bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antagonism of platelet activating factor‐induced chemiluminescence in guinea‐pig peritoneal macrophages in differing states of activation
Authors: Parnham Michael J. , Bittner Christine , Lambrecht Günter 
Published: July 2012

The effects of the platelet activating factor (Paf) antagonists alprazolam, BN 52021, kadsurenone, L 652,731 and SRI 63119 have been studied on Paf‐induced chemiluminescence (CL) of guinea‐pig, C. parvum‐activated peritoneal macrophages in vitro.
All antagonists produced a shift to the right in the dose‐response curve to Paf (0.001–10 μmol l−1). Schild plots for BN 52021, L 652,731, kadsurenone and SRI 63119 were linear, but only for BN 52021 and kadsurenone did the mean slope not differ significantly from unity. Mean pA2 values for BN 52021 and kadsurenone were 6.60 ± 0.05 and 6.41 ± 0.14 (mean + s.e.mean) respectively. Calculation of IC50 values for all antagonists (at 0.1 μmol l−1 Paf) gave an order of potency: L 652731 > kadsurenone ≥ BN 52021 > alprazolam > SRI 63119.
When individual pA2 values for BN 52021 and kadsurenone were plotted against the maximal CL response to Paf of cell suspensions in the absence of antagonist (reflecting the degree of activation of the macrophages by the C. parvum), it was found that the affinity of both antagonists for macrophage Paf receptors remained relatively constant irrespective of the activation state of the cells.
We conclude that activation of guinea‐pig peritoneal macrophages does not account for the increased affinity for macrophage Paf receptors previously observed for kadsurenone. Kadsurenone and BN 52021 presumably bind to a site on Paf receptors which is not affected by the activation process, while alprazolam and SRI 63119 are non‐specific antagonists. The reason for the difference between the competitive nature of kadsurenone and its structural analogue L 652,731 is unclear.
Probucol attenuates the development of aortic atherosclerosis in cholesterol‐fed rabbits
Authors: Daugherty Alan , Zweifel Ben S. , Schonfeld Gustav 
Published: July 2012

Probucol was administered to rabbits fed a cholesterol‐enriched (2% wt/wt) diet to determine potential anti‐atherogenic effects in a preparation in which the disease process is due to elevated plasma concentrations of cholesterol ester‐rich very low density lipoproteins (CER‐VLDL).
Probucol was supplemented to the diet at 1% wt/wt which resulted in plasma concentrations rising steadily to 53 ± 8 μg ml−1 after 14 days, with no significant changes during continued administration. Dietary consumption and body weight gains were comparable in the drug‐treated and control groups during the observation period.
Probucol treatment did not significantly affect plasma concentrations of total cholesterol, unesterified cholesterol, triglycerides or phospholipids.
The concentration of CER‐VLDL in plasma and its physicochemical characteristics were not significantly changed during administration of probucol. CER‐VLDL from both control and probucol‐treated animals was a potent stimulant of the augmentation of the intracellular incorporation of [3H]‐oleate into cholesteryl‐[3H]‐oleate in cultured macrophages.
Despite the lack of effect of probucol on concentrations of plasma lipids and the cell interaction characteristics of CER‐VLDL, administration of the drug markedly decreased the extent of intimal aortic surface area covered by grossly discernible atherosclerotic lesions from 55.6 ± 11.8% to 11.6 ± 1.9% in thoracic sections, and from 49.1 ± 10.2% to 7.2 ± 0.4% in abdominal sections. Furthermore, probucol treatment significantly reduced the deposition of total cholesterol in vascular tissue.
Probucol reduced the extent of aortic atherosclerosis produced by diet‐induced hypercholesterolemia in rabbits. This reduction occurred in the absence of any significant change in the characteristics of plasma lipoproteins that were determined. These results indicate that either there is a role of oxidation in the disease process of this animal model of atherosclerosis or that probucol is acting via a presently undefined mechanism.
Interaction of the Paf antagonist WEB 2086 and its hetrazepine analogues with human platelets and endothelial cells
Authors: Korth R. , Hirafuji M. , Keraly C. Lalau , Delautier D. , Bidault J. , Benveniste J. 
Published: July 2012

