bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vagal mechanisms and the effect of indomethacin on bronchoconstrictor stimuli in the guinea‐pig
Authors: Mitchell H.W. , Adcock J. 
Published: July 2012

In urethane‐anaesthetized guinea‐pigs, under spontaneous respiration, indomethacin (1 mg kg−1 i.v., 10–45 min) approximately doubled the bronchoconstrictor effect (increase in airways resistance, Raw) of equieffective doses of histamine and 5‐hydroxytryptamine (5‐HT), but not that of acetylcholine or leukotriene D4 (LTD4).
In mechanically ventilated guinea‐pigs indomethacin increased Raw responses to histamine as well as increasing the fall in dynamic compliance (Cdyn) evoked by this agent.
Cooling the cervical vagi, to temperatures shown to block efferent and probably afferent pathways (∼9°C), abolished the effect of indomethacin on airways responses. Inhibition of indomethacin‐induced hyperreactivity was also observed after vagal section.
Electrical stimulation of the peripheral vagus (1–20 Hz, 0.75–5 ms pulses) increased Raw and decreased Cdyn but these responses were not markedly altered by indomethacin.
It was concluded that the indomethacin‐induced hyperreactivity of tracheal smooth muscle, which was demonstrated in vitro, may not account for the airways hyperreactivity observed in the present in vivo experiments. The hyperreactivity to histamine induced by indomethacin in vivo depends on the functional integrity of vagal reflex pathways.
Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: biochemical assessment in vitro and ex vivo
Authors: Tateson J.E. , Randall R.W. , Reynolds C.H. , Jackson W.P. , Bhattacherjee P. , Salmon J.A. , Garland L.G. 
Published: July 2012

The chemically novel acetohydroxamic acids, BW A4C, BW A137C and BW A797C, are potent inhibitors of the synthesis of leukotriene B4 (LTB4) from arachidonic acid by human leucocyte homogenates: the concentrations required for 50% inhibition (IC50) were 0.1 μm, 0.8 μm and 0.5μm respectively. Inhibition was less at higher concentrations of arachidonic add.
These compounds also inhibited the synthesis of [14C]‐5‐HETE from [14C]‐arachidonic acid and the calcium‐dependent synthesis of LTB4 from 5‐HPETE. This, therefore, suggests that they inhibit 5‐lipoxygenase and LTA4 synthase.
Concentrations of acetohydroxamic acids required to inhibit metabolism of arachidonic acid by cyclo‐oxygenase, 12‐lipoxygenase and 15‐lipoxygenase were 10 to 100 times higher than those required to inhibit 5‐lipoxygenase.
The compounds were potent inhibitors of LTB4 synthesis induced by the ionophore, A23187, in human intact leucocytes. This inhibition was reversed by washing the cells. They were also potent, selective inhibitors of LTB4 synthesis induced by A23187 in whole rat blood: binding to rat plasma proteins did not greatly reduce the effectiveness of the compounds.
The effects of the acetohydroxamic acids, administered either intravenously or orally to rats, on the synthesis of LTB4, and thromboxane B2 (TXB2) in A23187‐stimulated blood ex vivo was studied. The three compounds caused dose‐dependent inhibition of the synthesis of LTB4 but not TXB2. Inhibition of LTB4 synthesis persisted for up to 6 h after a single oral dose of 50 mg kg−1.
The plasma concentrations of unchanged compound determined by h.p.l.c. correlated with the inhibition of LTB4 synthesis ex vivo.
Selective inhibition of arachidonate 5‐lipoxygenase by novel acetohydroxamic acids: effects on acute inflammatory responses
Authors: Higgs G.A. , Follenfant R.L. , Garland L.G. 
Published: July 2012

