bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of vanadate‐induced contraction of airways smooth muscle of the guinea‐pig
Authors: Nayler Ross A. , Sparrow Malcolm P. 
Published: July 2012

The characteristics of vanadate‐induced contraction of airways smooth muscle are described in isolated preparations of guinea‐pig central and peripheral airways. Vanadate (1–1000 μM) induced sustained contractions of trachea and lung parenchymal strips within 1 min of challenge. It was more potent (P < 0.001) on the lung strip (EC50 = 63 μM) than on the trachea (EC50 =123 μM). The lung strip also developed greater maximum isometric tension (P < 0.001) than the trachea. The efficacy on the lung strip was 2 and the trachea 0.6, relative to the response to acetylcholine (efficacy = 1).
Vanadate‐induced contractions of the trachea were not inhibited by atropine, mepyramine, phentolamine or indomethacin, nor after mast cell depletion by compound 48/80, showing that contractions were not mediated via specific receptors or by release of endogenous mediators of tone.
Inorganic phosphate specifically inhibited vanadate responses in a dose‐dependent and reversible manner, suggesting a common site of action.
Contractions could be elicited in depolarized muscle and after treatment with ouabain plus propranolol, showing that membrane depolarization and inhibition of the Na, K‐ATPase system were not involved in the contractile action of vanadate.
Pretreatment of tracheal smooth muscle with verapamil had no influence on contractions elicited by vanadate. After removal of extracellular calcium, vanadate‐induced contractions declined slowly with time, indicating that influx of extracellular calcium was not giving rise to contractions elicited by vanadate.
Vanadate markedly increased the rate of calcium efflux from trachealis muscle loaded with 45Ca into both Ca2+‐free and normal Krebs solutions; this is compatible with vanadate mobilizing an intracellular store of Ca2+. Such a store involving sites with Ca‐ATPase activity would be consistent with the action of vanadate in isolated membrane preparations.
Membrane‐skinned tracheal fibres contracted by micromolar Ca2+ were relaxed by vanadate in a reversible dose‐related manner, indicating that the contractile action of vanadate was not related to its interaction with proteins at the cross‐bridge level.
Stimulation of endothelial prostacyclin production plays no role in endothelium‐dependent relaxation of the pig aorta
Authors: Gordon John L. , Martin William 
Published: July 2012

Stimulation of prostacyclin production by pig aortic endothelial cells adhering to microcarrier beads supervised in columns, or 3H release from cells prelabelled with [3H]‐arachidonate, was studied in response to a range of agents that induce endothelium‐dependent vascular relaxation.
Bradykinin, adenosine triphosphate (ATP) and ionophore A23187 each stimulated release of prostacyclin from unlabelled cells and of 3H from prelabelled cells but acetylcholine did not.
Bradykinin induced a parallel, dose‐dependent increase in 3H release and 86Rb efflux, measured simultaneously from columns of aortic endothelial cells preloaded with 86Rb and [3H]‐arachidonate.
The rank‐order of effectiveness at inducing both 3H and 86Rb release, measured simultaneously from columns of aortic endothelial cells prelabelled with 86Rb and [3H]‐arachidonate and challenged with maximal doses of each agonist, was: A23187 > bradykinin > ATP.
The similarity between agonist‐induced 3H release (from cells prelabelled with [3H]‐arachidonate) and 86Rb efflux indicates that a common mechanism may be responsible, and the effectiveness of ionophore A23187 suggests that a rise in the intracellular level of calcium may be involved.
The lack of effect of acetylcholine on release of prostacyclin from unlabelled cells or of 3H from cells prelabelled with [3H]‐arachidonate provides further evidence that acetylcholine acts on endothelial cells by a mechanism that does not involve calcium mobilisation.
Although bradykinin, ATP and ionophore A23187 each induced release of prostacyclin from aortic endothelial cells, prostacyclin did not relax the pig aorta. Furthermore, endothelium‐dependent relaxation was unaffected by pretreating aortic strips with aspirin. It therefore appears that neither prostacyclin nor any other cyclo‐oxygenase product mediates endothelium‐dependent relaxation of the pig aorta.
The effect of p‐chloromercuribenzoate on structure‐binding relationships of muscarinic receptors in the rat cerebral cortex
Authors: Birdsall N.J.M. , Burgen A.S.V. , Hulme E.C. , Wong E.H.F. 
Published: July 2012

