bluuebunny/crossref_metadata_2025 huggingface dataset:
LOCAL KALLIKREIN AND TRYPSIN RESPONSES IN THE RAT
Authors: BENNETT A.J. , WEST G.B.
Published: July 2012

Locally administered commercial hog pancreatic kallikrein (Depot‐Glumorin) and bovine pancreatic tyrpsin both increased vascular permeability in the skin and paws of rats.

By the use of numerous antagonists and enzyme inhibitors, this vascular response was found to be the result not of kinin formation but of a direct action mostly on histamine receptors.

Highly purified kallikrein did not increase vascular permeability in rats, suggesting either that the effect was due to an impurity in the commercial preparation or that a structural change in the enzyme occurred on purification.

Soya bean trypsin inhibitor prevented the trypsin response when both were injected locally. On intraperitoneal injection, the inhibitor was effective only against local kallikrein.

The kallikrein inhibitor, aprotinin (Trasylol), was not effective against local kallikrein but it reduced the trypsin response when both were injected locally.
STRUCTURE‐ACTIVITY RELATIONSHIPS OF CLONIDINE‐ AND TOLAZOLINE‐LIKE COMPOUNDS AT HISTAMINE AND α‐ADRENOCEPTOR SITES
Authors: MALTA E. , ONG JENNY S.B. , RAPER C. , TAWA PAULINE E. , VAUGHAN G.N.
Published: July 2012

Thirty clonidine‐ and tolazoline‐like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H1‐receptors (guinea‐pig ileum), histamine H2‐receptors (guinea‐pig driven right ventricular strips), post‐junctional α‐adrenoceptors (rat desheathed vas deferens) and pre‐junctional α‐adrenoceptors (inhibition of sympathetic stimulation in guinea‐pig driven left atria).

All compounds were inactive at histamine H1‐receptors, while 21 of the 30 compounds displayed varying stimulant activity at H2‐receptors.

At post‐junctional α‐receptors all 30 compounds produced stimulant actions, whereas at prejunctional α‐receptors the compounds displayed either agonistic or antagonistic actions.

Thus structure‐activity relationships (SAR) could only be validated for histamine H2‐ and post‐junctional α‐receptor effects. These studies show that the most potent compounds are those with 2,6‐phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H2‐ than at α‐receptors.

The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H2‐receptors, while α‐receptor stimulant activity is retained.
PRESYNAPTIC REGULATION OF THE RELEASE OF ACETYLCHOLINE BY 5‐HYDROXYTRYPTAMINE
Authors: HIRAI K. , KOKETSU K.
Published: July 2012

The effect of 5‐hydroxytryptamine (5‐HT) on the release of acetylcholine (ACh) from bullfrog sympathetic preganglionic nerve terminals and frog sciatic nerve terminals was studied with intracellular microelectrodes.

The change in transmitter release was measured from the mean quantal content calculated by the variance method from evoked fast e.p.s.ps or e.p.ps in low Ca2+‐high Mg2+ Ringer solution.

5‐HT facilitated the release of ACh in low concentrations and depressed it in relatively high concentrations at both preganglionic and motor nerve terminals.

These results suggest the possibility that 5‐HT may play a role in regulating cholinergic transmission in general.
A COMPARISON OF THE SKELETAL NEUROMUSCULAR AND AUTONOMIC GANGLION‐BLOCKING POTENCIES OF FIVE NONDEPOLARIZING RELAXANTS
Authors: BIRMINGHAM A.T. , HUSSAIN S.Z.
Published: July 2012

Results from in vitro experiments on the phrenic nerve—diaphragm and the hypogastric nerve—vas deferens preparations of the guinea‐pig have been used to plot log concentration‐effect curves for skeletal neuromuscular and ganglion blockade, respectively, for (+)‐tubocurarine, pancuronium, alcuronium, gallamine and fazadinium (AH 8165).

From the log concentration‐effect curves, EC50s and equipotent ratios were calculated. The order of neuromuscular blocking potency was pancuronium = alcuronium > (+)‐tubocurarine > fazadinium = gallamine. The ratio EC50 for ganglion blockade/EC50 for neuromuscular blockade was 2.3 for fazadinium, 6.7 for (+)‐tubocurarine, 22.9 for alcuronium, 24.3 for gallamine and 200.0 for pancuronium.

For pancuronium and gallamine there was a range of concentrations below those producing ganglion blockade at which the response of the vas deferens to hypogastric nerve stimulation was augmented.

The results are compared with some of those available in the literature, measured on other species by other methods.
PURINE RECEPTORS IN THE TRACHEA: IS THERE A RECEPTOR FOR ATP?
Authors: CHRISTIE J. , SATCHELL D.G.
Published: July 2012

In guinea‐pig trachea adenosine 5′‐triphosphate (ATP), adenosine 5′‐diphosphate (ADP), adenosine 5′‐phosphate (AMP), adenosine and adenine were similarly potent in causing relaxation of the smooth muscle. This is in contrast to gut where ATP and ADP are 30 times more potent than adenosine. Studies with dipyridamole suggest that in trachea, as in gut, nucleotides are rapidly metabolized to adenosine. A polyphosphate modified analogue of ATP, the α,β‐methylene isostere, which resists degradation to adenosine was inactive in trachea although it is a potent relaxant in gut. This result may suggest that the intact ATP molecule is also inactive in the tracheal preparation: i.e. ATP acts only via its adenosine metabolite implying that receptors for adenosine but not ATP are present in the tissue.
INTERACTIONS BETWEEN MORPHINE AND THE OPIOID‐LIKE PEPTIDES IN THE RAT VAS DEFERENS
Authors: HUIDOBRO F. , HUIDOBRO‐TORO J. PABLO , MIRANDA H.
Published: July 2012

Morphine, methadone, levorphanol, pethidine, etonitazene and related morphine‐like alkaloids produced an increase in the electrically‐evoked muscular contraction of the rat vas deferens. In contrast, the enkephalins and β‐endorphin caused inhibition of the twitching.