Two selective inhibitors of arachidonate 5‐lipoxygenase, BW A4C and BW A797C, have been studied for their effects on acute inflammatory responses following oral administration to rats and mice.
The concentrations of the lipoxygenase product leukotriene B4 (LTB4) in 6h inflammatory exudates, induced in rats by the subcutaneous implantation of carrageenin‐soaked polyester sponges, were reduced dose‐dependently by BW A4C (ED50 = 2.6 mg kg−1) or BW A797C (ED50 = 14.3 mg kg−1).
BW A4C and BW A797C had little or no effect on prostaglandin E2 (PGE2) concentrations in inflammatory exudates (ED50S > 100 mg kg−1).
Doses of up to 200 mg kg−1 of either BW A4C or BW A797C had no effect on carrageenin‐induced oedema in rat paws.
BW A4C and BW A797C had little or no effect on carrageenin‐induced hyperalgesia in rats or phenyl‐benzoquinone‐induced writhing in mice.
Yeast‐induced pyrexia in rats was reduced by both BW A4C (ED50 = 32 mg kg−1) and BW A797C (ED50 = 23 mg kg−1).
The accumulation of leucocytes in sponge exudates was reduced dose‐dependently by BW A4C (ED50 = 54 mg kg−1) and BW A797C (ED50 = 16.7 mg kg−1).
The selective lipoxygenase inhibitors BW A4C and BW A797C do not suppress inflammatory oedema or pain although they are anti‐pyretic and they do inhibit leucocyte migration. There is not, however, a close agreement between these in vivo activities and their potencies as lipoxygenase inhibitors.
Pharmacological characterization of muscarinic receptors involved in McN‐A‐343‐induced effects on intestinal motility and heart rate in conscious dogs
Authors: Schiavone A. , Sagrada A. , Micheletti R. , Giachetti A. 
Published: July 2012

Intravenous injection of the muscarinic agonist, McN‐A‐343, in conscious dogs equipped with an ileal Thiry fistula produced a dose‐related inhibition of intestinal phasic contractile activity, and an increase in heart rate.
The inhibitory action of McN‐A‐343 on motility was antagonized with different potencies by antimuscarinic drugs. The non‐selective drug, N‐methylatropine, blocked the McN‐A‐343 effect as well as the reflex phasic activity. The M1‐selective compound, pirenzepine (1–30 μg kg−1), was a potent antagonist of the McN‐A‐343 effect, whereas the cardioselective M2‐antagonist, AF‐DX 116, and the smooth muscle selective compound, 4‐diphenylacetoxy‐N‐methyl piperidine (4‐DAMP), were completely ineffective at the doses tested.
The McN‐A‐343‐induced inhibition of intestinal motility was blocked by locally applied lignocaine, suggesting the involvement of a neural inhibitory pathway. The resistance to hexamethonium and (α1‐, α2‐ β−) adrenoceptor blocking drugs excluded transmission through a nicotinic synapse or release of catecholamines.
McN‐A‐343‐induced tachycardia was also the result of muscarinic receptor activation. It was very sensitive to antagonism by 4‐DAMP, while being completely unaffected by AF‐DX 116. Pirenzepine displayed an intermediate profile, reducing tachycardia at doses fully active in reversing the agonist‐mediated effect on intestinal motility. Propranolol partially reduced McN‐A‐343 tachycardia, suggesting catecholamine release.
The two McN‐A‐343 effects investigated in the present study appear to be mediated by different muscarinic receptor subtypes. While the inhibitory action on intestinal motility results from stimulation of M1‐muscarinic receptors, the tachycardia is mediated by receptors blocked selectively by 4‐DAMP.
Effect of atenolol and pindolol on the phorbol ester‐induced coronary vasoconstriction in the isolated perfused heart of the rat
Authors: Ruskoaho Heikki 
Published: July 2012

