bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence against the formation of 13,14‐dihydro‐15‐keto‐prostaglandin F2α following inhalation of prostaglandin D2 in man
Authors: Hardy Christopher C. , Holgate Stephen T. , Robinson Clive 
Published: July 2012

There is evidence that an important step in the metabolism of prostaglandin D2 (PGD2) involves 11‐keto‐reduction and that such a conversion might account for the reported increase in plasma concentrations of 13,14‐dihydro‐15‐keto‐PGF2α in allergic asthmatic subjects challenged with inhaled allergen.
Plasma concentrations of immunoreactive 13,14‐dihydro‐15‐keto‐PGF2α were measured by specific radioimmunoassay both before and after inhalation of PGD2 and PGF2α in 7 normal and 7 asthmatic men.
In both groups of subjects, PGF2α produced an approximate two fold increase in plasma concentrations of 13,14‐dihydro‐15‐keto‐PGF2α that was maximal 5–7 min after inhalation. There was no significant difference in response between the normal and asthmatic subjects.
In contrast, PGD2 failed to produce a change in plasma 13,14‐dihydro‐15‐keto‐PGF2α concentration in either group.
These results provide evidence that the conversion of PGD2 to PGF2α with subsequent metabolism to 13,14‐dihydro‐15‐keto‐PGF2α is unlikely to occur when PGD2 is released from mast cells in the airways.
Mechanisms of intrinsic tone in bullfrog lung: relaxant effects of indomethacin, ouabain and potassium
Authors: Downes Hall , Edelstein Robert A. , Taylor Stephen M. 
Published: July 2012

Bullfrog hemilungs showed minimal relaxation (9 ± 2% of the maximal relaxant effect of theophylline, Imax) after a 16 h incubation in 10−5 M indomethacin, indicating that prostaglandin synthesis plays little or no role in the high intrinsic tone characteristic of this preparation.
A higher concentration of indomethacin (10−4 M) produced greater relaxation (23 ± 3% of Imax), but also markedly potentiated isoprenaline‐induced relaxation. The interaction with isoprenaline was similar to that previously found for papaverine, a phosphodiesterase inhibitor.
Ouabain (10−5 and 10−4 M) produced an initial contraction followed by marked relaxation (50% of Imax), indicating that a ouabain‐sensitive mechanism is of major importance in the maintenance of intrinsic tone.
Ouabain‐treated hemilungs showed (a) reversal (relaxation) of the normal contractile response to 26 mM potassium and (b) marked impairment of the contractile response to calcium in calcium‐depleted preparations. These effects suggest that ouabain‐induced relaxation reflects a drug action on calcium movements.
The marked relaxation (30 to 40% of Imax) produced by 26 mM potassium in ouabain‐treated hemilungs is of particular interest in that it indicates a mechanism of potassium‐induced relaxation distinct from stimulation of sodium‐potassium ATPase.
Acetylcholine output and foetal vascular resistance of human perfused placental cotyleda
Authors: Bourn A.L.A. , Gude N.M. , King R.G. , Walters W.A.W. 
Published: July 2012

The foetal villous vessels of single cotyleda of human placentae have been perfused with a constant flow of Krebs solution, recording inflow pressure and passing the venous perfusate in cascade over guinea‐pig ileum and rat stomach strip preparations in vitro.
Each cotyledon released for at least 4 h a substance that was probably acetylcholine. The perfusate caused contractions of both preparations which were inhibited by atropine or hyoscine and potentiated by physostigmine. Contractile activity was destroyed after incubation at 37°C of perfusate with acetylcholinesterase but not with acetylcholinesterase plus physostigmine.
When the perfusion temperature was lowered to 34°C or below, acetylcholine output was reduced, the extent depending on the fall in temperature.
No change in resistance of the villous vessels occurred during the changes in temperature or in the presence at 37°C of atropine, hyoscine, hexamethonium, (+)‐tubocurarine, hemicholinium‐3 or bretylium.
Submaximal vasoconstrictor responses of the villous vessels to the thromboxane A2‐mimetic U46619 were not affected by reduction of the perfusion temperature to 30°C, which lowered acetylcholine‐like output by approximately 70%. Responses to U46619, at 37°C, were unchanged during the presence of atropine or hyoscine.
Acetylcholine is released into the foetal circulation of the human placenta but no evidence could be obtained that it affects villous vascular smooth muscle tone or vasoconstrictor responses.
Morphine attenuates cholinergic nerve activity in human isolated colonic muscle
Authors: Burleigh David E. , Trout Stephen J. 
Published: July 2012