The concentration of β‐endorphin required to inhibit by 50% the muscular twitch was about 50 to 100 times less than that of the enkephalins.

Pretreatment of the vasa with morphine antagonized the inhibition of the neuromuscular transmission caused by either β‐endorphin or enkephalin.

Conversely, pretreatment with β‐endorphin sensitized the vasa to the increase in twitch tension caused by morphine.

Morphine did not alter the sensitivity to exogenously administered noradrenaline, dopamine or potassium.
EXOCYTOTIC RELEASE OF CATECHOLAMINE FROM PERFUSED ADRENAL GLAND OF GUINEA‐PIG INDUCED BY VERATRIDINE
Authors: ITO S. , NAKAZATO Y. , OHGA A.
Published: July 2012

Experiments were carried out on perfused adrenal glands of guinea‐pig to determine whether veratridine caused the exocytotic release of catecholamine by comparing its effect with that of splanchnic nerve stimulation and secretagogues such as acetylcholine and excess K+.

Veratridine (100 μm) and excess K+ (56 mm) caused secretion of catecholamine and dopamine‐β‐hydroxylase (DBH) activity in the venous effluents in the presence of atropine (30 μm) and hexamethonium (2 mm). Splanchnic nerve stimulation in the presence or absence of physostigmine (100 nm) and infusion of acetylcholine in the presence of physostigmine had the same effect. In all the responses, the release of DBH tended to last for a longer period than that of catecholamine.

The ratio of catecholamine to DBH activity appearing in the venous effluents was approximately 9, regardless of the method of stimulation. This value was close to the ratio of catecholamines to the ‘soluble’ DBH activity found in the chromaffin granules.

All the types of stimulation used caused a proportional release of adenine nucleotides and catecholamines in the effluents. The adenine nucleotides were mainly adenosine 5′‐phosphate.

The ratio of catecholamine to adenine nucleotides was approximately 11, regardless of the method of stimulation.

It is suggested that the release of catecholamine induced by veratridine occurs by exocytosis in adrenal glands of guinea‐pig.
ELECTRICALLY‐EVOKED RELEASE OF [3H]‐HISTAMINE FROM THE GUINEA‐PIG HYPOTHALAMUS
Authors: BIGGS MARILYN J. , JOHNSON E.S.
Published: July 2012

[3H]‐histamine was taken up by slices of guinea‐pig hypothalamus against a concentration gradient.

Electrical field stimulation of the superfused slices resulted in an increased efflux of radioactivity, the major part of which was shown to be associated with histamine by paper chromatography.

The evoked release of histamine was dependent on calcium ions in the superfusate and was increased by 56% when the frequency of stimulation was doubled from 5 to 10 Hz.
EFFECTS OF ADRENALECTOMY AND HYPOPHYSECTOMY ON ENKEPHALIN CONTENT OF THE RAT HYPOTHALAMUS
Authors: GIBSON A. , GINSBURG M. , HART S.L. , KITCHEN I.
Published: July 2012

Hypothalamic content of enkephalin in rats has been measured by bioassay against methionine‐enkephalin on field‐stimulated mouse vas deferens after acid extraction and purification using Amberlite XAD‐2 resin.

Surgical stress lowered hypothalamic enkephalin content initially but 6 days after operation the content was higher in sham‐operated than in adrenalectomized animals.

Corticosteroid replacement therapy showed that hypothalamic enkephalin content was not related directly to circulating corticosteroid levels and that it was increased by the stress of handling and injection.

Hypothalamic enkephalin content of rats that had undergone hypophysectomy 11 days earlier did not differ from that of intact animals but surgical stress, which lowered content in intact rats and had no effect after adrenalectomy, produced a rise in content in these hypophysectomized animals.

The ingestion of 0.9% saline, in place of water, by sham‐adrenalectomized rats altered the effect of surgical stress on hypothalamic enkephalin content without affecting the resting levels.

Of extracts from adrenalectomized rats, 10% contained a substance that behaved atypically on the mouse vas deferens, showing a slower onset and offset of action. The mol. wt. of the substance and sensitivity to naloxone reversal appeared to be similar to enkephalin, but it was resistant to carboxypeptidase‐A and protease treatment.

It is concluded that the enkephalin content of the hypothalamus is affected by activity in the hypothalamus‐pituitary‐adrenal system but that it is not related in a simple manner to the levels of corticotrophin releasing hormone, corticotrophin or corticosteroids.
A COMPARISON OF THE BRONCHOCONSTRICTOR AND β‐ADRENOCEPTOR BLOCKING ACTIVITY OF PROPRANOLOL AND ACEBUTOLOL
Authors: MACLAGAN JENNIFER , NEY URSULA M.
Published: July 2012

The bronchoconstrictor and β‐adrenoceptor blocking activity of (±)‐propranolol, acebutolol and two of its analogues were compared in a group of littermate rats. Whilst the analogues of acebutolol had similar bronchoconstrictor potency to propranolol, acebutolol had considerably less activity. No correlation could be found between the degree of bronchoconstriction produced by the four drugs and their β‐adrenoceptor blocking activity in the airway smooth muscle. Acebutolol and its analogues show a wide variation in lipid solubility and membrane stabilizing actions but neither of these properties could be related to the production of bronchospasm.
FAILURE OF ANTI‐INFLAMMATORY STEROIDS TO INHIBIT PROSTAGLANDIN PRODUCTION BY RAT POLYMORPHONUCLEAR LEUCOCYTES
Authors: DRAY F. , McCALL ELAINE , YOULTEN L.J.F.
Published: July 2012

Like rabbit polymorphonuclear (PMN) leucocytes, rat peritoneal glycogen‐induced PMN leucocytes produced much greater amounts of prostaglandin when incubated with killed bacteria than in the absence of phagocytosable material.