The effects of atenolol (β1‐adrenoceptor antagonist without partial agonistic activity) and pindolol (β1 and β2‐antagonist with partial agonistic activity) were studied on basal coronary vascular tone and on the phorbol ester‐induced coronary vasoconstriction in the rat perfused heart.
The addition of the phorbol ester 12‐0‐tetradecanoyl‐phorbol‐13‐acetate (TPA; 1.8 × 10−8‐1.6 × 10−7 m) into the perfusion fluid during perfusion of rat heart at constant flow caused a dose‐dependent, sustained increase in perfusion pressure. The vasoconstrictor response in hearts of reserpine‐treated rats to infusion of TPA was similar to that of non‐reserpine treated hearts.
Infusion of a calcium channel agonist Bay K 8644 at a concentration of 4 × 10−7m enhanced, whereas isoprenaline (1 × 10−5m), dibuturyl‐cyclic AMP (1.6 × 10−4m) and forskolin (1 × 10−6m), which elevate intracellular concentrations of cyclic AMP, all inhibited the coronary vasoconstriction induced by TPA.
Pindolol, in doses which produced comparable inhibition of isoprenaline‐induced tachycardia, dose‐dependently attenuated the phorbol ester‐induced increase in perfusion pressure, whereas atenolol had no effect. The inhibitory action of pindolol (2 × 10−5m) on TPA‐induced vasoconstriction was blocked by addition of 2.2 × 10−5 propranolol into the perfusion fluid. When infused alone, atenolol (2 × 10−4 m) significantly increased coronary vascular tone, but pindolol had no effect.
The present results indicate that pindolol has coronary vasodilator properties due to stimulation of vascular β‐adrenoceptors. If stenosis dilatation of coronary artery spasm is an important component of the anti‐anginal effect of β‐blocking drugs, the possession of partial agonistic property by a β‐blocking drug may be of importance in maintaining coronary flow.
Effect of adenosine on the formation of prostacyclin in the rabbit isolated heart
Authors: Karwatowska‐Prokopczuk Ewa , Ciabattoni Giovanni , Wennmalm Åke 
Published: July 2012

The effect of adenosine on cardiac biosynthesis of prostacyclin (PGI2) was investigated. Rabbit hearts were perfused according to Langendorff at controlled pressure (with or without theophylline), or at controlled flow. The content of 6‐keto‐prostaglandinlflt (6‐keto‐PGF1α, metabolite of PGI2) in the coronary effluent under basal conditions and during infusion of adenosine was determined using a highly specific radioimmunoassay.
In other experiments, rings of rabbit aorta were incubated with or without adenosine and the production of 6‐keto‐PGF1α was analysed as above.
Administration of adenosine (10 μm) to hearts perfused at controlled pressure increased the coronary flow by up to 38%. The peak concentration of 6‐keto‐PGF1α in the effluent exceeded the control by 177% (P < 0.01), and the total efflux of 6‐keto‐PGF1α exceeded the control by 179% (P < 0.001). Theophylline (50 μm) reduced these effects of adenosine by 23%, 43% and 51%, respectively, without influencing the uptake of adenosine into the heart.
When adenosine (1–10 μm) was administered to hearts perfused at controlled flow, a dose‐dependent decrease in the perfusion pressure, by 27% and 44% respectively, was observed. In parallel, the resulting increase in 6‐keto‐PGF1α efflux was considerably lower (49% (P < 0.05) and 43% (NS), respectively). A similar decrease in perfusion pressure induced in the absence of adenosine decreased the efflux of 6‐keto‐PGF1α, by 15% (P < 0.01) and 32% (P < 0.001), respectively.
Addition of adenosine (1–10 μm) to incubates of rabbit aortic rings did not significantly affect the concentration of 6‐keto‐PGF1α in the incubation medium in comparison with control.
We conclude that adenosine stimulates rabbit heart PGI2 formation, mainly by an action related to the vasodilator effect of the nucleoside.
Adenosine 3′,5′‐cyclic monophosphate‐mediated enhancement of calcium‐evoked prolactin release from electrically permeabilised 7315c tumour cells
Authors: Guild Simon , Frey Elisabeth A. , Pocotte Susan L. , Kebabian John W. 
Published: July 2012