Muscarinic receptors in the rat cerebral cortex, reacted with p‐chloromercuribenzoate (PCMB) under different conditions (Phase I and II), have modified binding sites.
These exhibit remarkable changes in the structural dependence of the binding of drugs.
In Phase I, the structure‐binding profile of agonists for both the high and low affinity agonist sites are altered.
In Phase II, the structure‐binding profile of antagonists is also observed.
In Phase II, the ability of potent agonists to discriminate between sub‐classes of agonist binding sites is eliminated. There is also a loss of heterogeneity in the binding of the selective antagonist pirenzepine.
Of the 16 agonists examined, only pilocarpine has a heterogeneous binding profile in Phase II, the dispersity of binding being increased.
The changes in binding properties of the receptors are discussed in terms of general theories of drug‐receptor interactions.
Dual effect of (−)‐N6‐phenylisopropyl adenosine on guinea‐pig trachea
Authors: Caparrotta L. , Cillo F. , Fassina G. , Gaion R.M. 
Published: July 2012

The effect of (−)‐N6‐phenylisopropyl adenosine (PIA), a metabolically stable P1‐receptor agonist, was investigated on guinea‐pig isolated trachea.
PIA showed two opposite effects: contraction, evident at low concentrations (10−7 to 2–5 × 10−6m), and relaxation at higher doses.
Relaxation by PIA was antagonized in an apparently competitive manner by two antagonists of extracellular (P1) adenosine receptors: theophylline (Theo) and 8‐phenyltheophylline (PT).
Contraction by PIA was not inhibited by methylxanthines and was not mediated by stimulation of cholinergic or histaminergic systems.
Inhibitors of arachidonic acid cascade acting at different levels, i.e. indomethacin, nordihyd‐roguaiaretic acid (NDGA) and BW755C, all inhibited the contraction by PIA, while they potentiated the relaxation in a concentration‐dependent manner. Mepacrine, an inhibitor of phospholipase A2, inhibited the contraction by PIA, but did not affect the relaxation.
These results indicate that the contractile effect induced by PIA is supported by an indirect mechanism involving the release of arachidonic acid derivatives (via P2‐purinoceptor?). Thus the balance between the two opposite effects of adenosine on tracheal tone is possibly modulated by the prostaglandin turnover.
The role of accelerated colonic transit in prostaglandin‐induced diarrhoea and its inhibition by prostacyclin
Authors: Rush Bob D. , Ruwart Mary J. 
Published: July 2012

Rats treated with subcutaneous 16,16‐dimethyl prostaglandin E2 (16,16‐dimethyl PGE2, 100 μg kg−1) exhibited diarrhoea even when their ileo‐caecal junctions were tied, thereby eliminating contributions from small intestinal transit or fluid accumulation (enteropooling).
The origin of the watery stool appeared to be the caecum, since tying the caecal‐colonic junction eliminated it.
The acceleration of colonic transit is likely to be a primary mechanism of PGE2‐induced diarrhoea in the rat, since both normal animals and those with tied ileo‐caecal junctions exhibited almost the same incidence of diarrhoea.
Subcutaneous prostacyclin (PGI2) (2 mg kg−1 every 60 min) suppressed 16, 16‐dimethyl PGE2‐induced diarrhoea in normal rats and in those with tied ileo‐caecal junctions.
Colonic transit measured in rats with cannula preimplanted in their proximal colon indicated that 16, 16‐dimethyl PGE2 enhanced colonic transit and PGI2 suppressed this increase. Thus, PGI2 can inhibit diarrhoea in the rat caused by 16, 16‐dimethyl PGE2 by suppressing colonic transit exclusive of its effects on small intestinal transit and enteropooling.
The effects of verapamil, prenylamine, flunarizine and cinnarizine on coronary artery occlusion‐induced arrhythmias in anaesthetized rats
Authors: Fagbemi O. , Kane K.A. , McDonald F.M. , Parratt J.R. , Rothaul A.L. 
Published: July 2012