The action of morphine on cholinergic nerves in human sigmoid taenia coli muscle strips (taenia) was investigated using a radiolabelling technique.
Basal release of tritiated material from taenia was increased by electrical field stimulation (EFS). This increase was tetrodotoxin (3.14 μM)‐sensitive and calcium‐dependent. Analysis of basal and stimulated release of tritiated material indicated that evoked release (i.e. stimulated minus basal) is almost entirely due to an increase in [3H]‐acetylcholine ([3H]‐ACh) output.
Evoked release of [3H]‐ACh was dependent on the current strength and could be greatly reduced by exposing taenia to hemicholinium (34.8, 87.0 μM) before and during incubation with [3H]‐choline (4 μCi ml−1, 15 Ci mmol−1).
Spontaneous activity, muscle tone and the motor response of taenia to EFS were unaffected by morphine.
Evoked, but not basal, release of tritiated material was inhibited by morphine (1.32‐13.20 μM) in a concentration‐dependent manner. The inhibition of release was frequency‐dependent and naloxone (0.28 μM)‐sensitive.
The possible relationship between the effects of morphine on cholinergic nerves in taenia muscle and its actions in vivo are discussed.
Binding of a radioiodinated 13‐azapinane thromboxane antagonist to platelets: correlation with antiaggregatory activity in different species
Authors: Narumiya Shuh , Okuma Minoru , Ushikubi Fumitaka 
Published: July 2012

Binding of a 125I‐labelled derivative of the 13‐azapinane thromboxane antagonist (ONO‐11120), [125I]‐9,11‐dimethylmethano‐11,12‐methano‐16‐(3‐iodo‐4‐hydroxyphenyl)‐13,14‐dihydro‐13‐aza‐15‐β‐ω‐tetranor‐thromboxane A2 ([125I]‐PTA‐OH), to washed platelets of human, dog and rabbit was studied. Results were compared with the in vitro inhibitory potency of ONO‐11120 on platelet aggregation induced by arachidonate and a thromboxane agonist, 9,11‐epithio‐11,12‐methanothromboxane A2 (STA2).
[125I]‐PTA‐OH bound to washed human platelets in a reversible, saturable and temperature‐dependent manner, and specific binding displaced by 20 μM ONO‐11120 constituted about 40% of the total binding. Scatchard analyses revealed a single class of specific binding and the equilibrium dissociation constant (KD) and maximal concentration of binding sites (Bmax) were 22 nM and 390 fmol per 108 platelets (about 2,300 sites per platelet), respectively. In addition to ONO‐11120, STA2 and another thromboxane receptor agonist, (15S)‐hydroxy‐11,9‐epoxymethano‐prosta‐5Z,13E‐dienoic acid (U‐46619), effectively displaced the binding with IC50 values of 44 and 125 nM respectively. Prostaglandin D2 (PGD2) partially displaced the binding only at a concentration above 1 μM. PGE1 and thromboxane B2 (TXB2) were without effect up to 100 μM.
Similar binding of [125I]‐PTA‐OH was observed on dog platelets. The KD and Bmax were 12 nM and 110 fmol per 108 platelets (about 680 sites per platelet), respectively, and these values did not change significantly after adrenaline treatment which potentiated arachidonate‐induced aggregation of platelets in this species. On the other hand, no specific binding of [125I]‐PTA‐OH was found on rabbit platelets.
Consistent with the results from binding studies, ONO‐11120, 0.5 μM, completely suppressed arachidonate‐induced aggregation of human platelets, whereas, at concentrations up to 5 μM, this agent did not significantly inhibit aggregation of rabbit platelets induced by the same stimulus. STA2‐induced aggregation of rabbit platelets also showed less sensitivity to ONO‐11120. When a similar extent of irreversible aggregation was induced by STA2 and the inhibitory potency of ONO‐11120 was compared in human and rabbit platelets, about one hundred times greater concentration of ONO‐11120 was required to suppress aggregation of rabbit platelets than that of human platelets.
These results suggest that [125I]‐PTA‐OH binds to a platelet thromboxane receptor, and that the structure of the binding site(s) on the receptor may vary between species.
The sulphoxide moiety of substituted benzimidazoles is essential for inhibition of parietal cell K+/H+‐ATPase
Authors: Beil W. , Eltze M. , Heintze K. , Klemm K. , Riedel R. , Schudt C. , Sewing K.‐Fr. , Simon A. 
Published: July 2012