Intact platelets and confluent human umbilical vein endothelial cells bound [3H]‐Paf‐acether (platelet activating factor, [3H]‐Paf) at 20°C in the presence of 0.25% (w/v) bovine serum albumin (BSA).
[3H]‐Paf binding to platelets was inhibited in a concentration‐dependent manner by WEB 2086. An excess of WEB 2086 indicated the presence of specific, saturable Paf binding which reached a maximum of 28.3 ± 3.7 fmol [3H]‐Paf per 5 × 107 platelets. In platelets, different hetrazepines (WEB 2098, 2105, but not 2118) also inhibited [3H]‐Paf binding in a concentration‐dependent manner.
WEB 2086 partially displaced platelet‐bound [3H]‐Paf in a concentration‐dependent manner reaching a plateau at 400 nM WEB 2086. No further displacement was observed when WEB 2086 and an excess of unlabelled Paf were added together.
The hetrazepines inhibited platelet aggregation. Platelet aggregation IC50 values correlated well with the IC50 values of the hetrazepines against [3H]‐Paf binding (r2 = 0.99). WEB 2086 shifted the Paf dose‐response curve rightwards in a parallel manner. Tested against platelet aggregation the pA2 obtained for WEB 2086 was 7.9.
WEB 2086 inhibited [3H]‐Paf binding to endothelial cells in a concentration‐dependent manner. WEB 2086 also inhibited the Paf‐mediated cytosolic calcium increase in endothelial cells with an IC50 value of 23.1 ± 10.4 nM as compared with an IC50 of 21.6 ± 10.4 nM WEB 2086 for platelet aggregation.
These results demonstrate an inhibition of [3H]‐Paf binding to platelets and endothelial cells by different hetrazepines, most probably at the Paf receptor level.
Effects of iloprost (ZK 36374) on glutathione status during ischaemia and reperfusion of rabbit isolated hearts
Authors: Ferrari Roberto , Cargnoni Anna , Curello Salvatore , Boffa Giovanni M. , Ceconi Claudio 
Published: July 2012

Reperfusion of rabbit isolated hearts after 60 min of ischaemia resulted in poor recovery of mechanical function, release of creatine Phosphokinase (CPK) and of reduced (GSH) and oxidized (GSSG) glutathione, reduction of mitochondrial superoxide dismutase (Mn SOD) activity and of tissue GSH/GSSG ratio with a shift of cellular thiol redox state toward oxidation, suggesting the occurrence of oxidative stress.
Pretreatment of the isolated heart with the stable prostacyclin analogue (iloprost) at 27 or 270 nM, but not at 2.7 nM, improved the functional recovery of the myocardium, reduced CPK, GSH and GSSG release, maintained Mn SOD activity and attenuated the occurrence of oxidative stress.
This effect of iloprost cannot be explained by a decreased demand or an enhanced delivery of oxygen during ischaemia or by a direct effect on glutathione peroxidase and reductase activity.
Voltage‐dependence of ryanodine‐sensitive component of contraction in A23187‐ and isoprenaline‐treated cardiac muscles
Authors: Kondo Noriaki 
Published: July 2012

The ryanodine‐sensitive component (RSC) of contraction electrically induced in the presence of A23187 (10−6 M) and isoprenaline (5 × 10−8 M) was investigated in guinea‐pig papillary muscles that had been partially depolarized to various membrane potentials by increasing [K+]o, and current and voltage clamp techniques.
Two components of contraction were produced by A23187 and isoprenaline at a stimulation frequency of 0.2 Hz. The early component was sensitive to ryanodine (10−6 M) (corresponding to RSC), while the late component was sensitive to nifedipine (10−6 M).
In the presence of nifedipine, RSCs produced by these drugs were selectively observed. Under these conditions, RSCs were voltage‐dependently inhibited by a reduction in resting potential that was brought about by increasing [K+]o (10–26 mM). The onset of inhibition of RSCs appeared at a resting potential between −75 and −70 mV, and almost complete inhibition was observed at a potential between −55 and −50 mV, indicating that RSCs produced by these drugs have the same voltage‐dependence.
In the absence of nifedipine, this voltage‐dependent inhibition was also observed on the early component of contraction produced by A23187 without affecting the late component.
RSC produced by A23187 was not affected by blocking Na channel activation with tetrodotoxin (6 × 10−6 M).
In current and voltage clamp experiments, this RSC was inhibited by reducing the resting and the holding potentials in much the same way as observed on the preparations depolarized by increasing [K+]o. Such dependence on voltage was not observed with either the slow action potential or the slow Ca inward current.
These results suggest that the dependence of RSC on resting potentials is not due to the changes in the fast Na and the slow Ca inward currents. The present RSC via ryanodine‐sensitive internal Ca release may be mainly triggered by a mechanism different from Ca influx through slow channels.
Baclofen and phaclofen modulate GABA release from slices of rat cerebral cortex and spinal cord but not from retina
Authors: Neal M.J. , Shah M.A. 
Published: July 2012