In male rats, anaesthetized with pentobarbitone, ligation of the main left coronary artery causes an early phase of ventricular arrhythmias which last about 30 min. In approximately 60% of control animals, ventricular fibrillation occurs but since spontaneous reversion to sinus rhythm may occur, mortality is of the order of 30%.
When administered intravenously 15 min prior to ligation, verapamil (0.01 and 0.05 mg kg−1), prenylamine (0.5 mg kg−1), flunarizine (0.1, 0.25, 0.5 and 1.0 mg kg−1) and cinnarizine (0.25, 0.5 and 1.0 mg kg−1) protected against these arrhythmias.
Higher doses of verapamil (0.1 and 0.5 mg kg−1), prenylamine (5 mg kg−1) and flunarizine (2.5 mg kg−1) did not afford a similar protection and mortality was increased to or above control values. Death was due in prenylamine‐treated rats to atrioventricular block leading to asystole whereas in those administered verapamil or flunarizine it was a consequence of persistent ventricular fibrillation.
Prior to ligation, a sustained fall in mean arterial blood pressure was observed only following the administration of the highest doses of prenylamine, flunarizine and cinnarizine. Heart rate was reduced by administration of only the highest dose of prenylamine.
These studies show that although the four calcium antagonists studied, i.e. verapamil, prenylamine, flunarizine and cinnarizine do suppress ischaemia‐induced arrhythmias, this protective effect may be limited to a narrow concentration range.
Leukotriene B4‐like material in scale of psoriatic skin lesions
Authors: Brain S.D. , Camp R.D.R. , Cunningham F.M. , Dowd P.M. , Greaves M.W. , Black A. Kobza 
Published: July 2012

Acidic lipid extracts of scale from the lesions of the skin disease, psoriasis, were purified by straight phase high performance liquid chromatography (h.p.l.c). Assay of fractions by an agarose microdroplet chemokinesis method showed the presence of biologically active material that co‐eluted with standard leukotriene B4 (LTB4).
LTB4‐like chemokinetic activity was also detected in fractions collected on reversed phase h.p.l.c. of psoriatic scale extracts that were initially purified by straight phase h.p.l.c.
No LTB4‐like activity was detected after similar purification of scale obtained by abrasion of large areas of normal skin.
The LTB4‐like material found in extracts of psoriatic scale may play a role in the pathogenesis of the neutrophil infiltrate which characterizes psoriasis.
Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5‐hydroxytryptamine involvement in muscimol's effect
Authors: Romandini Stefano , Samanin Rosario 
Published: July 2012

The effect of morphine (3 mg kg−1 subcutaneously) on tail flick in the tail immersion test was studied in rats which had received a muscimol (100 ng) injection either in the nucleus raphé dorsalis (DR) or medianus (MR).
The levels of 5‐hydroxyindoleacetic acid (5‐HIAA) were measured in the hippocampus and striatum of muscimol‐injected animals.
Muscimol injections in the DR reduced 5‐HIAA concentrations in the striatum but not in hippocampus, whereas in animals which had received muscimol in the MR a selective decrease in hippocampal 5‐HIAA levels was found.
Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR.
An injection of 5,7‐dihydroxytryptamine (6 μg in 3 μl) in the DR did not change the effect of morphine or muscimol.
These findings indicate that muscimol‐sensitive neurones in the DR, which are probably not 5‐hydroxytryptaminergic, are involved in the effect of morphine on tail flick in tail immersion. The muscimol‐sensitive neurones involved in this effect of morphine do not seem to exist in the MR.
Lymphocytes sensitize rat isolated atria to the inotropic and chronotropic effects of sodium arachidonate
Authors: Borda Enri S. , de Bracco María M. , Finiasz Marta , Sterin‐Borda Leonor 
Published: July 2012

