bluuebunny/crossref_metadata_2025_split huggingface dataset:
Studies on L‐640,035: a novel antagonist of contractile prostanoids in the lung
Authors: Carrier R. , Cragoe E.J. , Ethier D. , Ford‐Hutchinson A.W. , Girard Y. , Hall R. A. , Hamel P. , Rokach J. , Share N.N. , Stone C.A. , Yusko P. 
Published: July 2012

The effects of L‐640,035 (3‐hydroxymethyl‐dibenzo [b,f] thiepin‐5,5‐dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo.
When studied in vitro on guinea‐pig tracheal chains, L‐640,035 produced significant shifts in the dose‐response curves to a prostaglandin (PG) endoperoxide analogue (U‐44069) (pA2 7.0), PGF2α (pA2 5.9) and PGD2 (pA2 6.5). L‐640,035 produced no significant shift in the dose‐response curves to leukotriene D4 or histamine and produced a small but statistically significant shift in the dose‐response curve to 5‐hydroxytryptamine (5‐HT) (pA2 5.2). With the exception of PGF2α, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L‐640,035, L‐636,499, also produced significant parallel shifts in the dose‐response curves to U‐44069 (pA2 6.0) and PGF2α (pA2 6.0), but with some reduction in the maximal contraction.
When L‐640,035 was administered intravenously to guinea‐pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U‐44069 (ED50 0.16 mg kg−1), leukotriene D4 (ED50 0.25 mg kg−1) and 5‐HT (ED50 3.4 mg kg−1) but not histamine (ED50> 10 mg kg−1) was observed.
When L‐640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U‐44069 (ED50 0.85 mg kg−1) but not histamine (ED50> 30 mg kg−1) was observed.
When L‐640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg−1 significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mg kg−1 i.v.) was observed with a duration of action of > 255 min.
It is concluded that L‐640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.
Sodium‐potassium ATPase inhibition potentiates compound 48/80‐induced histamine secretion from mast cells
Authors: Amellal M. , Binck M. , Frossard N. , Ilien B. , Landry Y. 
Published: July 2012

The effect of ouabain on the histamine secretion induced by compound 48/80 has been studied using rat peritoneal mast cells.
Ouabain did not modify histamine release in the presence of millimolar concentrations of extracellular calcium.
However, when mast cells were previously washed with a calcium‐free buffer, ouabain strongly potentiated histamine release elicited by compound 48/80.
The full potentiation of mast cell secretion by ouabain required 30 min preincubation before adding compound 48/80. It was inhibited by lanthanum and EGTA.
Potassium deprivation mimicked the effect of ouabain. A 30 min preincubation time without potassium was also required.
Potassium concentrations below 2.7 mm increased the effect of ouabain whereas higher potassium concentrations reversed this effect.
The potentiation of compound 48/80‐induced histamine release by ouabain or potassium deprivation was not immediately reversed by washing away ouabain or by adding potassium, respectively.
The data confirm that sodium‐potassium ATPase is involved, through a calcium‐dependent process, in the regulation of histamine release from mast cells.
Identification of benzomorphan‐κ opiate receptors in cerebral arteries which subserve relaxation
Authors: Altura Bella T. , Altura Burton M. , Quirion Remi 
Published: July 2012