The effects of (−)‐baclofen, muscimol and phaclofen on endogeneous γ‐aminobutyric acid (GABA) release from rat cortical slices, spinal cord slices and entire retinas were studied.
The spontaneous resting release of GABA from the three tissues was 3 to 6 pmol mg−1 wet wt 10 min−1 Depolarization of cortical slices with KCl (50 mM) (high‐K) produced an 8 fold increase in GABA release but high‐K did not evoke an increased release of GABA from spinal slices or retinas.
When rats were injected with γ‐vinyl‐GABA (250 mg kg−1 i.p.) (GVG) 18 h before death, the tissue GABA stores were increased 3 to 6 fold and high‐K then evoked striking Ca‐dependent releases of GABA from all three tissues. Thus, in subsequent experiments, unless otherwise stated, the nervous tissues were taken from GVG‐treated rats.
(−)‐Baclofen (10 μm) significantly reduced the K‐evoked release of GABA from cortical and spinal slices but retinal release was not affected, even at a concentration of (±)‐baclofen of 1 mM. For cortical slices, the IC50 for baclofen was approximately 5.2 μm The inhibitory effect of baclofen on GABA release from cortical slices also occurred in slices prepared from saline‐injected rats, indicating that GVG treatment did not qualitatively affect the results.
The inhibitory effect of (−)‐baclofen on the K‐evoked release of GABA from cortical and spinal slices was antagonised by phaclofen (500 μm), confirming that baclofen was producing its effects by acting at the GABAB‐receptor.
Phaclofen (500 μm) increased the spontaneous resting release of GABA from cortical slices taken from GVG‐treated rats but not from saline‐injected rats. Phaclofen did not increase GABA release from spinal slices or retinas taken from GVG‐treated rats.
Baclofen (10 μm) significantly reduced the K‐evoked release from cortical slices of glutamate, aspartate, glycine and taurine.
Muscimol (10 μm) and δ‐aminolaevulinic acid (10 μm) had no effect on either the resting or K‐evoked release of GABA from cortical slices prepared from saline‐injected or GVG‐treated rats.
The results obtained with cortical and spinal slices are consistent with the presence of inhibitory GABAB‐autoreceptors. The phaclofen‐induced increase in GABA release from cortical slices taken from GVG‐treated rats, but not from saline‐injected rats, implies that under conditions of high GABA release, considerable feedback inhibition is occurring via activation of the GABAB inhibitory autoreceptors. No evidence was found for GABAB‐autoreceptors on retinal GABAergic amacrine cells or for GABAA‐autoreceptors in cortical slices or spinal cord slices.
Comparative effects of bepridil, its quaternary derivative CERM 11888 and verapamil on caffeine‐induced contracture in ferret hearts
Authors: Leboeuf J. , Leoty C. , Lamar J‐C. , Massingham R. 
Published: July 2012

The effects of bepridil, its quaternary derivative: CERM 11888 (methyl‐pyrrolidinium bromide) (10−7‐10−5 M), and verapamil (10−7‐10−6 M) were compared on caffeine‐induced contracture of isolated ventricular trabeculae of the ferret.
Bepridil diminished the amplitude of contracture in a concentration‐dependent fashion, and this effect was significantly different from that of CERM 11888 which, like verapamil, only reduced the amplitude at the highest concentration used.
Bepridil (10−6 M) significantly shortened the time to peak tension and accelerated the relaxation phase of contracture. This latter effect was different from that of CERM 11888. Verapamil (10−6 M) also tended to accelerate the relaxation phase. At 10−5 m these actions of bepridil on the time to peak and relaxation tended to reverse.
At all concentrations bepridil and verapamil reduced the rate of repriming of contracture and this effect of bedpridil was significantly different from that of its quaternary derivative which only showed a significant effect at 10−5 M.
These results demonstrate a clear intracellular effect of bepridil in the ferret heart. Verapamil and CERM 11888 had only weak intracellular effects even at high concentrations.
Analysis of the results suggests that the main sites of action of bepridil in this model are the sarcoplasmic reticulum and one or two calcium compartments in the sarcolemma.
Effects of verapamil on ischaemia‐induced impairment of ATP‐dependent calcium extrusion in rat heart sarcolemma
Authors: van Amsterdam F. Th. M. , Goddijn M.M. , Haas M. , Punt N.C. , Zaagsma J. 
Published: July 2012