The antisecretory action of the benzimidazole sulphoxide derivative B 823‐10, 2[(4‐methoxy‐3‐methyl‐2‐pyridylmethyl)‐sulphinyl]‐5‐trifluoromethyl(1H)‐benzimidazole, was compared with the effect of the corresponding sulphide B 823‐08 in several in vivo and in vitro test systems.
The sulphide B 823‐08 and the sulphoxide B 823‐10 were found to be equipotent in the Shay rat. The sulphide was found to inhibit H+ secretion in intact rabbit gastric glands and enriched guinea‐pig parietal cells with lower potency than the corresponding sulphoxide. The relative potency in antisecretory activity (sulphide/sulphoxide) decreased in the following rank order: Shay rat: gastric glands: parietal cells.
Purified K+/H+‐ATPase was not blocked by the sulphide, whereas the sulphoxide inhibited the overall as well as the partial reactions of this enzyme.
In all in vitro systems tested, inhibition of H+ secretion and enzyme activity by the sulphoxide, but not by the sulphide, was antagonized by SH‐compounds such as dithiothreitol.
It is concluded that in vivo sulphoxidation of the sulphide plays an important role in acid inhibition. In vitro an additional inhibitory mechanism of the sulphide has to be considered.
β‐Adrenoceptor‐mediated modulation of calcium ionophore activated polymorphonuclear leucocytes
Authors: Mack James A. , Nielson Christopher P. , Stevens Dennis L. , Vestal Robert E. 
Published: July 2012

β‐Adrenoceptor‐mediated modulation of calcium‐mediated stimulus‐response coupling was studied using calcium ionophore (A23187) activation of polymorphonuclear leucocytes (PMNL). Oxygen metabolite generation was measured with luminol‐ and lucigenin‐dependent chemiluminescence in both whole blood and isolated PMNL.
Isoprenaline reduced PMNL response by 53% in a dose‐dependent fashion. The effect was saturable, stereoselective, antagonized by propranolol and significant at isoprenaline concentrations as low as 0.01 nM. Fifty % maximal response was induced by 0.26 nM, 3 nM, and 125 nM isoprenaline, adrenaline and noradrenaline respectively.
Because the effects of β‐adrenoceptor agonists in PMNL have not consistently correlated with measurements of cyclic AMP, alternative means of increasing cyclic AMP were studied. Forskolin and dibutyryl cyclic AMP inhibited PMNL with significant effects at 1.0 μM and 10 μM respectively.
The effects of β‐adrenoceptor agonists were much greater when PMNL were activated by calcium ionophore compared with opsonized zymosan. Isoprenaline had no effect upon l‐oleoyl‐2‐acetylglycerol activated PMNL.
Because catecholamine modulation of oxygen metabolite generation can be characterized pharmacologically, PMNL activation by calcium ionophore is an excellent model for study of β‐adrenoceptor function in viable human cells.
In contrast to previously described β‐adrenoceptor agonist modulation of PMNL function, inhibition of calcium‐mediated activation is significant at physiological concentrations. The clinical consequences of such catecholamine effects are dependent upon the mechanism of PMNL activation in a specific circumstance.
Apomorphine‐induced inhibition of histamine release in rat peritoneal mast cells
Authors: Battistella Antonio , Boarato Elena , Bruni Alessandro , Mietto Lucia , Palatini Pietro , Toffano Gino 
Published: July 2012

