bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelium‐dependent contractile responses to 5‐hydroxytryptamine in the rabbit basilar artery
Authors: Seager Joanna M. , Clark Angela H. , Garland C.J. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) and 5‐carboxamidotryptamine (5‐CT) stimulated additional, endothelium‐dependent contractions in rabbit isolated basilar arteries which had been submaximally contracted with either histamine or potassium chloride.
The additional contractions to 5‐HT were not altered by the 5‐HT2 antagonist, ketanserin (1 μm), but were abolished in the presence of the cyclo‐oxygenase inhibitor indomethacin (3 μm).
The additional smooth muscle contraction stimulated by 5‐HT was increased in the presence of the competitive substrate inhibitor for nitric oxide synthase, NG‐nitro‐l‐arginine methyl ester (l‐NAME, 100 μm).
Neither of the selective 5‐HT agonists, 8‐hydroxy‐dipropylaminotetralin (8‐OH DPAT) or α‐methyl 5‐HT stimulated endothelium‐dependent contraction, but these agonists did reduce the rate at which histamine‐induced tension spontaneously declined. This effect represented a direct action on the smooth muscle cells, as it was independent of the presence of endothelial cells.
Smooth muscle relaxation was not obtained in response to 5‐HT, whether or not indomethacin was present to block endothelium‐dependent contraction. None of the other selective 5‐HT agonists, 5‐CT, 8‐OH DPAT or α‐methyl 5‐HT produced endothelium‐dependent smooth muscle relaxation, when applied against a background of contraction.
These data show that endothelium‐dependent smooth muscle contraction can be produced by stimulating 5‐HT receptors in the partially contracted rabbit basilar artery. Similar contraction to 5‐CT indicates an involvement by 5‐HT1 receptors. The susceptibility of the contractions to indomethacin suggest they are mediated by a metabolite of arachidonic acid.
Capsaicin‐induced bronchoconstriction in the guinea‐pig: contribution of vagal cholinergic reflexes, local axon reflexes and their modulation by BW443C81
Authors: Buchan P. , Adcock J.J. 
Published: July 2012

The objective of the study was to investigate the central vagal and local axon reflex components of bronchoconstrictor responses evoked by inhalation of capsaicin aerosol in anaesthetized guinea‐pigs. This was accomplished by comparing the effects of bilateral vagotomy, atropine and the peripherally‐acting polar enkephalin analogue, BW443C81, on bronchoconstrictor responses evoked by capsaicin. The effects of codeine were also determined.
Aerosols of capsaicin were generated from a 0.9 μg ml−1 solution. Inhalation of capsaicin aerosol in 5, 10 and 15 breaths evoked dose‐related bronchoconstrictor responses. The responses were immediate in onset and of extended duration.
Capsaicin‐induced bronchoconstrictor responses were significantly inhibited following bilateral vagotomy or atropine (0.3 mg kg−1, i.v.) pretreatment by 46% ± 14% (P < 0.05) and 59% ± 13% (P < 0.01), respectively.
Administration of BW443C81 by intravenous infusion (3, 30 and 100 μg kg−1 min−1) caused a significant inhibition of capsaicin‐induced bronchoconstrictor responses which achieved a greater maximum than either bilateral vagotomy or atropine. Codeine (100 μg kg−1 min−1, i.v.) did not significantly inhibit the bronchoconstrictor responses.
Inhibition of capsaicin‐induced bronchoconstrictor responses by BW443C81 (30 μg kg−1 min−1, i.v.) was significantly (P < 0.05) reduced by the peripherally‐acting opioid antagonist N‐methyl nalorphine (100 μg kg−1 min−1, i.v.).
These results show that capsaicin‐induced bronchoconstrictor responses are mediated by at least two mechanisms, a vagal and/or cholinergic reflex pathway and a non‐cholinergic pathway. BW443C81, but not codeine, significantly inhibited (P < 0.005) both mechanisms of capsaicin‐induced bronchoconstriction probably by an action on peripheral opioid receptors located on vagal sensory nerves.
Comparison of pyrrolidinyl and piperidinyl benzamides for their anticonvulsant activity and inhibitory action on sodium channel
Authors: Zhu Yu , Im Wha Bin , Lewis Richard A. , VonVoigtlander Philip F. 
Published: July 2012

