure at 4 and 6 h.

The dopamine antagonists, metoclopramide, sulpiride, haloperidol and pimozide, had little or no effect on the hypotensive response to bromocriptine, 10 mg/kg orally, in SH‐rats.

Pretreatment with α‐methyl‐p‐tyrosine augmented the hypotensive response to bromocriptine, 10 mg/kg orally, in SH‐rats.

In adrenal demedullated SH‐rats, the hypotensive response to bromocriptine, 3 to 30 mg/kg orally, was abolished.

In SH‐rats the hypotensive response to bromocriptine, 10 mg/kg orally, was prevented by the β‐adrenoceptor blocking drugs, propranolol and oxprenolol, but was unaffected by (+)‐propranolol and by the cardio‐selective β‐adrenoceptor blocking drug, atenolol.

In SH‐rats pretreated with bromocriptine, 10 mg/kg orally, and then anaesthetized, the pressor responses to low doses of intravenous adrenaline were reversed to depressor, indicating that bromocriptine possesses α‐adrenoceptor blocking activity.

The results suggest that the hypotensive response to bromocriptine in conscious SH‐rats is mediated by adrenaline released from the adrenal medullae which, in the presence of α‐adrenoceptor blockade, stimulates vascular β‐adrenoceptors producing vasodilatation.
COMPARISON OF THE ACTIONS OF U‐46619, A PROSTAGLANDIN H2‐ANALOGUE, WITH THOSE OF PROSTAGLANDIN H2 AND THROMBOXANE A2 ON SOME ISOLATED SMOOTH MUSCLE PREPARATIONS
Authors: COLEMAN R.A. , HUMPHREY P.P.A. , KENNEDY I. , LEVY G.P. , LUMLEY P.
Published: July 2012

The actions of the prostaglandin H2 (PGH2) analogue, U‐46619, have been compared with those of PGH2 and thromboxane A2 (TxA2) on a range of isolated smooth muscle preparations in a superfusion cascade system.

U‐46619 was a potent agonist on guinea‐pig lung strip, dog saphenous vein and rat and rabbit aortae. In contrast, U‐46619 was weak or inactive on guinea‐pig ileum and fundic strip, cat trachea and dog and cat iris sphincter muscles, preparations on which either PGE2 or PGF2α was the most potent agonist studied.

PGH2 was active on all of the preparations and displayed little selectivity. On some of the preparations, the actions of PGH2 may have been mediated indirectly by conversion to other prostanoids.

In contrast, TxA2 displayed the same pattern of selectivity as U‐46619, being a potent agonist on the lung strip and vascular preparations but weak or inactive on the others.

It is suggested that U‐46619 is a selective TxA2‐mimetic and that it should therefore be a valuable tool in the study of the actions of TxA2