Rat PMN leucocytes produced mainly prostaglandin E2 (PGE2), in amounts up to 17 ng/106 cells in 90 min incubation, some 25 times the amount produced by resting cells.

Indomethacin and meclofenamic acid inhibited prostaglandin production by resting and phagocytosing cells, the IC50 being of the order of 10−6 to 10−7 M for both drugs.

Hydrocortisone and dexamethasone at concentrations up to 10−4 M did not cause significant dose‐related inhibition of prostaglandin production in this system.

It is suggested that the phagocytosing PMN leucocyte is insensitive to the action of anti‐inflammatory steroids with respect to prostaglandin production.
THE FACTORS INFLUENCING THE TIME COURSE OF DRUG ACTION AT α‐ADRENOCEPTORS: AN INVESTIGATION OF THE EFFECTS OF CLONIDINE IN THE PITHED RAT
Authors: DOCHERTY J.R. , McGRATH J.C.
Published: July 2012

The time courses of the pre‐ and post‐junctional effects of clonidine were examined on heart rate and blood pressure and on the isometric tension responses of the vas deferens and anococcygeus in situ in the pithed rat. Plasma levels of clonidine were also monitored.

The time courses of the pre‐junctional inhibition of sympathetic nerve mediated responses in all tissues monitored were related to the plasma levels of clonidine, but the degree of inhibition which was observed varied with the tissue and with the test stimulus employed.

The post‐junctional agonist effects of clonidine, especially at low doses, exhibited an initial ‘peak’ followed by a decline to a lower plateau. This decline of the response was not due to receptor desensitization but was related to a decline in the plasma clonidine level from an initially high value caused by injection of a bolus.

The factors determining the time course of drugs' effects in the preparation are discussed and it is concluded that pre‐ and post‐junctional responses should be compared at a point in time after injection of the drug, at which equilibration has occurred.
ADENINE NUCLEOTIDES AND SYNAPTIC TRANSMISSION IN THE in vitro RAT HIPPOCAMPUS
Authors: DUNWIDDIE T.V. , HOFFER B.J.
Published: July 2012

The effects of adenosine and various derivatives were examined in the in vitro hippocampal slice preparation from rat.

The amplitudes of extracellularly recorded field potentials from the CA1 region were depressed by adenosine, and this effect could be antagonized by methylxanthines. Because presynaptic field potentials were unaffected by adenosine, while the field e.p.s.p. was depressed, adenosine would appear to act at a synaptic site to depress transmission.

Adenosine deaminase, which breaks down adenosine to inosine, increased the amplitude of synaptic responses, while hexobendine, which blocks reuptake of adenosine, had a depressant effect. This strongly suggests that the endogenous release of adenosine from the hippocampal slice preparation is sufficient to exert a tonic inhibitory influence on the amplitude of synaptic responses.

Cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) and its dibutyryl derivative had depressant effects on the amplitude of field responses which were blocked by theophylline, suggesting that they are able to act at the extracellular adenosine receptor. (−)‐Isoprenaline (which raises tissue cyclic AMP levels), and the 8‐p‐chlorophenylthio derivative of cyclic AMP both increased the amplitude of population spike responses, and these effects were not blocked by theophylline, suggesting that the physiological effects of adenosine are not mediated via a cyclic AMP‐dependent mechanism.

Since adenosine is not the transmitter at this CA1 pyramidal cell synapse, but is apparently present in the extracellular compartment in sufficient concentrations to affect the synaptic physiology of this region, this provides strong evidence in favour of the concept of a neuromodulatory role for adenosine in the central nervous system.
DESENSITIZATION OF THE ACETYLCHOLINE RECEPTOR OF DENERVATED RAT SOLEUS MUSCLE AND THE EFFECT OF CALCIUM
Authors: ANWYL ROGER , NARAHASHI TOSHIO
Published: July 2012

Desensitization of the extrajunctional acetylcholine receptors of denervated rat soleus muscle has been studied by evoking iontophoretic acetylcholine potentials at a high frequency (10 Hz).

Desensitization occurred with a slow and at least one fast component.

Increasing the dose of acetylcholine decreased the half time of onset of desensitization, but did not alter recovery half time.

Alteration of external calcium between 0 and 50 mm, or perfusion with agents which increase intracellular calcium such as 2,4‐dinitrophenol and the calcium ionophores, X537A and A23187, did not alter desensitization half time.

The cholinoceptor agonists acetylcholine, acetylthiocholine, tetramethylammonium and phenyltrimethylammonium all caused desensitization at the same rate.
α‐FLUPENTHIXOL: AN ANTAGONIST OF DOPAMINE‐EVOKED FLUID SECRETION BY AN INSECT SALIVARY GLAND PREPARATION
Authors: BREWARD J. , HOUSE C.R. , SMITH R.K.
Published: July 2012

We have demonstrated inhibition of secretory responses of cockroach salivary glands to dopamine, adrenaline, noradrenaline and neurotransmitter by α‐flupenthixol. This inhibition was slow in onset (60 min) and in reversal (> 2 h).

Inhibition of responses to adrenaline and noradrenaline was non‐competitive, since the maxima and slopes of dose‐response curves of these agonists were reduced.

Although at low concentrations (< 3 μm) the antagonism of responses to dopamine showed some characteristics of competitive inhibition, at higher doses non‐competitive inhibition was clearly demonstrated.

These results are explained in terms of different efficacies of the agonists for the receptors antagonized by α‐flupenthixol.