The apomorphine‐induced inhibition of histamine release in rat peritoneal mast cells was studied by means of secretagogues stimulating different pathways of mast cell activation.
Apomorphine inhibited the mast cell response to all releasing agents (lysophosphatidylserine plus nerve growth factor, compound 48/80, substance P, ATP, tetradecanoylphorbolacetate, melittin). The IC50 ranged from 4 μM to 24 μM at concentrations of secretagogues releasing 30–50% of mast cell histamine. However, the potency of the drug decreased at higher segretagogue concentrations.
Mast cells, pretreated with apomorphine and washed, released little histamine upon stimulation. The secretory response could be partially restored on increasing the concentration of secretagogues.
The results suggest that apomorphine affects a regulatory step controlling the terminal sequence of mast cell secretory activity. As indicated by the reduced potency of the drug, the control by the apomorphine‐sensitive reaction loses efficiency under conditions of massive histamine release.
The depolarizing action of 5‐hydroxytryptamine on rabbit vagal afferent and sympathetic neurones in vitro and its selective blockade by ICS 205–930
Authors: Round Alison , Wallis D.I. 
Published: July 2012

Depolarizing responses to 5‐hydroxytryptamine (5‐HT) were recorded from rabbit nodose (NG) and superior cervical (SCG) ganglia using the sucrose‐gap technique. The antagonist potency and selectivity of ICS 205–930 ([3α‐tropanyl]‐1H‐indole‐3‐carboxylic acid ester) were investigated.
In NG, 5‐HT (5 to 80 nmol) evoked depolarizations of graded amplitude. The ED50 was 18.2 (10.9–30.5) nmol (geometric mean, 95% confidence limits). Responses were blocked surmountably by ICS 205–930, 10−11 and 10−10 M, the threshold for blockade being below 10−11 M. Parallel, rightward shifts in dose‐response curves were seen with these concentrations of antagonist, but at higher concentrations (10−9 and 10−8 M) there was a further rightward shift with reduction in slope and maximum of the curves.
In SCG, where 5‐HT (20 to 320 nmol) evoked depolarizations of graded amplitude and the ED50 was 55.8 (22.3–139.6) nmol (geometric mean, 95% confidence limits), ICS 205–930 had a similar inhibitory effect to that observed in NG.
The apparent pA2 values for the surmountable blockade produced by ICS 205–930 at concentrations of 10−11 and 10−10 M were 10.2 ± 0.2 for NG and 10.4 ± 0.1 for SCG (means ± s.e. mean).
ICS 205–930 was selective in its action since it had no effect on dimethylphenylpiperazinium (DMPP) responses in either ganglion or on GABA responses in NG.
This study provides quantitative evidence on the blocking action of ICS 205–930 at neuronal 5‐HT receptors using a technique that allows the depolarizing responses evoked by the amine to be directly recorded.
An investigation into the α‐adrenoceptor mediating renal nerve‐induced calcium reabsorption by the rat kidney
Authors: Johns Edward J. , Manitius Jacek 
Published: July 2012