The 7315c tumour cell was used as a model system for the investigation of adenosine 3′,5′‐cyclic monophosphate (cyclic AMP)‐mediated enhancement of calcium‐evoked prolactin release.
7315c cells were permeabilised by subjecting the cells to intense electric fields. Studies investigating the penetration of the dye ethidium bromide indicated that the cells were completely permeabilised after 2 discharges of 2000 volts and that the pores remained open for at least 30 min before beginning to reseal. These permeabilisation parameters were consistent with those which gave maximal calcium‐stimulated prolactin release.
In the absence of calcium and in the presence of EGTA (1 mm), permeabilised 7315c cells secreted prolactin at a rate of 0.23 ng min−1 per 106 cells. When EGTA was replaced by 1.5 mM calcium, permeabilised cells secreted prolactin at a rate of 2.20 ± 0.30 ng min−1 per 106 cells in the first 5 min of exposure. Maximal calcium‐dependent prolactin secretion from permeabilised cells occurred at 37°C.
The amount of prolactin secreted, in a 5 min incubation at 37°C, from permeabilised cells depended upon the free calcium concentration in the permeabilisation medium. Calcium stimulated prolactin release from permeabilised cells in the concentration range 0.1–10 μm (half maximal = 5.8 μm). When permeabilised cells were exposed to cyclic AMP (100 μm) for 5 min prior to and during a 5 min challenge with various concentrations of calcium, the amount of prolactin secreted at each effective concentration of calcium was increased. However, cyclic AMP did not alter the potency of calcium as a stimulant of prolactin secretion.
The results suggest that cyclic AMP potentiates calcium‐evoked secretion from 7315c cells, not by increasing the entry of calcium into the cytosol, but at a step in the secretory process, distal to calcium entry, which modulates the ability of an increase in cytosolic calcium concentration to stimulate prolactin release.
Age and the antihypertensive effect of aspirin in rats
Authors: Tuttle Richard S. , Yager Janice , Northrup Nicole 
Published: July 2012

We previously showed that chronic exposure to aspirin (100 mg kg−1 daily, by mouth) is effective in preventing the onset of hypertension in young (28–84 day old) spontaneously hypertensive rats (SHRs). This is contrary to what others have reported using older SHRs.
Renal prostaglandin F2α was also reduced in young SHRs and Wistar‐Okamoto strain rats (WKYs) exposed to aspirin.
In the present study we extended the period of aspirin treatment in young rats to beyond 84 days of age. We found that aspirin lost its antihypertensive effect in SHR and WKY rats at 110 ± 7 days of age regardless of whether the exposure to aspirin had begun at age 28, 49 or 87 days.
We conclude that the loss of antihypertensive effect of aspirin in the SHR and in older WKY rats, is determined by some factor(s) probably not related to prostaglandin F2α, which reaches full expression in the 110 ± 7 day old rat, or is fully dissipated at this age.
The anti‐PGF2α activity of aspirin in the SHR and WKY rat was short‐lived and apparently unrelated in time to the antihypertensive effect of aspirin.
The release of prostaglandin D2 from human skin in vivo and in vitro during immediate allergic reactions
Authors: Barr R.M. , Koro O. , Francis D.M. , Black A. Kobza , Numata T. , Greaves M.W. 
Published: July 2012

The release of prostaglandin D2 (PGD2) during immediate allergic reactions in human skin was investigated in vivo and in vitro.
Skin exudates were collected from abraded sites on the thigh of atopic subjects sensitive to D. pteronyssinus antigen and from non‐atopic control subjects. Challenge with antigen caused the release of PGD2 and histamine, but not PGE2, from the skin of the atopic subjects. The molar ratio of histamine to PGD2 was about 140:1. Control subjects were unresponsive.
PGD2 was released from passively sensitized human skin challenged with antigen in vitro. The time course was similar in vitro and in vivo. The ratio of histamine to PGD2 in vitro was 78:1.
The identities of the prostaglandins were confirmed by high performance liquid chromatography and radioimmunoassay to PGD2 and PGE2.
PGD2 is the major arachidonic acid cyclo‐oxygenase product synthesized by human mast cells. It is pro‐inflammatory in human skin but its functions as a mediator in immediate hypersensitivity reactions in human skin are not clear. The results of this study suggest that, relative to histamine, PGD2 contributes little to the oedema and erythema of immediate reactions in human skin.
[3H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine, a quaternary radioligand for the histamine H1‐receptor
Authors: Treherne J.M. , Young J.M. 
Published: July 2012