β‐Flupenthixol was shown to antagonize responses to dopamine; however it was 10 to 100 times less potent than α‐flupenthixol.
ANTAGONIST DISCRIMINATION BETWEEN GANGLIONIC AND ILEAL MUSCARINIC RECEPTORS
Authors: BROWN D.A. , FORWARD A. , MARSH S.
Published: July 2012

The effects of four antagonists on the depolarization of isolated superior cervical ganglia and the contraction of isolated ileal segments of the rat were compared. pA2 values estimated from Schild plots indicated significantly higher affinities of stercuronium (x 100) and pirenzepine (x 23) and a significantly lower affinity of 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (x 0.39) for the ganglion than for the ileum. The affinities of N‐methylscopolamine for the two tissues were not significantly different. It is concluded that the two types of muscarinic receptor are not identical.
THE PHARMACOLOGY OF ISAMOXOLE [2‐METHYL‐N‐BUTYL‐N(4‐METHYLOXAZOL‐2‐YL) PROPANAMIDE] LRCL 3950, A NEW ANTI‐ALLERGIC COMPOUND
Authors: DAWSON W. , SWEATMAN W.J.F.
Published: July 2012

Isamoxole [2‐methyl‐N‐butyl‐N(4‐methyloxazol‐2‐yl) propanamide] is an effective orally active anti‐allergic compound in animals.

Isamoxole inhibits the immunological release of mediators, notably slow‐reacting substance of anaphylaxis (SRS‐A) from sensitized human and guinea‐pig chopped lung in vitro.

In vivo, allergic responses were inhibited in guinea‐pigs and rats by doses as low as 25 mg/kg given orally 180 and 30 min before challenge. The effect of Isamoxole was still present 4 h after a single dose of 100 mg/kg orally in the guinea‐pig and 3 h in the rat.

Isamoxole is a moderately potent, selective inhibitor of SRS‐A activity on the guinea‐pig ileum in vitro, at concentrations that do not antagonize histamine, 5‐hydroxytryptamine, or bradykinin.

Isamoxole causes human bronchial muscle to relax and antagonizes the bronchoconstriction induced by SRS‐A.
THE EFFECTS OF TIME AND INDOMETHACIN ON CONTRACTILE RESPONSES OF THE GUINEA‐PIG GALL BLADDER in vitro
Authors: DOGGRELL SHEILA A. , SCOTT GERALD W.
Published: July 2012

The effects of time and of indomethacin on contractile responses of the guinea‐pig gall bladder were studied in vitro.

The tissues contracted to field stimulation at 5 Hz (in the absence and presence of atropine 10−6 m), (‐)‐noradrenaline (10−5 m), acetylcholine (10−5 m), and adenosine 5′‐triphosphate (ATP, 10−4 m); the magnitude of the contractile responses increased with time.

(‐)‐Isoprenaline 10−5 m either relaxed (17 of 23 preparations tested) or had no effect on gall bladder strips.

The responses of strips of guinea‐pig gall bladder to field stimulation at 5 Hz (in the absence or presence of atropine 10−6 m), (‐)‐noradrenaline (10−5 m), and acetylcholine (10−5 m) obtained 4 h 45 min after setting up the tissue were reduced following incubation with indomethacin (7.9 times 10−6 m for 1 h). The responses to (‐)‐isoprenaline (10−5 m) and to ATP (10−4 m) were abolished by incubation with indomethacin.

These results suggest that, in the guinea‐pig gall bladder in vitro, the magnitude of the contractile responses to field stimulation at 5 Hz, (‐)‐noradrenaline (10−5 m), and acetylcholine (10−5 m) and the ability of the tissue to respond to (‐)‐isoprenaline (10−5 m) and ATP (10−4 m), may be dependent on the synthesis of a prostaglandin‐like substance.
CLONIDINE DISTRIBUTION IN THE RAT: TEMPORAL RELATIONSHIP BETWEEN TISSUE LEVELS AND BLOOD PRESSURE RESPONSE
Authors: CONWAY E.L. , JARROTT B.
Published: July 2012

The time course of the distribution of clonidine (20 μg/kg, i.v.) was determined in the rat by use of a sensitive and specific radioimmunoassay, and was compared with the hypotensive response following this dose.

Levels of clonidine were determined in tissues at 2 min, corresponding to the beginning of the hypotensive phase of the drug, and then at 10, 30 and 120 min during recovery of blood pressure to the pre‐dose level. The peak tissue concentrations of clonidine were found at 2 min, after which they declined in a mono‐exponential manner. The half‐lives of clonidine in the various tissues were similar to the half‐life of the recovery of blood pressure.

Regional variations in clonidine distribution in the brain were not very great; however, the half‐life was longer in the corpus striatum and shorter in the cerebellum than in other brain regions.

Clonidine concentrations were highest in the kidney and similarly distributed between the cortex and medulla. Concentrations of the drug in other tissues approximated those in brain.

Although clonidine is thought to act primarily through the central nervous system, this distribution study shows that at the peak of the hypotensive response less than 2% of the injected dose is present in brain and at least equal concentrations of the drug are found in most peripheral tissues. Thus the possibility of peripheral mechanisms contributing to the hypotensive effect cannot be dismissed.
ACTIONS OF NITROGLYCERINE ON SMOOTH MUSCLES OF THE GUINEA‐PIG AND RAT PORTAL VEINS
Authors: KARASHIMA TSUYOSHI
Published: July 2012

Effects of nitroglycerine (NG) on the electrical and mechanical activities of smooth muscle cells of the rat and guinea‐pig portal veins were studied by a microelectrode technique and an isometric tension recording method.

The membrane potentials of smooth muscle cells in the rat and guinea‐pig were −44.4 mV and −47.6 mV, respectively. In both species the smooth muscle cells generated spikes as burst discharges.

In the guinea‐pig portal vein, NG (2.8 times 10−8 m) produced biphasic potential changes, an initial transient hyperpolarization followed by depolarization. The hyperpolarization suppressed and depolarization enhanced spike activities.

From the changes in the membrane potential produced by NG in various concentrations of [K]o, [Na]o or [Ca]o, it is postulated that the hyperpolarization is due to an increase in the K‐permeability and the depolarization is due to an increase in the Na‐permeability of the membrane.

NG (2.8 times 10−5 m) had no effect on the membrane activity of the rat portal vein.

NG consistently suppressed mechanical activities generated in both tissues. The minimum concentration required to suppress the mechanical activity was lower in the guinea‐pig than in the rat portal vein.

