bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition by anti‐inflammatory agents of contraction induced by epidermal growth factor‐urogastrone in isolated longitudinal smooth muscle strips from guinea‐pig stomach
Authors: Itoh H. , Muramatsu I. , Patel P. , Lederis K. , Hollenberg M.D. 
Published: July 2012

Epidermal growth factor‐urogastrone (EGF‐URO) caused a concentration‐dependent contractile response of longitudinal muscle strips from the gastric body of the guinea‐pig stomach. The contractile response to EGF‐URO was monophasic, with tension returning rapidly to baseline. Desensitization was evident in that further addition of EGF‐URO to the organ bath did not cause a second contraction.
Preincubation with indomethacin, ibuprofen, naproxen and aspirin markedly inhibited the contractions induced by EGF‐URO with an order of potency (indomethacin > naproxen > ibuprofen > aspirin) that reflected the ability of these agents to inhibit cyclo‐oxygenase.
The data indicate that prostanoids mediate the action of EGF‐URO in the longitudinal muscle preparation.
Auranofin (0.5 to 50 μm), a chrysotherapeutic agent with antiproliferative properties used for treating rheumatoid arthritis, also markedly inhibited the EGF‐URO response; however, other gold‐containing compounds (aurothioglucose or gold sodium thiomalate at 30 to 100 μm) failed to cause significant inhibition.
Preincubation of preparations for 2 h with 1 μm hydrocortisone, prednisolone or dexamethasone caused an inhibition of EGF‐URO‐induced contraction of approximately 50%. However, steroids lacking either a 17α‐hydroxyl (corticosterone) or an 1lβ‐hydroxyl (cortisone, deoxycorticosterone, prednisone) substituent did not inhibit the contraction caused by EGF‐URO. For hydrocortisone, the inhibitory effect was half‐maximal at 0.2 μm and was maximal at 1 μm. Cycloheximide (10 μm) blocked the inhibitory action of hydrocortisone and potentiated the contractile action of EGF‐URO.
The ability of a variety of steroidal and non‐steroidal anti‐inflammatory agents to interfere with the action of EGF‐URO in a smooth muscle preparation suggests that these agents may also inhibit the action of EGF‐URO mediated by prostanoids in other target tissues.
The data also point to a potential role for EGF‐URO in regulating gastric motility.
The mechanism of the inotropic action of striatoxin, a novel polypeptide toxin from a marine snail, in isolated cardiac muscle
Authors: Ohizumi Yasushi , Kobayashi Masaki , Muroyama Akiko , Nakamura Hideshi , Kobayashi Jun'ichi 
Published: July 2012

Striatoxin (StTX), a novel polypeptide from a marine snail, caused a dose‐dependent increase in contractility in the isolated atria of guinea‐pig and rat in the concentration‐range of 2 × 10−9 to 3 × 10−8m and 3 × 10−8 to 10−6m, respectively.
In guinea‐pig atria, the StTX‐induced inotropic effect was inhibited by tetrodotoxin but not by cimetidine or chlorpheniramine. Practolol, propranolol or reserpine caused only partial block of this inotropic action.
In isolated single cells from rat hearts, StTX caused an increase in the degree and the rate of contraction.
In guinea‐pig atria, StTX provoked action potentials with a plateau phase of long duration without affecting the maximum rate of rise, the amplitude of action potential and the resting membrane potential. This prolongation was also reversed by tetrodotoxin.
In guinea‐pig cardiac myocytes, whole‐cell patch‐clamp experiments showed that StTX slowed Na channel inactivation without affecting the time course of channel activation. The voltage dependence of Na currents was not altered by StTX.
The residual currents, but not peak currents were markedly enhanced by StTX.
These results suggest that StTX causes prolongation of the action potential duration probably due to slowed inactivation of Na inward currents and enhanced residual currents and that this may result in an increase in Ca2+ availability in cardiac muscle cells. This could explain the cardiotonic action of StTX.
The mode of inotropic action of ciguatoxin on guinea‐pig cardiac muscle
Authors: Seino Asami , Kobayashi Masaki , Momose Kazutaka , Yasumoto Takeshi , Ohizumi Yasushi 
Published: July 2012