A series of derivatives of 4‐methyldiphenhydramine have been examined as potential quaternary radioligands for the histamine H1‐receptor.
[3H]‐(+)‐N‐methyl‐4‐methyldiphenhydramine ([3H]‐QMDP), 83 Ci mmol−1, was synthesized by methylation of the tertiary analogue and purified by high‐voltage electrophoresis.
[3H]‐QMDP bound to H1‐receptors in a washed homogenate from guinea‐pig cerebellum with an affinity constant, Ka, of 1.14 ± 0.03 × 109 M−1. The proportion of non‐specific binding of 0.3–0.6 nM [3H]‐QMDP, defined by 0.4 μm mepyramine, was usually in the range 15–45%, depending on the method of measurement of binding. The affinity of [3H]‐QMDP was similar in guinea‐pig cerebellum, cerebral cortex and hippocampus, but was lower, 1.4 × 108 M−1, in rat cerebral cortex.
Evidence was obtained for the presence of a secondary, non‐muscarinic, binding site for [3H]‐QMDP in guinea‐pig cerebellum, approximate Ka 1.5 × 107M−1, accounting for circa 4% of the total binding of 1 nM [3H]‐QMDP.
There was a very good correlation between the affinities of 15 compounds for the H1‐receptor determined from inhibition of [3H]‐QMDP binding and from inhibition of [3H]‐mepyramine binding.
The potential utility of [3H]‐QMDP for studies of H1‐receptors in the plasma membrane of cells in culture is discussed.
Potassium channel blocking actions of β‐bungarotoxin and related toxins on mouse and frog motor nerve terminals
Authors: Rowan E.G. , Harvey A.L. 
Published: July 2012

β‐Bungarotoxin and other snake toxins with phospholipase activity augment acetylcholine release evoked from mouse motor nerve terminals before they produce blockade. This action of the toxins is independent of their phospholipase A2 activity, but the underlying mechanism for the facilitation of release is unclear. To determine whether the toxins affect ionic currents at motor nerve terminals, extracellular recordings were made from perineural sheaths of motor nerves innervating mouse triangularis sterni muscles.
Perineural waveforms had a characteristic shape, with two major negative deflections, the first being associated with nodal Na+ currents and the second with terminal K+ currents. Block of the K+ currents revealed a Ca2+‐dependent component.
During the facilitatory phase of its action, β‐bungarotoxin (150 nm) reduced the second negative component of the perineural waveform by 30–50%.
The reduction could be a consequence of a decreased K+ ion contribution or of an increase in the current carried by Ca2+. As β‐bungarotoxin had similar effects in solutions which contained no added Ca2+, it is unlikely to be acting on the Ca2+ current. Also, it is unlikely to be blocking the Ca2+‐activated K+ current, which is suppressed in zero Ca2+ conditions.
Other prejunctionally active snake toxins (taipoxin, notexin and crotoxin) had similar effects to those of β‐bungarotoxin, but a similar basic phospholipase of low toxicity from cobra venom had no effect.
Thus, β‐bungarotoxin and related toxins block a fraction of the K+ current in the motor nerve terminals of mouse preparations. Such an effect could explain the facilitation of acetylcholine release caused by these toxins before the onset of presynaptic blockade.
In frog cutaneous pectoris preparations, β‐bungarotoxin reduced endplate potential amplitude but had little effect on perineural waveforms. Therefore, the consequences of toxin binding must be different in frog terminals.
Interactions of benztropine, atropine and ketamine with veratridine‐activated sodium channels: effects on membrane depolarization, K+‐efflux and neutrotransmitter amino acid release
Authors: Erecińska Maria , Nelson David , Silver Ian A. 
Published: July 2012