NG suppressed the contraction due to noradrenaline more than that evoked by excess [K]o in both species.

From these experiments, it is concluded that NG relaxes the muscular bed of portal veins of both species. In the rat portal vein, suppression of mechanical activity had no causal relation to the membrane activity. In contrast, in the guinea‐pig portal vein, suppression of mechanical activity was slightly modified by changes in the membrane activity, i.e. hyperpolarization additively contributes to the relaxation and depolarization slightly suppresses the relaxation.
EFFECT OF VARIATION IN ENDOGENOUS LEVELS OF ASCORBIC ACID ON THE in vitro IMMUNOLOGICAL RELEASE OF HISTAMINE AND SLOW REACTING SUBSTANCE OF ANAPHYLAXIS FROM ACTIVELY SENSITIZED GUINEA‐PIG LUNG FRAGMENTS
Authors: HITCHCOCK MARGARET
Published: July 2012

The in vitro immunological release of histamine and slow reacting substance of anaphylaxis (SRS‐A) from actively sensitized guinea‐pig lung fragments was greatly reduced when the animals were maintained on an ascorbic acid‐deficient diet. Excessive dietary levels of ascorbic acid did not increase mediator release above normal levels.

Restoration of ascorbic acid in the diet of scorbutic guinea‐pigs restored in vitro immunological histamine to normal levels.

Variation in dietary levels of ascorbic acid had no effect on lung histamine content.

The lung ascorbic acid content was proportional to the dietary intake. Approximately 60% of the total lung ascorbic acid was removed by the process of chopping and washing of the tissue. This relationship was independent of dietary intake.

The results indicate that the immunological release of mediators of inflammation from guinea‐pig lung is dependent on adequate endogenous levels of ascorbic acid.
FACTORS AFFECTING PROSTACYCLIN FORMATION BY THE RAT PREGNANT MYOMETRIUM
Authors: EL TAHIR K.E.H. , WILLIAMS K.I.
Published: July 2012

The scraped myometrium of the pregnant uterus of the rat, when chopped and incubated, released an antiaggregatory material closely resembling prostacyclin (PGI2). The material was conclusively identified as PGI2 by identification of its hydrolysis product 6‐oxo‐prostaglandin F1α (6‐oxo‐PGF1α) by gas chromatography‐mass spectrometry (GC‐MS).

Peak concentrations of PGI2 were detected after 15 min incubation at 20°C. These concentrations were significantly higher than those detected at 37°C, when largest amounts of prostacyclin were formed after 3 min incubation. The concentrations of 6‐oxo‐PGF1α detected were similar at the different temperatures.

When samples were incubated at pH 8 and 20°C, peak concentrations of prostacyclin were maintained between 15 and 35 min of incubation. When pH 7.4 was employed, prostacyclin concentration in the incubate fell to undetectable limits within this time.

Incubation of the chopped myometrium with arachidonic acid or phospholipase A2 stimulated prostacyclin production.

Preincubation of myometrial tissue for 10 min at 37°C with inhibitory drugs before chopping reduced prostacyclin output. The doses needed to reduce PGI2 output by 50% (ID50) were: mepacrine (280 μg/ml), indomethacin (20 μg/ml), 5,8,11,14 eicosatetraynoic acid (23 μg/ml), 15‐hydroperoxy arachidonic acid (23 μg/ml) and tranylcypromine (225 μg/ml).

It is suggested that due to the large amounts of material available, the rat pregnant myometrium is a useful model for the study of factors affecting prostacyclin synthesis.
THE ROLE OF CYCLIC NUCLEOTIDES AND RELATED COMPOUNDS IN NERVE‐MEDIATED VASODILATATION IN THE CAT SUBMANDIBULAR GLAND
Authors: JONES CHRISTOPHER J. , MANN G.E. , SMAJE L.H.
Published: July 2012

Intra‐arterial administration of a number of purine compounds to the cat submandibular salivary gland led to an increased blood flow. The threshold concentration of the most potent vasodilators, adenosine 5′‐triphosphate (ATP) and adenosine 5′‐diphosphate (ADP) was about 2 μmol/l. Adenosine and guanosine 5′‐triphosphate (GTP)required about 25 μmol/l, adenosine 3′,5′‐cyclic monophosphate (cyclic AMP) 40 μmol/l, guanosine 5′‐diphosphate (GDP) 125 μmol/l and dibutyryl guanosine 3′,5′ cyclic monophosphate (db cyclic GMP) 400 μmol/l. Dibutyryl cyclic AMP and cyclic GMP were ineffective.

The cyclic nucleotide phosphodiesterase inhibitors, theophylline, papaverine, quinine and 3‐isobutyl‐1‐methylxanthine (IBMX), all acted as vasodilators.

When intra‐arterial infusion of theophylline or IBMX was combined with sympathetic nerve stimulation, the vasodilatation observed after the stimulus ceased was significantly potentiated.

Theophylline and IBMX also potentiated the vasodilatation accompanying parasympathetic nerve stimulation and this response persisted after atropine.

These results are discussed in relation to the possible mediators of sympathetic and parasympathetic vasodilatation in the gland.
COMPARISON OF PHARMACOLOGICAL AND BINDING ASSAYS FOR TEN β‐ADRENOCEPTOR BLOCKING AGENTS AND TWO β‐ADRENOCEPTOR AGONISTS
Authors: BIETH NICOLE , ROUOT BRUNO , SCHWARTZ JEAN , VELLY JEANNE
Published: July 2012

The inhibition constants evaluated by binding assays for ten β‐adrenoceptor blocking agents and two β‐adrenoceptor agonists, were compared with the pA2 and pD2 values determined in vitro and in vivo.

There was only a limited correlation between β1 or β2 selectivities observed with the different methods.