Ciguatoxin (CTX) caused a dose‐dependent increase in the contractile force of the guinea‐pig isolated left atria at concentrations ranging from 0.1 to 10 ng ml−1 with the ED50 value of 0.5 ng ml−1.
In the atria, tetrodotoxin (5 × 10−7 m) inhibited markedly the inotropic action of CTX. The inotropic effect of CTX at low concentrations was abolished by practolol (10−5 m) and reserpine (2 mg kg−1 daily, for 3 days), whereas that of CTX at high concentrations was partially inhibited by both drugs.
In single atrial cells, CTX (3 ng ml−1) produced a marked increase in the amplitude of longitudinal contractions.
CTX (3 ng ml−1) caused marked prolongation in the falling phase of action potentials of atrial strips without affecting the maximum rate of rise of action potentials and membrane resting potentials. The effect of CTX on action potentials was abolished by tetrodotoxin (10−6m).
The whole‐cell patch‐clamp experiments on myocytes revealed that CTX (20 ng ml−1) shifted the current‐voltage curve of Na inward currents by 40 mV in the negative direction. CTX caused a small sustained Na inward current even at resting membrane potentials.
These results suggest that the inotropic action of lower concentrations of CTX is primarily due to an indirect action via noradrenaline release, whereas that of higher concentrations is caused not only by an indirect action but also by a direct action on voltage‐dependent Na channels of cardiac muscle. It is also suggested that CTX activates cardiac muscle Na channels by modifying the voltage‐dependence of channel activation to increase Na inward currents, thus producing cardiotonic actions.
Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat
Authors: Cartheuser Carl F. 
Published: July 2012

The protective effects of ten slow channel inhibitor drugs against severe progressive hypoxia were investigated in rats breathing spontaneously during light anaesthesia. Respiration, heart rate, electrocorticogram (ECoG) and/or electroencephalogram (EEG) were recorded.
Tolerance times were monitored from hypoxia onset until cessation of respiration, ECoG, EEG synchronization, and ‘background‐EEG’. Drugs were administered i.v. 5 min before the onset of hypoxia.
Verapamil, gallopamil, and nimodipine resulted in a significant increase of tolerance times; fendiline and bepridil showed a small increase (not significant); bencyclan and prenylamine were ineffective; cinnarizine and diltiazem slightly reduced tolerance times as did flunarizine at low doses.
At protective doses, verapamil, gallopamil, and nimodipine significantly raised the respiration rate but had little or no cardiac depressor effects. Bencyclan showed ventilatory drive but cardiocirculatory depression. A clear‐cut ventilatory drive did not occur with the other ineffective slow channel inhibitors.
It is suggested that the protective actions observed were not due to slow channel inhibition per se, nor to spasmolytic potency or increased cerebral blood flow. Ventilatory drive associated with other cardiopulmonary actions which secondarily raise the brain oxygen supply are likely to be responsible for this effect.
Enhanced oxidative phosphorylation in rat liver mitochondria following prolonged in vivo treatment with imipramine
Authors: Katyare Surendra S. , Rajan Rema R. 
Published: July 2012

Effects of prolonged in vivo administration of the tricyclic antidepressant drug imipramine on oxidative energy metabolism in rat liver mitochondria were examined.
Imipramine treatment resulted in an increase in state 3 respiration rates with all the substrates tested as early as one week after treatment; this was sustained through the second week of treatment.
The changes in respiration rates were accompanied by a selective increase in the intramitochondrial cytochrome aa3 and c + c1 contents after both one and two weeks of treatment.
Administration of imipramine did not alter the total liver protein content per g tissue, the mitochondrial protein content per g tissue or the mitochondrial yield.
Kinetic analyses of succinoxidase activity in terms of Arrhenius plots indicated possible alterations in mitochondrial membrane lipid milieu and membrane fluidity after the drug treatment, especially in the second week.
Adrenergic modulation of the release of 5‐hydroxytryptamine from the vascularly perfused ileum of the guinea‐pig
Authors: Racké K. , Schwörer H. , Kilbinger H. 
Published: July 2012