The effects of ischaemia and reperfusion were studied on adenosine 5′‐triphosphate (ATP)‐dependent 45Ca2+‐transport in rat heart sarcolemma vesicles.
The effect of verapamil, 1 μmoll−1, was studied by pretreatment of the hearts during Langendorff‐perfusion and in vitro by adding the drug after isolation of the vesicles.
Without drug pretreatment the Ca2+‐uptake appeared to be strongly reduced after 30 and after 60 min of global ischaemia, whereas after 30 min of reperfusion it was restored to slightly above the control level.
Verapamil pretreatment during the Langendorff perfusion significantly increased Ca2+‐uptake in sarcolemma vesicles both before the onset of ischaemia and after 30 min of reperfusion, whereas no beneficial effect was found on the impaired uptake activity during the ischaemic period.
When tested in vitro after the isolation of the sarcolemma vesicles, verapamil only inhibited the Ca2+‐uptake activity with an IC50 of 112 μmol l−1, which was increased to 250μmol l−1 after ischaemia and reperfusion.
The present study indicates that pretreatment with verapamil, 1 μmol l−1, of the intact rat heart activates an ATP‐dependent Ca2+ extrusion process that may contribute to decrease cellular calcium levels in control and, more importantly, in a reperfusion situation. In contrast, in vitro only a less potent inhibition of the extrusion process was found, indicating that physiological regulatory mechanisms may be altered in the vesicles.
Binding and functional properties of antimuscarinics of the hexocyclium/sila‐hexocyclium and hexahydro‐diphenidol/hexahydro‐sila‐diphenidol type to muscarinic receptor subtypes
Authors: Waelbroeck M. , Tastenoy M. , Camus J. , Christophe J. , Strohmann C. , Linoh H. , Zilch H. , Tacke R. , Mutschier E. , Lambrecht G. 
Published: July 2012

In an attempt to assess the structural requirements for the muscarinic receptor selectivity of hexahydro‐diphenidol (hexahydro‐difenidol) and hexahydro‐sila‐diphenidol (hexahydro‐sila‐difenidol), a series of structurally related C/Si pairs were investigated, along with atropine, pirenzepine and methoctramine, for their binding affinities in NB‐OK 1 cells as well as in rat heart and pancreas.
The action of these antagonists at muscarinic receptors mediating negative inotropic responses in guinea‐pig atria and ileal contractions has also been assessed.
Antagonist binding data indicated that NB‐OK 1 cells (M1 type) as well as rat heart (cardiac type) and pancreas (glandular/smooth muscle type) possess different muscarinic receptor subtypes.
A highly significant correlation was found between the binding affinities of the antagonists to muscarinic receptors in rat heart and pancreas, respectively, and the affinities to muscarinic receptors in guinea‐pig atria and ileum. This implies that the muscarinic binding sites in rat heart and the receptors in guinea‐pig atria are essentially similar, but different from those in pancreas and ileum.
The antimuscarinic potency of hexahydro‐diphenidol and hexahydro‐sila‐diphenidol at the three subtypes was influenced differently by structural modifications (e.g. quaternization). Different selectivity profiles for the antagonists were obtained, which makes these compounds useful tools to investigate further muscarinic receptor heterogeneity. Indeed, the tertiary analogues hexahydrodiphenidol (HHD) and hexahydro‐sila‐diphenidol (HHSiD) had an M1 = glandular/smooth muscle > cardiac selectivity profile, whereas the quaternary analogues HHD methiodide and HHSiD methiodide were M1 preferring (M1 > glandular/smooth muscle, cardiac).
Selectivity of bradykinin analogues for receptors mediating contraction and relaxation of the rat duodenum
Authors: Paiva Antonio C.M. , Paiva Therezinha B. , Pereira Claudia C. , Shimuta Suma I. 
Published: July 2012