An investigation was undertaken in pentobarbitone‐anaesthetized rats to determine the sub‐type of α‐adrenoceptor responsible for the renal nerve‐induced increases in the reabsorption of calcium and sodium by the tubules of the kidney.Stimulation of the renal nerves at low frequencies (0.8‐1.5 Hz) did not change either renal blood flow or glomerular filtration rate but significantly reduced urine flow by 32%, calcium excretion by 36% and absolute and fractional sodium excretions by 36% and 22%, respectively.In the presence of the selective α1‐adrenoceptor antagonist prazosin, renal nerve stimulation (2–3 Hz) caused a significant reduction in renal blood flow of 7% but did not change either glomerular filtration rate, urine flow, calcium excretion or absolute and fractional sodium excretions.During administration of the selective α1‐adrenoceptor antagonist, idazoxan, renal nerve stimulation (1.0–1.5 Hz) significantly reduced renal blood flow by 4% and glomerular filtration rate by 7%; at the same time there were significant falls in urine flow of 43%, calcium excretion of 43% and absolute and fractional sodium excretions of 41% and 37%, respectively.These results show that low frequency renal nerve stimulation causes an anticalciuresis, independent of renal haemodynamics, which represents an increase in tubular reabsorption of calcium. This effect was blocked by prazosin but not idazoxan which is consistent with the mediation of α1‐adrenoceptors. The neurally‐induced antinatriuresis also appeared to be dependent on the activation of α1‐adrenoceptors.
Vasoactive intestinal peptide in bovine pulmonary artery: localisation, function and receptor autoradiography
Authors: Barnes Peter J. , Cadieux Alain , Carstairs Jill R. , Greenberg Barry , Polak Julia M. , Rhoden Kerry 
Published: July 2012

The role of vasoactive intestinal peptide (VIP) in the control of pulmonary vascular tone was investigated by functional response, immunocytochemical localisation and receptor autoradiography in bovine pulmonary arteries.
VIP‐immunoreactive nerve fibres were present at the adventitial‐medial junction and in the media of the vessels.
Exposure of precontracted bovine pulmonary artery segments to VIP in vitro resulted in almost complete (86 ± 3%; mean ± s.e.mean) relaxation, the concentration needed for 50% relaxation being 4.47 ± 0.37 × 10−9 M. VIP effects did not depend on the presence of intact endothelial cells.
The distribution of VIP receptors was studied by autoradiography using [125I]‐VIP. A high density of VIP receptors was found in arterial vascular smooth muscle, with a gradient of density from adventitia to luminal surface. There were no receptors on endothelial cells.
These data show that VIP is a potent vasodilator of bovine pulmonary arteries, via direct activation of VIP receptors in vascular smooth muscle. VIP‐immunoreactive nerves may influence pulmonary vascular tone directly and could, therefore, be important in regulating pulmonary blood flow.
Stimulation and suppression of renin release from incubations of rat renal cortex by factors affecting calcium flux
Authors: May Clive N. , Peart W.S. 
Published: July 2012

Inhibition of renin secretion from incubations of rat kidney cortex by angiotensin II (AII), ouabain and K+ depletion, depended on the presence of external Ca2+.
AII inhibition of isoprenaline‐stimulated renin secretion was only partially dependent on external Ca2+.
Ouabain and K+ depletion inhibited isoprenaline‐stimulated renin release but only in the presence of external Ca2+. Since, in Ca2+‐free medium, isoprenaline stimulated renin release when the Na+/K+‐ATPase was blocked, isoprenaline probably does not act through the Na+/K+‐ATPase.
Lanthanum blocked the stimulation of renin release by isoprenaline.
Ethylenediamine tetra‐acetic acid (EDTA) and ethyleneglycol‐bis‐(β‐amino‐ethyl ether) N,N'‐tetra‐acetic acid (EGTA) increased renin secretion to a similar degree in Ca2+‐ and Mg2+‐free buffer. When Mg2+ was present the effect of EGTA, but not EDTA, was considerably reduced.
Verapamil reduced the fall in basal renin secretion in normal but not Ca2+‐free buffer. Verapamil did not block the inhibitory effects of AII or ouabain and did not alter the stimulation of renin secretion by isoprenaline.
Bay K 8644 inhibited renin secretion from cortex incubated in medium containing 15 mM K+ and this was dependent on extracellular Ca2+. In normal buffer (5.9 mM K+) Bay K 8644 increased renin secretion.
The effect of mepyramine and ranitidine on the oestrogen and anti‐oestrogen stimulated rat uterus
Authors: Marshall K. , Senior J. 
Published: July 2012