Normal human lymphocytes (4 × 105 ml−1) incubated with sodium arachidonate (8 × 10−7m) (NaA‐L) induced a strong enhancement of the tension and frequency of spontaneously beating rat atria. Normal human lymphocytes (L) or NaA alone at 8 × 10−7m did not modify this contractile activity.
Between 2 × 10−6m to 1 × 10−5m NaA alone increased the tension of the atria without effect on the rate. In the presence of L (4 × 105 ml−1) the dose‐response curve to NaA shifted to the left, the potency and the efficiency of NaA were enhanced and the chronotropic action was triggered.
Inhibitors of cyclo‐oxygenase (indomethacin 1 × 10−6m or acetylsalicylic acid (ASA) 1.8 × 10−4m) completely blocked the positive inotropic effect induced by NaA alone. Inhibitors of lipoxygenase/s (nordihidroguaiaretic acid (NDGA) 1 × 10−5m or 5,8,11,14‐eicosatetraynoic acid (ETYA) 1 × 10−7 m did not modify this effect.
Indomethacin and ASA did not block the positive inotropic and chronotropic effects of the lower concentration of NaA‐L and significantly reduced the inotropic effect of the higher ones.
NDGA and ETYA shifted to the right the inotropic and chronotropic dose‐response curve to NaA‐L. FPL‐55712 (1 × 10−7m), the slow reacting substance of anaphylaxis (SRS‐A) antagonist, significantly reduced the overall inotropic and chronotropic effect of NaA‐L.
Direct contact of NaA‐L with the atria was not necessary. Cell‐free supernatants of L exposed to NaA increased the tension and the frequency of beating rat atria.
The stimulatory effect of NaA‐L supernatants did not occur if rat atria had been previously incubated with NDGA 1 × 10−5 m. On the other hand, the generation of stimulatory products from NaA‐L was not prevented by preincubating L with 1 × 10−5 m NDGA. Hence SRS‐A and/or other oxidative metabolites of arachidonic acid were produced by the atria.
These results suggest that NaA‐L react in vitro with spontaneous beating rat atria, inducing inotropic and chronotropic effects. Moreover, the stimulatory action of NaA itself was potentiated by L. These reactions involved a balance between cyclo‐oxygenase and lipoxygenase oxidative products with a central role for SRS‐A.
Antimuscarinic action of quinidine on the heart? A study in myocardial preparations from cat hearts
Authors: Nawrath Hermann , Sack Ulrich , Xian‐Gang Zong 
Published: July 2012

Quinidine exerts anticholinergic effects which have been ascribed to atropine‐like properties of the drug. We have examined the effects of acetylcholine on the force of contraction in isolated heart muscle preparations from cats and compared the inhibitory effects of atropine with those of quinidine.
The effects of acetylcholine were antagonized competitively in the presence of atropine. The Schild‐plot yielded a straight line; the slope was not significantly different from unity.
In the presence of quinidine, the concentration‐response curve of acetylcholine was shifted to the right as with atropine, however, the Schild‐plot yielded a regression line which was not linear; the slope was statistically different from unity.
The negative inotropic response to acetylcholine in cat ventricular heart muscle (revealed in the presence of the phosphodiesterase inhibitor, papaverine) was antagonized by atropine but not influenced by quinidine.
We conclude that the inhibitory action of quinidine on the effects of acetylcholine in atrial heart muscle is not merely antimuscarinic. The antagonistic effects of acetylcholine and quinidine on atrial heart muscle may also be due to the opposite effects of the drugs on potassium conductance of the myocardial cell membrane.
Uptake of [3H]‐nicotine and [3H]‐noradrenaline by cultured chromaffin cells
Authors: Ceña V. , García A.G. , Montiel C. , Sánchez‐García P. 
Published: July 2012

Three day‐old cultured bovine adrenal chromaffin cells incubated at room temperature with Krebs‐HEPES solution containing different concentrations of [3H]‐nicotine, took up and retained increasing amounts of the drug by a mechanism that did not saturate.
Concentrations of cold nicotine as high as 100 μm did not alter the amount of [3H]‐nicotine retained by cells.
Imipramine, cocaine, tetracaine or mecamylamine, at concentrations (10 μm) that blocked the catecholamine secretory effects of nicotine completely, did not modify the uptake of [3H]‐nicotine.
Both imipramine and cocaine drastically inhibited [3H]‐noradrenaline uptake by cells in a concentration‐dependent manner (IC50s of 0.08 and 1 μm, respectively).
These data indicate that the secretory effects of nicotine are not coupled to its previous uptake into cells, and are evidence in favour of a site of action for nicotine located in or at the surface of the chromaffin cell membrane.
The regulation of δ‐opiate receptor density on 108CC15 neuroblastoma × glioma hybrid cells
Authors: Moses Margaret A. , Snell Christopher R. 
Published: July 2012