Isolated segments of the guinea‐pig ileum were vascularly perfused and the release of 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) into the portal venous effluent was determined by h.p.l.c. with electrochemical detection. Test substances were applied via the arterial perfusion medium.
Isoprenaline (0.1 μm) increased the outflow of 5‐HT and 5‐HIAA maximally by about 75% and this was antagonized by propranolol (0.1 μm). Forskolin (1–10 μm) increased the outflow of 5‐HT by approximately 105% and that of 5‐HIAA by approximately 55%. The phosphodiesterase inhibitor AH 21–132 (0.1–1 μm) increased the outflow of 5‐HT and 5‐HIAA by about 70%. Isoprenaline (1 nm) and AH 21–132 (10 nm), which alone had no effect, increased the outflow of 5‐HT and 5‐HIAA by 75%, when applied in combination.
Clonidine (1 μm) reduced the outflow of 5‐HT by 45%, an effect blocked by tolazoline (1 μm), but not by prazosin (0.1μm).
The effects of isoprenaline, forskolin and clonidine were also observed in the presence of tetrodotoxin (1 μm) demonstrating a direct modulation of 5‐HT release from the enterochromaffin cells.
In conclusion, the release of 5‐HT from enterochromaffin cells is facilitated by activation of β‐adrenoceptors and inhibited via α2‐adrenoceptors. Enhancing intracellular cyclic AMP, by direct stimulation of adenylate cyclase with forskolin or by inhibition of phosphodiesterase, also facilitates the release of 5‐HT. The β‐adrenoceptor‐mediated effect on 5‐HT release appears to involve an increase in cyclic AMP, as the effect of isoprenaline was potentiated after inhibition of phosphodiesterase.
Characterization of the binding of [3H]‐CGS 19755: a novel N‐methyl‐d‐aspartate antagonist with nanomolar affinity in rat brain
Authors: Murphy Deborah E. , Hutchison Alan J. , Hurt Steven D. , Williams Michael , Sills Matthew A. 
Published: July 2012

CGS 19755 (cis‐4‐phosphonomethyl‐2‐piperidine carboxylic acid), a rigid analogue of 2‐amino‐5‐phosphonopentanoic acid (AP5), is one of the most potent competitive N‐methyl‐d‐aspartate (NMDA) antagonists described. Using Triton‐treated crude synaptic membranes from rat brain, binding studies indicated that [3H]‐CGS 19755 bound with high affinity and selectivity to the NMDA‐type excitatory amino acid receptor.
[3H]‐CGS 19755 binding was saturable, reversible, heat‐labile, pH‐dependent and linear with protein concentration. Specific binding represented 80–85% of the total amount bound.
Using a centrifugation assay, saturation experiments revealed two distinct binding components with Kd values of 9 and 200 nM, and corresponding Bmax values of 0.55 and l.00 pmol mg−1 protein. In contrast, a single binding component with a Kd value of 24 nM and an apparent value of 0.74 pmol mg−1 protein was observed with a filtration assay.
Competition experiments in which both assay techniques were used, showed that [3H]‐CGS 19755 selectively labels the NMDA receptor. The most active inhibitors of [3H]‐CGS 19755 binding were l‐glutamate and CGS 19755 (IC50 values = 100 nm).
In the centrifugation assay, a number of excitatory amino acids were found to generate shallow inhibition curves, and computer analysis indicated the presence of two binding components. The quisqualate receptor ligand AMPA (D,L‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate), kainic acid and the non‐competitive NMDA antagonists, such as phencyclidine, tiletamine and MK‐801, were without activity.
The high affinity binding obtained with [3H]‐CGS 19755 by use of filtration techniques thus permits the more rapid evaluation of compounds as potential NMDA antagonists and agonists. Therefore, this rigid analogue of AP5 is a more suitable radioligand for NMDA receptors than [3H]‐CPP (3‐(±)−(2‐carboxypiperazin‐4‐yl)propyl‐l‐phosphonic acid), the corresponding analogue of 2‐amino‐7‐phosphonoheptanoic acid (AP7).
Effects of the anaesthetic 2,6‐diisopropylphenol on synaptic transmission in the rat olfactory cortex slice
Authors: Collins G.G.S. 
Published: July 2012