Several ‘so‐called’ κ‐opiate receptor agonists e.g., ketocyclazocine (Kc), ethylketocyclazocine (Eke), bremazocine, MR‐2034 and U‐50488H, were tested on basilar and middle cerebral arteries of the dog in vitro for relaxant or contractile activities.
Eke, Kc and bremazocine were found to produce concentration‐dependent reductions in basal tone and to relax cerebral arteries contracted with prostaglandin F2α (PGF2α). All three agonists appear to act on benzomorphan‐κ opiate receptors which subserve relaxation in cerebral blood vessels.
MR‐2034 and U‐50488H were found to induce contraction in the cerebral arteries. These opiate agonists appear to act on phencyclidine (PCP) or σ‐opiate receptors which subserve contraction.
A variety of pharmacological antagonists (phentolamine, propranolol, methysergide, atropine, diphenhydramine, cimetidine, naloxone) did not modify any of the cerebral vascular effects produced by the opiates.
These results suggest: (1) specific benzomorphan‐κ opiate receptors which subserve relaxation exist in cerebral blood vessels; (2) some κ agonists appear to produce, primarily, contraction in cerebral vessels via PCP or σ‐opiate receptors: and (3) cerebral vascular muscle may provide a useful tool to analyse the molecular constitution of these two distinct and opposite‐acting opiate receptors.
Actions of γ‐aminobutyric acid on neurones of guinea‐pig myenteric plexus
Authors: Cherubini E. , North R. A. 
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) applied by ionophoresis, pressure ejection and superfusion to myenteric neurones of the guinea‐pig ileum were investigated by intracellular recording techniques.
Ionophoretic or pressure application of GABA (10 pC‐30 nC) caused membrane depolarizations of AH neurones but not S neurones. This depolarization was associated with a conductance increase. It reversed polarity at a membrane potential of — 18 mV when intracellular electrodes contained KCl, and −39 mV when electrodes contained K acetate, citrate or sulphate.
The ionophoretic depolarization was antagonized by bicuculline (1–30 μM) in an apparently competitive manner.
During prolonged or repeated ionophoretic application of GABA, both the depolarization and conductance increase desensitized.
Superfusion of GABA (1–100 μM) caused a membrane depolarization in AH neurones, associated with an increase in membrane conductance. The increase in conductance was always smaller than that evoked by ionophoresis of GABA.
Bicuculline only partially depressed the depolarization induced by superfusion of GABA, particularly slowing its rising phase. β‐p‐Chlorophenyl GABA (baclofen) (10 μM) caused a depolarization similar to that observed with GABA in the presence of bicuculline.
The depolarization induced by baclofen and GABA (in presence of bicuculline) superfusion did not decline during prolonged applications; superfusion of GABA but not baclofen reversibly reduced or eliminated the effects of GABA ionophoresis.
It is concluded that GABA has two effects on the membrane of myenteric neurones. The first is a bicuculline‐sensitive, rapidly desensitizing chloride activation: the second is a bicuculline‐insensitive, non‐desensitizing depolarization.
An investigation into the selectivity of a novel series of benzoquinolizines for α2‐adrenoceptors in vivo
Authors: Paciorek P.M. , Pierce Vanessa , Shepperson N.B. , Waterfall J.F. 
Published: July 2012

The potencies and selectivities of a novel series of benzoquinolizines for the α2‐adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin.
Peripheral postjunctional α2‐ and α1‐adrenoceptor blockade was measured as the reversal of B‐HT 933 and methoxamine‐induced pressor responses, respectively, in the pithed rat.
Peripheral prejunctional α2‐adrenoceptor blockade was measured as the reversal of B‐HT 933‐induced inhibition of an electrically evoked tachycardia in the pithed rat.
Central α2‐adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine.
Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3–3 mg kg−1 i.v.) evoked dose‐dependent shifts to the right of the dose‐response curves to B‐HT 933 whilst having minimal effects on the methoxamine dose‐response curve.
The selectivity for α2‐adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 > Wy 26392 > Wy 26703 > yohimbine.
Indoramin (1 mg kg−1 i.v.) shifted the methoxamine pressor dose‐response curve to the right without affecting the B‐HT 933 dose‐response curves, confirming its selective α1‐antagonist activity.
Peripheral administration of all three benzoquinolizines (1–100 μg kg−1 i.v.) led to a dose‐dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. A similar degree of hypotension induced by the ganglion blocking agent chlorisondamine (1 mg kg−1 i.v.) was not reversed by the benzoquinolizines.
It is concluded that Wy 25309, Wy 26392 and Wy 26703 are selective α2‐adrenoceptor antagonists which readily penetrate the CNS.
Release of kallikrein‐like esterase and tonin from dispersed cells of the rat submandibular gland
Authors: Izumi Hiroshi 
Published: July 2012