The aims of this study were to elucidate further the role of histamine in the rat uterotrophic response and to investigate the differences between the oestrogen and the anti‐oestrogen induced uterine responses.
The parameters examined were uterine blood flow (measured by the microsphere technique), uterine wet and dry weights.
17β‐Oestradiol and the anti‐oestrogen, tamoxifen, were used to stimulate the ovariectomised rat uterus and the antihistamines mepyramine (H1) and ranitidine (H2) were employed to modify these responses.
The uterine changes evoked by oestradiol proved to be more susceptible to modification by the antihistamines than the tamoxifen‐stimulated responses.
The results suggest that histamine is involved in the early uterine response to oestradiol but histamine does not appear to play a major role in the uterine response to tamoxifen.
Feline endotoxin shock: effects on tissue histamine and histidine decarboxylase activity
Authors: Parratt James R. , Saleh Samira , Waton N. Graham 
Published: July 2012

Tissue histamine levels as well as specific and non‐specific histidine decarboxylase were examined before and at various times (5 and 10 min) after the intravenous injection of a lethal dose (2 mg kg−1) of E. coli endotoxin in anaesthetized cats.
Histamine levels were increased 5 min after endotoxin, especially in the skin, liver, lung and stomach.
There was evidence, in most of the cats, for a rapid and substantial activation of specific histidine decarboxylase especially in the lungs, liver, heart and gastrointestinal tract 5–10 min after endotoxin administration.
It is suggested that endotoxin induces the local formation of histamine and that this formation and local release may contribute to the pathophysiology of endotoxin shock in this species.
A further search for selective antagonists at M2‐muscarinic receptors
Authors: Barlow R.B. , Shepherd M.K. 
Published: July 2012

In an attempt to obtain more selective antagonists acting at muscarinic M2‐receptors, analogues of 4‐diphenylacetoxy‐N‐methylpiperidine methobromide (4‐DAMP methobromide) have been synthesized. These were tested, along with silabenzhexol, procyclidine, sila‐procyclidine and AFDX‐116, in dose‐ratio experiments with guinea‐pig isolated atria at 30°C and ileum at 30°C and 37°C. The agonist was carbachol and the selectivity was assessed from the difference between log K for receptors in ileum and log K for receptors in atria.
The selectivity was not related to the affinity and some weakly active compounds retained appreciable selectivity but no compound had greater selectivity than 4‐DAMP methobromide or pentamethylene bis‐(4‐diphenylacetoxy‐N‐methylpiperidinium) bromide.
Structure‐activity relations are discussed. There seem to be steric limits to affinity but there are no obvious indications of the structural features associated with selectivity. It is suggested that more selective drugs may be obtained by introducing groups which may reduce affinity.
Stimulation of receptors of γ‐aminobutyric acid modulates the release of cholecystokinin‐like immunoreactivity from slices of rat neostriatum
Authors: Conzelmann Ute , Meyer Dieter K. , Sperk Günter 
Published: July 2012

Slices of rat dorsal neostriatum were incubated in Krebs‐Henseleit medium and the release of cholecystokinin‐like immunoreactivity (CCK‐IR) was induced by veratridine or high concentrations of K+. It was investigated whether drugs which act at receptors for γ‐aminobutyric acid (GABA) affected the release.
The GABAA‐receptor agonists muscimol and isoguvacine enhanced the veratridine‐induced release of CCK‐IR. This effect was abolished by the GABAA‐receptor antagonist, bicuculline. When used alone, bicuculline decreased the release.
The GABAB‐receptor agonist, (‐)‐baclofen, decreased the veratridine‐induced release of CCK‐IR. The stereoisomer (+)‐baclofen, which has low intrinsic activity, had no effect when used alone, but antagonized the effect of (‐)‐baclofen as did δ‐amino‐n‐valeric acid, another antagonist at GABAB‐receptors.
When the release of CCK‐IR was stimulated by K+ (40 mM) in the presence of tetrodotoxin, it was no longer affected by GABAA‐receptor agonists or antagonists. Thus, their sites of action were probably not in the immediate vicinity of the nerve‐endings which release CCK‐IR.
Under these conditions, stimulation of GABAB‐receptors still reduced the release of CCK‐IR. Therefore, it is concluded that these receptors are in the immediate vicinity of or even on the terminals which release CCK‐IR.