The effects of the general anaesthetic 2,6‐diisopropylphenol (DIP) on synaptic transmission and the actions of amino acid transmitter candidates have been investigated in rat olfactory cortex slices.
On electrical stimulation of the lateral olfactory tract (LOT), DIP (20 to 200 μm) increased the area of those surface field potentials which reflect γ‐aminobutyric acid (GABA)‐mediated transmission in a concentration‐dependent manner in 6 out of 12 slices. In a series of conditioning experiments, DIP (50 μm) also potentiated GABA‐mediated pre‐ and post‐synaptic inhibition.
Perfusion of slices with DIP (50 μm) potentiated the reduction in the excitability of the terminals of the LOT produced by exogenous GABA in a picrotoxin‐sensitive manner.
DIP (50μm) markedly potentiated the surface depolarizations evoked by GABA, muscimol and 3‐aminopropanesulphonic acid. The effect on the response to 3‐aminopropanesulphonic acid was observed over a concentration range of DIP of 6.25 to 50μm and was not blocked by the benzodiazepine receptor antagonist Ro 15–1788.
In slices in which GABA‐mediated transmission was abolished by picrotoxin (25 μm), DIP (50 μm) had no significant effect on monosynaptically‐evoked excitatory transmission but depressed the areas of those field potentials which reflect di‐/polysynaptic excitations in a concentration‐dependent manner (from between 1.6 and 6.25 to 50 μm).
In a series of conditioning experiments DIP (50 μm) abolished the increase in the excitability of the pyramidal cells evoked on stimulation of deep association fibres.
DIP (50μm) had no significant effect on surface depolarizations evoked by N‐methyl‐d‐aspartate, quisqualate and kainate or by the transmitter candidates l‐glutamate and l‐aspartate.
It is concluded that, at clinically relevant concentrations, DIP potentiates GABA‐mediated transmission probably by an interaction with the GABA receptor complex and inhibits di‐/polysynaptic excitations, possibly by inhibiting the release of excitatory transmitters.
The mechanism by which monoamine oxidase inhibitors give rise to a non‐calcium‐dependent component in the depolarization‐induced release of 5‐HT from rat brain synaptosomes
Authors: Evans Suzanne M. , Collard Keith J. 
Published: July 2012

The effects of the monoamine oxidase inhibitors pargyline and nialamide on the Ca2+‐dependency of [3H]‐5‐hydroxytryptamine release from superfused rat brain synaptosomes has been studied in order to evaluate the discrepancies that have occasionally been observed in studying transmitter release by in vivo and in vitro techniques.
The application of K+ pulses of low concentration (12.5–20mm) caused an essentially Ca2+‐dependent release of [3H]‐5‐HT. However, at K+ concentrations above 30 mM, a small non‐Ca2+‐ dependent component appeared.
At high concentrations of K+ (30–55 mm), nialamide (18 μm) or pargyline (1 μm) increased the amount of [3H]‐5‐HT released which could be accounted for by an increase in the non‐Ca2+‐ dependent component of release.
The elevation of the non‐Ca2+‐dependent component of release caused by the monoamine oxidase inhibitors was totally abolished by the inhibitors of the plasma membrane 5‐HT carrier, chlomipramine (500 nm), citalopram (50 nm) and fluoxetine (1 μm).
The results suggest that the non‐Ca2+‐dependent component of release seen with high depolarizing concentrations of K+, particularly in the presence of monoamine oxidase inhibitors, is caused by the efflux of [3H]‐5‐HT through the plasma membrane carrier which seems to be activated during depolarization.
The significance of these findings to the physiological in vivo situation, and to the use of in vitro preparations in the study of transmitter release is discussed.
Contrasting in vitro lymphocyte chemotactic activity of the hydroxyl enantiomers of 12‐hydroxy‐5,8,10,14‐eicosatetraenoic acid
Authors: Bacon K.B. , Camp R.D.R. , Cunningham F.M. , Woollard P.M. 
Published: July 2012

The chemotactic activity of 12(R)‐hydroxy‐5,8,10,14‐eicosatetraenoic acid (12(R)‐HETE), 12(S)‐HETE and leukotriene B4 (LTB4) for human mixed peripheral blood lymphocytes has been assessed in a 48‐well microchemotaxis assay. Responses to the standard lymphocyte chemoattractants, zymosan‐activated plasma, casein and N‐formyl‐methionyl‐leucyl‐phenylalanine (fMLP) were also measured.
12(R)‐HETE was shown to be chemotactic for lymphocytes over the range 5 × 10−7 to 5 × 10−5 m. In contrast, negligible chemotactic responses to 12(S)‐HETE were obtained.
LTB4 was 200 times more potent than 12(R)‐HETE as a lymphocyte chemoattractant, although maximal responses to the two agonists were similar.
12(R)‐HETE and LTB4, which are present in extracts of samples from the skin lesions of psoriasis, may be, at least in part, responsible for the lymphocyte infiltrate which is a characteristic feature of this disease.
The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro
Authors: Eglen R.M. , Montgomery W.W. , Dainty I.A. , Dubuque L.K. , Whiting R.L. 
Published: July 2012