Selectivity is generally less pronounced in binding assays than for in vivo and in vitro experiments.
ON THE RELEASE OF CATECHOLAMINES AND DOPAMINE‐β‐HYDROXYLASE EVOKED BY OUABAIN IN THE PERFUSED CAT ADRENAL GLAND
Authors: GARCIA A.G. , HERNANDEZ M. , HORGA J.F. , SANCHEZ‐GARCIA P.
Published: July 2012

Secretion of catecholamines (CA) and dopamine‐β‐hydroxylase (DBH) activity from the retrogradely perfused cat adrenal gland was studied following ouabain infusion. Perfusion with ouabain (10−4 m) for 10 min caused a gradual release of CA in the effluent which reached its peak 30 min after the ouabain pulse, and was maintained constant for at least 1 h. The effect of ouabain seemed to be irreversible.

Mecamylamine, while blocking the CA secretory effects of acetylcholine (ACh) perfusion, did not affect the secretion of CA evoked by ouabain. In denervated adrenal glands, ouabain‐induced CA secretion was similar to that in the contralateral, innervated gland. However, physostigmine perfusion potentiated the CA secretory effects of ouabain.

The release of CA evoked by ouabain was accompanied by a proportional release of DBH activity. The time course of appearance of DBH activity followed the pattern of CA release.

The CA and DBH outputs in response to a pulse of ouabain were suppressed in the absence of calcium. Calcium reintroduction to a calcium‐free perfused, ouabain‐treated gland not only restored but greatly potentiated the release of CA and DBH. The amplitude of the secretory response to calcium reintroduction in ouabain‐treated glands was proportional to the extracellular calcium concentration, and was antagonized by an external sodium‐deficient medium.

These data demonstrate that ouabain releases CA from the perfused cat adrenal gland by a calcium‐dependent exocytotic mechanism. The secretory effect of ouabain is not secondary to the release of ACh from cholinergic nerve terminals present in the adrenal gland, but due to a direct action on the chromaffin cell itself. In addition, the results suggest that this action is exerted through redistribution of monovalent cations secondary to the inhibition by the glycoside of the sodium pump. Such monovalent cation redistribution may cause a rise of intracellular ionized calcium levels through the activation of an internal sodium‐dependent calcium influx system probably located in the chromaffin cell membrane.
INTERACTIONS BETWEEN HYDRALAZINE, PROPILDAZINE AND PURINES ON ARTERIAL SMOOTH MUSCLE
Authors: CHEVILLARD C. , SAIAG B. , WORCEL M.
Published: July 2012

The interaction of hydralazine (Hyd) and propildazine (Pyd) with purine compounds was studied in the isolated tail artery from normotensive Wistar (NW) rats.

Exogenously added purines inhibit non competitively the antispasmogenic response to Hyd in denervated NW segments. The order of potency is 2‐Cl‐adenosine > adenosine > adenosine 5′‐triphosphate (ATP)> inosine. Pyd action is modified only by the most active purine 2‐C1‐> adenosine, which displaces the dose‐response curves to the right. Hyd and Pyd seem to act on the same site, since their maximal effects are not additive.

Theophylline (Theo) 50μm induces the appearance of the antispasmogenic effect of Hyd in the usually poorly responsive innervated proximal NW arterial segments. The potentiating action of Theo is identical to the enhancement of the Hyd response observed after 6‐hydroxydopamine denervation. This result suggests that the release of endogenous purines from sympathetic nerves is sufficient to block the smooth muscle responses to Hyd, under our experimental conditions. A similar potentiating effect is obtained with propranolol (5 μm).

The spontaneous release of 3H, after loading with [3H]‐noradrenaline, was considered as an indirect indication of purine leakage from nerve terminals. There is an inverse relationship between the rate of 3H release, under these conditions, and the magnitude of the relaxant response to Hyd, i.e., 3H leakage is higher in proximal NW segments.

The most satisfactory explanation for the interaction of Hyd and Pyd with exogenous purines, and for the modulating actions of sympathetic nerve terminals, is that both antihypertensives act on a common receptor, sensitive to endogenous ATP and adenosine.
EFFECT OF ANTIMUSCARINIC AGENTS ON THE CONTRACTILE RESPONSES TO CHOLINOMIMETICS IN THE RAT ANOCOCCYGEUS MUSCLE
Authors: DOGGRELL SHEILA A.
Published: July 2012

The effects of antimuscarinic agents alone and in the presence of neostigmine on the contractile responses to exogenously applied cholinomimetics or (‐)‐noradrenaline were studied in the rat anococcygeus muscle.

Atropine (1 × 10_9‐1 × 10−6m) alone, in the presence of hexamethonium (1 × 10−4m), or phentolamine (1 × 10−6m), inhibited responses to acetylcholine but not to (—)‐noradrenaline. The inhibitory effect with the higher concentrations of atropine (1 × 10−8— × 10−6m), was seen as an increase in the slopes of the concentration‐response curves. Atropine (1 × 10−8m) alone inhibited the responses to methacholine and carbachol without altering the slopes of the concentration‐response curves.

Homatropine (1 × 10−6m) alone had no effect on responses to (‐)‐noradrenaline and inhibited responses to acetylcholine and methacholine. The inhibitory effect on responses to acetylcholine but not to methacholine, included an increase in the slopes of the concentration‐response curves.

Neostigmine (1 × 10−6m) alone had no effect on responses to (—)‐noradrenaline and potentiated responses to acetylcholine and methacholine. The potentiating effect included an increase in the slopes of the concentration‐response curves.

In the presence of neostigmine (1 × 10−6m), atropine (1times10−9m‐1times 10−6m) caused a parallel concentration‐dependent shift of the concentration‐response curves to acetylcholine. The pA2 values, in the presence of neostigmine, were independent of the concentration of atropine and of the agonist (acetylcholine, methacholine, or carbachol) used. In the presence of neostigmine (1 × 10−6m), homatropine (1 × 10−6m) also failed to alter the slopes of the concentration‐response curves to acetylcholine and was approximately 100 times less potent than atropine as an antimuscarinic agent.

