bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.