The action of methoctramine and himbacine at muscarinic receptors has been studied using guinea‐pig isolated trachea, oesophageal muscularis mucosae, paced left atria, and rat aortic preparations.
Methoctramine (1 × 10−6‐3.2 × 10−4 m), but not himbacine, elicited positive inotropic responses. These responses were enhanced by pretreating the animals with reserpine. The responses in reserpine‐treated animals were not antagonized by phentolamine (1 × 10−6 m) but were antagonized by propranolol (1 × 10−6 m).
Methoctramine, but not himbacine, exhibited allosteric inhibitory effects at cardiac muscarinic receptors, resulting in a curvilinear Schild plot. Deviations from competitive antagonism were also observed in combination dose‐ratio experiments using atropine and methoctramine. At 1 × 10−6 m, the pKB value for methoctramine was 7.88 ±0.15 (mean ± s.e.mean, n = 5). The pA2 value for himbacine at cardiac muscarinic receptors was 8.52 ± 0.06 (n = 3).
At tracheal and oesophageal muscularis mucosal smooth muscle receptors, the Schild plots for both antagonists were linear. The pA2 values for methoctramine at receptors in these two preparations were similar (6.08 ± 0.05 and 6.03 ± 0.09 respectively, n= 4) and were approximately 60 fold less than those values observed at atrial receptors. Himbacine, also exhibited similar values at muscarinic receptors in the trachea and oesophageal muscularis mucosae (7.61 ± 0.05 and 7.57 ± 0.04 respectively, n= 4).
Muscarinic receptors mediating relaxation of the rat aortic endothelium exhibited pA2 values for methoctramine (5.87 ± 0.12, n= 6) which were similar to those observed in the smooth muscle, but not the atria. The pA2 values for himbacine at endothelial muscarinic receptors were approximately 0.5 pA2 units lower than those observed at muscarinic receptors in smooth muscle (6.92 ± 0.80, n= 6). In addition, the Schild slopes for methoctramine and himbacine at these receptors were significantly (P < 0.05) less than unity.
Methoctramine, and to a lesser extent himbacine, are potent and selective antagonists for cardiac muscarinic receptors. However, caution should be used in interpretation of the data with methoctramine in view of the inhibitory allosteric properties and direct inotropic actions of this compound.
Electrophysiological mechanism for the antiarrhythmic action of propafenone: a comparison with mexiletine
Authors: Amerini Sandra , Bernabei Roberto , Carbonin Pierugo , Cerbaiz Elisabetta , Mugelli Alessandro , Pahor Marco 
Published: July 2012

The antiarrhythmic potency of propafenone was evaluated in the guinea‐pig isolated heart; arrhythmias were induced with (a) digitalis intoxication and (b) hypoxia followed by reoxygenation.
Propafenone, 0.5 μm, was found to be the minimal but effective antiarrhythmic concentration. The antiarrhythmic activity of propafenone developed slower than that of 10 μm mexiletine, which was the lowest effective concentration under the same experimental conditions.
The electrophysiological effects of propafenone were then studied on sheep cardiac Purkinje fibres (manifesting oscillatory afterpotentials and triggered automaticity induced by barium or strophanthidin) and compared with those of 10 μm mexiletine.
Both 0.5 μm propafenone and 10 μm mexiletine consistently blocked triggered activity in sheep Purkinje fibres. The onset of the effect of propafenone was slower than that of mexiletine.
Unlike mexiletine, propafenone did not reduce the amplitude of oscillatory afterpotentials.
In contrast, propafenone significantly reduced in barium‐ and strophanthidin‐treated preparations.
It is concluded that the antiarrhythmic action of propafenone on digitalis‐ and reoxygenation‐induced arrhythmias is probably due to an electrophysiological mechanism different from that of mexiletine. Mexiletine, by reducing the amplitude of oscillatory afterpotentials, prevents the attainment of the threshold; propafenone, by reducing the excitability of the cell, increases the threshold and consequently an oscillatory afterpotential of the same amplitude will not generate arrhythmias.