These results illustrate that, in the rat anococcygeus muscle, it is necessary to inhibit acetylcholinesterase before determining the relative potencies of antagonists at muscarinic receptors.
REACTIVITY OF ISOLATED TRACHEA, BRONCHUS AND LUNG STRIP OF CATS TO CARBACHOL, 5‐HYDROXYTRYPTAMINE AND HISTAMINE: EVIDENCE FOR THE EXISTENCE OF METHYSERGIDE‐SENSITIVE RECEPTORS
Authors: CHAND NARESH
Published: July 2012

The reactivity was investigated of cat isolated tracheal chains, bronchial spirals and lung parenchymal strips to carbachol, 5‐hydroxytryptamine (5‐HT) and histamine.

Carbachol and 5‐HT produced concentration‐dependent contractions of all three tissues, responses to the former drug being selectively blocked by atropine and to the latter by methysergide.

Histamine failed to elicit a contractile response from the tracheal or bronchial muscle. However, it induced dose‐related contractions of the lung strips, that were selectively blocked by mepyramine.

It is concluded that lung parenchymal strips of cats possess mepyramine‐sensitive histamine H1‐receptors. Receptors for 5‐HT, susceptible to methysergide, occur in the tracheobronchial smooth muscles as well as in lung strips of cats.
COMPARISON OF THE AGONIST ACTIVITY OF IMPROMIDINE (SK&F 92676) IN ANAESTHETIZED RABBITS AND ON THE RABBIT ISOLATED FUNDIC MUCOSA
Authors: CURWAIN B.P. , TURNER N.C.
Published: July 2012

The actions of impromidine in vivo and in vitro have been compared on gastric acid secretion. In both preparations impromidine was more potent than histamine.

There were no statistically significant differences between the maximum responses to impromidine and histamine in vivo or in vitro although in vitro the maximum response to impromidine was only 67% of that to histamine. In vivo the maximum response to impromidine was significantly less than the maximum response to histamine plus mepyramine.

The results are discussed in the light of recent findings.
POSSIBLE MECHANISM OF THE DUAL ACTION OF THE NEW POLYPEPTIDE (ANTHOPLEURIN‐B) FROM SEA ANEMONE IN THE ISOLATED ILEUM AND TAENIA CAECI OF THE GUINEA‐PIG
Authors: OHIZUMI Y. , SHIBATA S.
Published: July 2012

Anthopleurin‐B (AP‐B), a newly isolated polypeptide from a sea anemone (Anthopleura xanthogrammica) caused relaxation of the guinea‐pig isolated ileum following a transient contraction at concentrations greater than 3 × 10−9 m.

AP‐B caused a tonic contraction followed by rhythmic relaxation of the guinea‐pig isolated taenia caeci at a concentration of 3 × 10−9 m or more.

The other polypeptides, anthopleurin‐A (AP‐A) from the same species or anthopleurin‐C (AP‐C) from Anthopleura elegantissima elicited similar effects but higher concentrations were required in both tissues.

These responses induced by AP‐B in both tissues were abolished by treatment of each tissue with tetrodotoxin or incubation in a low‐Na+ medium.

In the ileum, the AP‐B‐induced contraction was markedly inhibited by atropine but not by mecamylamine, whereas the AP‐B‐induced relaxation was not affected by phentolamine or guanethidine.

The AP‐B‐induced contraction of the taenia caeci was also inhibited by atropine, but not mecamylamine. However, in contrast to the ileum, the spontaneous relaxation of this tissue was completely abolished in the presence of phentolamine or guanethidine.

These results suggest that the AP‐B‐induced contractions of both tissues are mainly caused by acetylcholine (ACh) release from the cholinergic nerve terminals and that the AP‐B‐induced relaxation of the taenia caeci is due to the excitation of adrenergic nerves, while the relaxation of the ileum is mediated through non‐adrenergic inhibitory mechanisms.
SL 75 102 AS A γ‐AMINOBUTYRIC ACID AGONIST: EXPERIMENTS ON DORSAL ROOT GANGLION NEURONES in vitro
Authors: DESARMENIEN MICHEL , FELTZ PAUL , HEADLEY P. MAX , SANTANGELO FRANCESCA
Published: July 2012

In anticipation that centrally active γ‐aminobutyric acid (GABA)‐mimetic drugs may be clinically useful, derivatives of GABA with an imine link (Schiff base) to a lipophilic carrier have recently been prepared. The present paper concerns the actions of [α(4‐chlorophenyl)5‐fluoro, 2‐hydroxy benzilidene‐amino]‐4‐butanoate Na+, SL 75 102.

To test one aspect of the GABA‐mimetic properties of SL 75 102, this compound was compared with GABA for activity on intracellularly‐recorded neurones in rat dorsal root ganglia in vitro. On these neurones GABA, administered either by microiontophoresis or direct into the superfusion medium, causes a depolarization, due to an increased chloride conductance, followed by a period of desensitization.

The actions of SL 75 102 were in nearly all respects identical to those of GABA; parameters examined were the effects on membrane potential and input conductance, desensitization, dose‐response characteristics and sensitivity to the GABA antagonists, bicuculline and picrotoxin.

SL 75 102 was less potent than GABA (mean relative potency 0·03:1).

SL 75 102 therefore appears to be a weak agonist at GABA receptors of these neurones.
ACTIONS ON THE CARDIOVASCULAR SYSTEM OF AN INHIBITORY MATERIAL EXTRACTED FROM THE BOVINE RETRACTOR PENIS
Authors: BOWMAN ANNE , GILLESPIE J.S. , MARTIN W.
Published: July 2012

A partially purified material has been isolated from methanol extracts of the bovine retractor penis muscle. This material exerts biological activity only after treatment with acid and subsequent neutralisation. The active principle in this extract, which appears to be no known autacoid, mimics the response to stimulation of the non‐adrenergic, non‐cholinergic nerves in the bovine isolated retractor penis muscle.