Viable dispersed cell preparations of rat submandibular gland were obtained by a tissue‐dissociation procedure using collagenase and gentle mechanical force.
The cells released kallikrein‐like esterase in a time‐ and calcium‐dependent manner in response to noradrenaline (10 μM) at 30°C. The net loss of kallikrein‐like esterase content from the dispersed cells corresponded with the increase in kallikrein‐like esterase activity in the suspending medium at all concentrations of noradrenaline. These results indicate the viability and functional integrity of this dispersed cell preparation of rat submandibular gland.
α‐Adrenoceptor agonists such as noradrenaline stimulated kallikrein‐like esterase and tonin release in a dose‐dependent manner, whereas the β‐adrenoceptor agonist isoprenaline and cholinoceptor agonist methacoline were both inactive. Noradrenaline‐induced release of kallikrein‐like esterase and tonin were completely blocked by prior addition of the α‐adrenoceptor antagonist, phenoxybenzamine.
It is concluded that the secretion of kallikrein‐like esterase and tonin in rat submandibular gland is mediated only via stimulation of α‐adrenoceptors.
Substance P in sensory nerve fibres contributes to the development of oedema in the rat hind paw after thermal injury
Authors: Saria A. 
Published: July 2012

Immersion of the hind paws of anaesthetized rats in hot water for 5 min induced massive plasma protein leakage as indicated by extravasation of Evans blue dye in the skin. The threshold temperature which caused noticeable plasma extravasation was 45°C, a maximal response was obtained between 55°C and 60°C.
Pretreatment of rats 2 days after birth with 50 mg kg−1 capsaicin significantly reduced the Evans blue extravasation induced by hot water at 50°C, 55°C and 60°C, whereas guanethidine pretreatment 24 h before the experiment caused a significantly increased response at 40°C, 45°C and 50°C.
When Evans blue was injected between 10 and 120 min after immersion of the paw in hot water, a significant extravasation of the dye was no longer detectable. However, the weight of the paw as well as the weight of the piece of skin taken for Evans blue quantification increased during this period indicating the progressive development of oedema in the skin and underlying tissues.
In rats treated with capsaicin as neonates, the increase in paw weight after immersion in water of 50°C for 5 min was significantly delayed during the first hour, but there was no difference after two hours.
In rats pretreated with D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11‐substance P, a substance P (SP) antagonist, the Evans blue extravasation was significantly reduced. However, the response, which remained in rats treated with capsaicin as neonates was not blocked by the SP‐antagonist.
It is concluded that activation of peripheral branches of sensory SP neurones contributes to the initial massive protein extravasation and to the subsequent rate of development of oedema following heat injury. Release of histamine did not significantly contribute to this response at the lower temperatures, although the response was reduced by histamine receptor blocking drugs at 55°C and 60°C. Decreasing the sympathetic vasoconstrictor tone by guanethidine resulted in an increased response.
Effects of α‐adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart
Authors: Brückner Reinhard , Scholz Hasso 
Published: July 2012

The mechanism of the cyclic AMP‐independent positive inotropic effect of cardiac α‐adrenoceptor stimulation was studied by analyzing the effects of phenylephrine on force of contraction, calcium‐dependent slow action potentials and the slow inward current (Isi) in bovine ventricular trabeculae. The preparations were electrically driven at 0.3 Hz in the presence of propranolol 1 μmol l−1.
Phenylephrine increased the force of contraction in a concentration‐dependent manner (maximum about 200% of control at 30 μmol l−1). The effect was surmountably antagonized by phentolamine.
The positive inotropic effect of phenylephrine was accompanied by a concentration‐dependent increase in time to peak force and occurred without any detectable increase in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels.
The positive inotropic effect of phenylephrine was accompanied by an increase in action potential duration both at 20% and 90% repolarization.
Calcium‐dependent slow action potentials were also prolonged by phenylephrine and there was a distinct increase in the maximal rate of depolarization (dV/dtmax) of these slow potentials. These effects were also completely reversible on washing and surmountably blocked by phentolamine. However, the increase in dV/dtmax was smaller than that of isoprenaline in concentrations producing similar inotropic effects.
Voltage‐clamp experiments with the single sucrose‐gap method showed that the phenylephrine‐induced increase in force of contraction was associated not only with an increase in peak slow calcium inward current, Isi max, but also with a delay in the inactivation of Isi. Outward currents were not detectably altered by phenylephrine.
It is concluded that the α‐adrenoceptor mediated, cyclic AMP‐independent positive inotropic effects of phenylephrine in bovine cardiac muscle are associated with an increase in slow inward current. Additionally, the amount of calcium influx during excitation is probably increased by a delay in the inactivation of Isi. Both effects can explain the phenylephrine‐produced prolongation of the action potential, and probably contribute to the positive inotropic effect of α‐adrenoceptor stimulation. However, as the effect on dV/dtmax is smaller than that of isoprenaline, other (still unknown) mechanisms may also be involved.
A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurones in the CNS of the rat
Authors: Archer Trevor , Jonsson Gösta , Ross Svante B. 
Published: July 2012