Bradykinin produces a biphasic response in the rat duodenum that consists of a relaxation (pD2 = 8.44) followed by a contraction (pD2 = 6.91).
The B1 agonist des‐Arg9‐bradykinin produced a contraction (pD2 = 7.16) but no relaxation. Des‐Arg9‐[Leu8]‐bradykinin, which is a B1 antagonist in other systems produced contraction (pD2 = 7.65) in the rat duodenum.
Four bradykinin analogues that are preferential B2 agonists in other tissues had a biphasic effect with pD2 values in the range 7.22‐8.68 for relaxation and 6.26‐6.91 for contraction.
[Thi5,8,D‐Phe7]‐bradykinin, which is a B2 antagonist in most other systems produced relaxation in the rat duodenum, with a pD2 of 7.49.
It is concluded that the contractile component of the response to bradykinin in rat duodenum may be mediated by a subtype of the B1 receptor and the relaxant component by a receptor of the B2 subtype.
Presynaptic β‐adrenoceptors in rat atria: evidence for the presence of stereoselective β1‐adrenoceptors
Authors: Heimburger M. , Montero M.J. , Fougeres V. , Beslot F. , Davy M. , Midol‐monnet M. , Cohen Y. 
Published: July 2012

Presynaptic β‐adrenoceptor activity was studied in rat isolated atria, previously loaded with [3H]‐noradrenaline. The stimulation‐induced release of 3H transmitter was measured in the presence of cocaine, and adrenaline was used as a facilitatory β‐adrenoceptor agonist.
Adrenaline (0.1 and 2 nM) increased, by about 50%, the evoked efflux of tritium. With phenoxybenzamine present, the same activity was shown with 10 nM adrenaline.
The β2‐selective adrenoceptor blocking drugs: IPS 339 and ICI 118 551 caused a concentration‐dependent decrease in the activity of adrenaline. Cardioselective β‐blocking drugs: acebutolol, betaxolol, nebivolol and its isomers (R 67 138 and R 67 145) also reduced dose‐dependently the agonistic action of adrenaline. The order of potency for nebivolol and its isomers was R 67 138 > nebivolol > R 67 145. The activity of pindolol was not concentration‐dependent. The inhibitory effect of acebutolol was also observed in the presence of blockade of α‐adrenoceptors.
The postsynaptic β‐adrenoceptor blocking activity of nebivolol and its isomers was studied in pithed rats. They reduced isoprenaline‐induced tachycardia without altering hypotensive responses. The order of potency was: R 67 138 > nebivolol > R 67 145.
It is concluded that in rat isolated atria, presynaptic β2‐ and β1‐adrenoceptors coexist and that facilitatory β1 ‐adrenoceptors are stereospecific.
Opposite central and peripheral control by endogenous opioids of intestinal motility in fed rats
Authors: Rivière Pierre J.‐M. , Liberge Martine , Murillo‐Lopez Divina , Bueno Lionel 
Published: July 2012

The effects of the inhibitors of endopeptidase EC 24.11, thiorphan and phosphoramidon administered i.c.v. (40 μg kg−1) i.p. (400 μgkg−1), or orally (400ugkg−1), on intestinal motor activity in fed rats was compared to the effects of similar doses of the angiotensin converting enzyme inhibitor, captopril and the synthetic enkephalin analogue [D‐Ala2 Met5] enkephalinamide (Dalamide). Drugs were administered alone or after pretreatment with naloxone or N‐methyl levallorphan (300 μg kg−1, i.p.) given 10 min prior to gavage with a standard meal.
In control conditions, in the duodenum, the disruption of the migrating myoelectric complex (MMC) by gavage with a standard meal lasted between 105.6 and 119.1 min. This duration was significantly decreased by thiorphan (60.3 ± 15.0 min), phosphoramidon (67.9 ± 7.3 min), captopril (26.3 ± 10.2 min) and Dalamide (42.4 ± 9.6 min), administered i.c.v.
In contrast, after the i.p. administration of thiorphan, phosphoramidon and Dalamide the delay in the return of the MMC pattern was increased. Such an effect was also seen after the oral administration of phosphoramidon or Dalamide. Neither i.p. nor oral captopril administration altered the duration of postprandial pattern.
A prior treatment with naloxone i.p. (300 μg kg−1) that had no effect per se, antagonized the effect produced by i.c.v. administration of thiorphan, phosphoramidon or Dalamide, but failed to reverse the effect of captopril. In contrast, i.p. administration of N‐methyl levallorphan (300 μg kg−1) did not affect the response induced by central administration of thiorphan, phosphoramidon, captopril or Dalamide, but was able to prevent that of thiorphan, phosphoramidon or Dalamide when they were administered i.p. or orally.
These data strongly support the hypothesis of a dual control by endogenous opioids of intestinal motility in the rat: a central component that favours, and a peripheral control that delays the occurrence of the MMC profile in fed rats.