This inhibitory extract did not alter the heart rate or blood pressure of the anaesthetized rat when administered either by intravenous or intra‐arterial injection, nor did it have any obvious effect on isolated cardiac muscle.

The extract produced relaxation of spiral strips of various arteries isolated from ox, cat, rabbit or rat, in which tone was induced by noradrenaline, K+ or Ba2+.

The extract also produced dilatation of the resistance vessels of the rat isolated mesenteric circulation and the rat hindquarters perfused with Krebs solution; tone was induced in these vessels by adrenaline or noradrenaline.

Lack of vasodilator activity of the extract in the whole animal appeared to be due to rapid inactivation in the blood, probably by binding to the erythrocytes.
SOME EFFECTS OF CHEMICAL IRRITANTS ON THE MEMBRANE OF THE GIANT AMOEBA
Authors: FOSTER R.W. , WESTON A.H. , WESTON K.M.
Published: July 2012

The effects of chemical irritants on the membrane potential and input resistance of the giant amoeba, Chaos carolinense, have been investigated. The membrane potential and input resistance were −111.5 mV and 8.6 MΩ respectively

In the resting state the cell membrane of Chaos carolinense was found to be impermeable to Na+ but permeable to K+. The distribution of K+ across the cell membrane conformed to a Donnan equilibrium with the resting membrane potential being the K+ equilibrium potential

The chemical irritants dibenzoxazepine and its 2‐chloro‐ and 3‐chloro‐analogues and o‐chlorobenzylidene malononitrile produced a fall in input resistance but no change in membrane potential. It is suggested that these effects are caused by an increase in K+ permeability

The potencies of a series of chemical irritants with respect to dibenzoxazepine were measured on the giant amoeba. These potencies did not reflect those found in mammalian preparations.
CLONIDINE ACTIVATES MEMBRANE POTASSIUM CONDUCTANCE IN MYENTERIC NEURONES
Authors: MORITA K. , NORTH R.A.
Published: July 2012

Intracellular recordings were made from neurones in the myenteric plexus of the ileum removed from guinea‐pigs. The effects of clonidine and adrenaline on membrane potential and resistance were observed

Clonidine (100 pM‐30 nM) caused a concentration‐dependent membrane hyperpolarization associated with a fall in neurone input resistance

The amplitude of the clonidine hyperpolarization, but not the conductance increase, was greater in cells with lower resting potentials and smaller in more polarized neurones. In a given cell, membrane hyperpolarization decreased and membrane depolarization increased the clonidine effect

Low potassium solutions enhanced and high potassium solutions reduced the hyperpolarizing action of clonidine but did not significantly change the conductance increase caused by clonidine

The concentration‐effect curve for clonidine was displaced to the left when the extracellular calcium concentration was reduced. Conversely, clonidine was almost ineffective in elevated calcium concentrations. This was true for both the hyperpolarization and the conductance increase

It is suggested that clonidine activates a potassium conductance by causing an elevation in the free intracellular calcium concentration

Clonidine reversibly depressed the amplitude of the nicotinic fast excitatory postsynaptic potential and the noncholinergic slow excitatory postsynaptic potential

All the effects of clonidine were shared by adrenaline and the actions of both were reversed or prevented by phentolamine (100 nM‐1 μM).
THE EFFECTS OF PIPERAZINE ON RAT SYMPATHETIC NEURONES
Authors: CONNOR J.D. , CONSTANTI A. , DUNN P.M. , FORWARD ANNE , NISTRI A.
Published: July 2012

The neuronal effects of the anthelmintic piperazine (Pip) on rat sympathetic ganglia were studied in vitro by means of intracellular and extracellular recording techniques

Surface potential recordings indicated that Pip (0.1–10 mM as citrate, 1–30 mM as hexahydrate) produced a sustained depolarization (reversible on washing) of rat ganglia. γ‐Aminobutyric acid (GABA, 1–100 μM) also evoked reversible depolarizations but, unlike Pip, responses to the higher doses of GABA declined during a 2 min exposure. Depolarizations produced by Pip or carbachol (but not GABA) were markedly depressed by hexamethonium bùt only slightly by bicuculline or picrotoxin

Intracellular recordings revealed that Pip‐induced depolarizations were accompanied by an increase in membrane conductance and a broadening and depression of the directly‐evoked spike

In the presence of hexamethonium (1 mM), the responses to Pip hexahydrate and to cholinoceptor agonists were abolished, but Pip citrate still changed the spike configuration and induced membrane hyperpolarization with a small conductance increase. These residual effects were mimicked by superfusing with Na citrate or Ca2+‐free medium, suggesting that significant Ca2+ binding by the citrate anion of the Pip salt was probably responsible for the observed activity of Pip citrate in the presence of hexamethonium

It is concluded that on rat ganglia Pip is a nicotinic agonist, with no detectable GABA‐mimetic activity.
PROSTAGLANDINS RELEASE PLASMA ‘RECIPROCAL COUPLING FACTOR’ IN ANAESTHETIZED RATS
Authors: HOULT J.R.S. , MOORE P.K.
Published: July 2012

Prostaglandins E1, E2, I2 and endoperoxide analogue U46619 injected intra‐arterially (i.a.) into anaesthetized rats at 2 μg/kg caused a substantial increase within 60 min of the plasma activity of prostaglandin ‘reciprocal coupling factor’ (RCF). RCF is the provisional name for the component(s) of plasma which inhibit microsomal prostaglandin synthesis and enhance cytosolic prostaglandin breakdown

RCF is not released by inactive metabolite 13, 14‐dihydro‐15‐keto prostaglandin E2 (10 μg/kg, i.a.) or acetylcholine or histamine (2 μg/kg, i.a.)

We suggest that release by prostaglandins of RCF could provide the basis in vivo for a negative feedback mechanism controlling the activity of the prostaglandin system.