The effect of benztropine, atropine and ketamine on veratridine‐induced efflux of K+, membrane depolarization and release of amino acid neurotransmitters was investigated in the preparation of rat brain synaptosomes.
All three drugs inhibited in a concentration‐dependent manner the processes measured: the most effective compound was benztropine which exhibited an approximate Kd of 2 μm. The inhibition was not competitive in nature.
The veratridine titration curves in the presence of drugs were sigmoid with Hill coefficients of about 1.4.
At higher concentrations, benztropine, atropine and ketamine blocked uptake of amino acid neurotransmitters into synaptosomes.
It is postulated that benztropine, atropine and ketamine interfere with the veratridine‐activated influx of sodium into synaptosomes through voltage‐dependent channels by acting at the same site as local anaesthetics. Interactions at this site alter allosterically binding and action of veratridine. In addition, at higher concentrations the drugs interact with the carrier proteins for amino acid neurotransmitters and block their transport.
Short‐term desensitization of guinea‐pig taenia caecum induced by carbachol occurs at intracellular Ca stores and that by histamine at H1‐receptors
Authors: Hishinuma Shigeru , Uchida Masaatsu K. 
Published: July 2012

In Ca‐free solution, the contractile response of guinea‐pig taenia caecum to 10−4 m carbachol was mediated through muscarinic receptors and was reduced time‐dependently by desensitization with 10−4 m carbachol, but not 10−4 m histamine. On the other hand, the response to 10−4 m histamine was shown to be mediated through H1‐receptors and to be reduced time‐dependently by desensitization with either 10−4 m histamine or 10−4 m carbachol.
The maximal K+ contraction was not changed by desensitization with carbachol or histamine. Thus, contractile proteins and voltage‐dependent Ca channels maintain their normal functions.
To study the coupling of Ca channel activity in cell surface membrane to receptor activation, the contractile responses elicited by carbachol and histamine added simultaneously with Ca to Ca‐free solution were measured. The response elicited by carbachol plus Ca was not changed by desensitization with carbachol, while that elicited by histamine plus Ca was reduced by desensitization with histamine. These results show that desensitization by carbachol occurs at a post‐receptor site, whereas that induced by histamine occurs at H1‐receptors.
After desensitization with carbachol, but not histamine, the contractile response to 5 × 10−2 m caffeine in Ca‐free solution was significantly reduced.
These results show that short‐term desensitization of guinea‐pig taenia caecum by carbachol is heterologous and occurs at intracellular Ca stores, while that induced by histamine is homologous and occurs at histamine H1‐receptors.
Analysis of the stimulative effect of thapsigargin, a non‐TPA‐type tumour promoter, on arachidonic acid metabolism in rat peritoneal macrophages
Authors: Ohuchi Kazuo , Sugawara Tadaki , Watanabe Masako , Hirasawa Noriyasu , Tsurufuji Susumu , Fujiki Hirota , Christensen S. Brøgger , Sugimura Takashi 
Published: July 2012

At concentrations above 10 ng ml−1, the tumour promoter thapsigargin stimulates the release of radioactivity from [3H]‐arachidonic acid‐labelled macrophages harvested from rat peritoneal cavity.
The release of radioactivity from prelabelled macrophages was augmented more than additively when the cells were incubated in the medium containing both thapsigargin (10 ng ml−1) and other tumour promoters (10 ng ml−1), such as 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA), teleocidin and aplysiatoxin.
Thapsigargin required extracellular Ca2+ for the stimulation of arachidonic acid release, while TPA did not.
Cytoplasmic free calcium level was increased by thapsigargin treatment but not by TPA treatment.
An inhibitor of protein kinases, H‐7 inhibited the effect of TPA dose‐dependently, whereas H‐7 did not inhibit that of thapsigargin.
These results suggest that thapsigargin stimulates arachidonic acid release by a mechanism different from that of TPA, viz by acting as a selective Ca2+ mobilizer, but not by activating protein kinase C as TPA does.