The effects of various doses of DSP4 on two‐way active avoidance acquisition in rats and on central noradrenaline neurones were compared.
Doses of DSP4 from 3 mg kg−1 i.p. and upwards injected one week before the onset of the avoidance trials significantly impaired two‐way avoidance learning.
The learning impairment caused by DSP4 (50 mg kg−1 i.p.) lasted for at least 10 weeks.
Desipramine (20 mg kg−1) injected either 30 or 60 min before DSP4 (50 mg kg−1) antagonized the active avoidance impairment.
A high dose of DSP4 (50 mg kg−1 i.p.) produced profound decreases in dopamine‐β‐hydroxylase activity in the frontal cortex and in the concentrations of noradrenaline in various brain regions indicating degeneration of the locus coeruleus noradrenaline system.
Low doses of DSP4 (3 and 6 mg kg−1 i.p.) produced small but significant decreases in the concentrations of noradrenaline (NA) in some regions, e.g. cerebral cortex, hippocampus, olfactory bulb and spinal cord.
The avoidance impairment caused by the low dose of DSP4 (3 mg kg−1) was absent when rats were tested 10 weeks after treatment nor was NA depletion present when NA was analysed 3 months after treatment.
Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats
Authors: Furman Brian L. , McKechnie Kenneth , Parratt James R. 
Published: July 2012

The effects of two thromboxane synthetase inhibitors (dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat.
Infusion of E. coli endotoxin (41.7 ng kg−1 min−1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia.
The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin‐treated 935 ± 150 pg ml−1 at 1 h compared with pre‐endotoxin values of 125 ± 30 pg ml−1).
The administration of either dazoxiben (30 mg kg−1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg−1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations.
Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality.
These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.
Regional differences in the response to vasoconstrictor agents of dog and monkey isolated coronary arteries
Authors: Miwa Kunihisa , Toda Noboru 
Published: July 2012

Contractile responses to vasoconstrictor agents were compared in helical strips of dog and monkey epicardial coronary arteries of different sizes. Contractions of large, medium and small arteries induced by KCl (30mM) were virtually identical.
Contractions induced by 5‐hydroxytryptamine (5‐HT) (10−9‐2 × 10−6 M) were in the order of large > medium > small arteries in dogs, and large = medium > small arteries in monkeys. Cinanserin suppressed these responses.
In contrast, contractions produced by angiotensin II (AII) (10−7 M) were in the order of small > medium > large arteries in dogs, and small > medium = large arteries in monkeys. Sar1‐Ala8‐angiotensin II markedly attenuated the peptide‐induced contractions.
Contractions induced by prostaglandin F2α (PGF2α) were significantly greater in large and medium sized arteries than in small arteries in dogs, while those of the arteries of different sizes isolated from monkeys did not differ. Contractions induced by carbocyclic thromboxane A2 (c‐TXA2), in arteries of different sizes in dogs and monkeys, did not differ.
These results suggest that the sensitivity and/or the population of 5‐HT receptors are greater in proximal coronary arteries than in distal arteries, while, in contrast, the sensitivity and/or population of AII receptors are greater in distal coronary arteries. Receptors for PGF2α and c‐TXA2 appear to react to a similar degree in monkey arteries of different sizes, although receptors for PGF2α appear to be fewer in distal coronary arteries in dogs.
Changes in carotid body amine levels and effects of dopamine on respiration in rats treated neonatally with capsaicin
Authors: McQueen D.S. , Mir A.K. 
Published: July 2012