The effect of exogenous substances on the expression of opiate receptors on 108CC15 neuroblastoma × glioma hybrid cells has been studied.
Cell differentiation by culture in the presence of N6‐O2‐dibutyryl adenosine 3′,5′‐cyclic monophosphate induced a three fold increase in opiate receptor density.
When the cells were grown in the presence of 10−5 m morphine hydrochloride for up to 23 days, opiate receptor densities were reduced by only 30% when compared with matched controls.
Culture in the presence of 10−7md‐Ala2‐d‐Leu5‐enkephalin produced opiate receptor down regulation of 73% compared to controls after only 4 h of treatment.
The down regulation process could be inhibited by continued exposure to d‐Ala2 d‐Leu5‐enkephalin at concentrations greater than 4 nm; below this concentration down regulation was rapid and irreversible.
A model to explain these observations is described.
A new in vivo method for the measurement of repetitive anaphylactic responses in the guinea‐pig
Authors: Bottomley Kevin M.K. , Lewis Stevan , Rising Trevor J. , Steward Alan 
Published: July 2012

The established Konzett‐Rossler bronchorespiratory model has been combined with a unique ovalbumin sensitization procedure to give a novel method to measure anaphylaxis in the anaesthetized guinea‐pig.
Following antigen challenge, up to eight equal bronchoconstrictor responses to the same dose can be generated from a single animal over a 120 min period.
Total inhibition of the anaphylactic response can be elicited by four different classes of compound, namely salbutamol, mepyramine, theophylline and dimaprit. Cromoglycate failed to cause any inhibition.
The method is discussed with particular reference to the antigen sensitization procedure, which differs substantially from other regimens previously employed and gives rise to heat labile antibody.
Mediators of the secretory response to kinins
Authors: Cuthbert A.W. , Halushka P.V. , Margolius H.S. , Spayne J. A. 
Published: July 2012

The output of immunoreactive (i) 6 keto prostaglandin F1α (i6ketoPGF1α), iPGE2 and ithromboxane B2 (iTXB2) from isolated colonic epithelium of the rat into the apical and basolateral bathing solution has been measured. In some instances tissues were also voltage clamped at 0 mV to measure short circuit current (SCC).
Kallidin (lysylbradykinin) stimulated the output of all three eicosanoids, specifically from the basolateral face of the tissue. The output was similar whether or not the tissues were short circuited.
Both the SCC response and eicosanoid output were dependent upon the concentration of kallidin, but not in a strictly proportional manner, there being relatively more eicosanoid output at submaximal kinin concentrations.
Indomethacin, 5 μm, abolished the eicosanoid output, in response to kinin, while some part of the SCC response remained.
Calcium removal from the basolateral bathing fluid severely attenuated the SCC response, reduced the output of i6ketoPGF1α to half, but left the output of iPGE2 unchanged. In the presence or absence of calcium it is probable that sufficient PGE material is released to cause part of the SCC changes seen with kinin.
Kinin and PGE1 increased the cyclic AMP content of intact epithelia, provided a phosphodiesterase inhibitor was added at the same time.
It is proposed that kinin causes an increase in calcium influx at the basolateral pole of the tissue. This calcium is necessary for the production of some eicosanoids and the subsequent generation of cyclic AMP, which then increases apical chloride permeability. In addition, calcium may facilitate entry of chloride through the basolateral face of the cells by activating a cotransport mechanism.
Inhibition of partially purified K/H+ ‐ATPase from guinea‐pig isolated and enriched parietal cells by substituted benzimidazoles
Authors: Beil W. , Sewing K.‐Fr. 
Published: July 2012

The cellular and subcellular distributions of adenosinetriphosphatases (ATPases) were examined in guinea‐pig gastric mucosal cells. All cell types displayed Mg2+‐ATPase and bicarbonate (HCO&3bar;)‐stimulated ATPase activity. K+‐ATPase was located only in fractions derived from parietal cells.
Differential and density‐gradient centrifugation of material prepared from parietal cells revealed that K+‐ATPase activity was located in a tubulo‐vesicular membrane fraction. Enzyme activity was ten fold greater in this fraction than in a crude parietal cell homogenate.
The substituted benzimidazoles, omeprazole and picoprazole, inhibited K+‐ATPase (IC50 1.8 ± 0.5 μmol 1−1 and 3.1 ± 0.4 μmol 1−1, respectively). Detailed kinetic analysis indicated that these compounds were non‐competitive and reversible inhibitors of the enzyme. In contrast cimetidine and verapamil were without effect on the enzyme.
The relevance of the inhibition of K+‐ATPase to the antisecretory activity of the benzimidazoles, in experimental animals and man, is discussed.