Dopamine levels in rat carotid bodies and the effects of intravenous dopamine injections on respiration in adult rats anaesthetized with pentobarbitone have been studied in animals which were treated with capsaicin neonatally.
Levels of dopamine were five fold higher in the carotid bodies of capsaicin‐treated rats as compared with vehicle‐treated controls, but there was no significant difference between capasicin‐treated and vehicle‐treated rats in their ID50 values for dopamine‐induced respiratory depression.
Domperidone, a dopamine D2‐receptor antagonist, substantially reduced the respiratory depression caused by dopamine, both in capsaicin‐treated and in control animals, suggesting that a D2‐receptor was involved in the response. Cutting the carotid sinus nerves greatly reduced the ventilatory‐depressant effect of dopamine, showing that sensory receptors, most probably arterial chemoreceptors, were responsible for most of the response.
Substantially less reflex hyperventilation was evoked in capsaicin‐treated rats by the peripheral chemoreceptor stimulants hypoxia and sodium cyanide, in comparison with the controls, and domperidone did not increase the responsiveness. About 80% of the reflex ventilatory change originated from carotid body chemoreceptors.
The hypoventilation caused by breathing 100% O2 was not significantly different in capsaicin‐treated rats when compared with controls. Domperidone substantially reduced this response in capsaicin‐treated rats, but not in vehicle‐treated animals.
Dopamine‐induced respiratory depression in capsaicin‐treated rats was slightly enhanced, rather than reduced, by oxygen breathing; domperidone remained an effective antagonist of dopamine‐induced ventilatory depression.
Most of the reduction in respiration caused by dopamine in rats anaesthetized with pentobarbitone can be attributed to actions on a dopamine D2‐receptor located in the carotid body. However, despite the increased levels of dopamine found in the carotid bodies, the reduced peripheral chemosensitivity observed in anaesthetized capsaicin‐treated rats does not appear to result from a change in sensitivity to dopamine.
Effects of adenosine, adenosine triphosphate and structural analogues on glucagon secretion from the perfused pancreas of rat in vitro
Authors: Chapal J. , Loubatières‐Mariani M.M. , Roye M. , Zerbib A. 
Published: July 2012

The effects of adenosine, adenosine triphosphate (ATP) and structural analogues have been studied on glucagon secretion from the isolated perfused pancreas of the rat in the presence of glucose (2.8 mM).
Adenosine induced a transient increase of glucagon secretion. This effect was concentration‐dependent in the range of 0.165 to 165 μM. ATP also induced an increase, but the effect was no greater at 165 μM than at 16.5 μM.
2‐Chloroadenosine, an analogue more resistant to metabolism or uptake systems than adenosine, was more effective. Among the three structural analogues of ATP or ADP studied, β,γ‐methylene ATP which can be hydrolyzed into AMP and adenosine had an effect similar to adenosine or ATP at the same concentrations (1.65 and 16.5 μM); in contrast α,β‐methylene ATP and α,β‐methylene ADP (resistant to hydrolysis into AMP and adenosine) were ineffective.
Theophylline (50 μM) a specific blocker of the adenosine receptor, suppressed the glucagon peak induced by adenosine, 2‐chloroadenosine, ATP and β,γ‐methylene ATP (1.65 μM).
An inhibitor of 5′ nucleotidase, α,β‐methylene ADP (16.5 μM), reduced the glucagon increase induced by ATP and did not affect the response to adenosine (1.65 μM).
These results support the hypothesis of adenosine receptors (P1‐purinoceptors) on the pancreatic glucagon secretory cells and indicate that ATP acts after hydrolysis to adenosine.