A pair of benzamide analogues containing a pyrrolidinyl or piperidinyl group was examined for their anticonvulsant activity against the electroshock‐induced seizures in mice and the ability to block the voltage‐gated Na channel in N1E‐115 cells, in comparison with the prototype compound, U‐54494A, (±)‐cis‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]‐benzamide, a potent anticonvulsant and a Na channel blocker.
The pyrrolidinyl benzamide (U‐49524E) was found to be effective against the electroshock‐induced seizures (ED50 = 35 mg kg−1, i.p.) whereas the benzamide with a piperidinyl moiety (U‐49132E) was inactive (ED50> 100 mg kg−1).
Using whole‐cell patch clamp techniques we found that U‐49132E was several times less potent, with an IC50 of 396 μm as compared to 118 μm for U‐49524E at the holding potential of − 80 mV, and was much slower in blocking Na channels with a half‐time of 10.7 ± 1.1 min vs. 2.2±0.4 min for its counterpart.
Qualitatively, their general modes of interaction with Na channels were similar to each other and to that of U‐54494A in that they interacted with the resting and slowly‐inactivated states of the channels and exhibited a use‐dependent inhibition because of a slow recovery from the inactivated state in the presence of the drugs.
Comparison of their physicochemical properties, shows the less potent and slowly acting U‐49132E is more hydrophobic and bulkier than U‐49524E, but has the same pKa. This suggests that the drugs approach the Na channel through a narrow and hydrophilic pathway.
Overall, this study underscores the importance of inhibiting the Na channel to the anticonvulsant activity of the benzamide compounds.
Stimulation of noradrenaline release in human cerebral cortex mediated by N‐methyl‐d‐aspartate (NMDA) and non‐NMDA receptors
Authors: Fink Klaus , Schultheiß Rolf , Göthert Manfred 
Published: July 2012

Human brain cortical slices from patients undergoing neurosurgery for treatment of epilepsy resistant to antiepileptic drugs were used to identify and characterize N‐methyl‐d‐aspartate (NMDA) and non‐NMDA receptors mediating stimulation of noradrenaline release. The slices preincubated with [3H]‐noradrenaline were superfused with Krebs‐Henseleit solution with or without Mg2+ (1.2 mmol 1−1) and were stimulated by 2‐min exposure to NMDA, kainic acid or (RS)‐α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA).
In slices superfused without Mg2+, NMDA induced a concentration‐dependent tritium overflow.
The NMDA‐evoked tritium overflow was almost abolished by tetrodotoxin (TTX), Mg2+ or by omission of Ca2+ from the superfusion fluid. 2‐Amino‐5‐phosphonopentanoic acid (AP5; a competitive NMDA receptor antagonist) or dizocilpine (formerly MK‐801; an antagonist at the phencyclidine receptor within the NMDA‐gated ion channel) inhibited the NMDA‐evoked tritium overflow. The stimulatory effect of NMDA was not significantly enhanced by glycine added to the superfusion fluid but was reduced by 7‐chlorokynurenic acid (an antagonist at the glycine site coupled to the NMDA receptor).
In slices superfused with solution containing Mg2+, kainic acid or AMPA induced a concentration‐dependent tritium overflow which was susceptible to blockade by TTX.
The kainic acid‐evoked tritium overflow was not affected by dl‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐3‐pentanoic acid (CGP37849; a competitive NMDA receptor antagonist), but was inhibited by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX; an antagonist at glutamate receptors of the non‐NMDA type).
The AMPA‐evoked tritium overflow was also inhibited by CNQX.
It is concluded that NMDA receptors as well as kainate‐ and AMPA‐recognizing non‐NMDA receptors stimulate noradrenaline release in the human brain cortex.
Haemodynamic effects of a new dihydropyridine calcium entry blocker, S‐12968‐(−), in a rat model of cardiovascular calcium overload
Authors: Makki Touria , Lartaud Isabelle , Boscs Laure Bray‐Des , Capdeville‐Atkinson Christine , Chillon Jean‐Marc , Hoffman Maurice , Nicolas Jean‐Pierre , Atkinson Jeffrey 
Published: July 2012

The haemodynamic effects of S‐12968‐(−), a new dihydropyridine calcium entry blocker (enantiomer of S‐11568), were compared with those of the stereoisomer, S‐12967‐(+), nifedipine, and sodium nitroprusside.
A first experiment was performed in conscious, young male rats chronically implanted with femoral artery and vein cannula and repeated in rats previously treated with vitamin D3 and nicotine. Such treatment produces marked vascular calcium overload, especially of the compliance arteries, with no overt sign of toxicity as far as can be judged from the plasma profile.
In conscious rats the hypotensive effects of S‐12968‐(−), nifedipine and sodium nitroprusside were of similar potency. The falls in blood pressure produced by nifedipine and sodium nitroprusside were accompanied by reflex tachycardia which was less marked in the vascular calcium overload model. S‐12968‐(−) did not induce reflex tachycardia. S‐12967‐(+) increased blood pressure in both models.
A second experiment was performed in open‐chest pentobarbitone‐anaesthetized rats with electromagnetic flowprobes on the ascending aorta. In controls the falls in blood pressure produced by low doses (0.1 and 0.3 mg kg−1, i.v.) of S‐12968‐(−) were accompanied by falls in total peripheral resistance. The higher dose (1 mg kg−1, i.v.) of S‐12968‐(−) produced no change in total peripheral resistance, and in rats pretreated with vitamin D3 and nicotine, cardiac output fell.
In conclusion, S‐12968‐(−) appears to have a dual action and to lower blood pressure at higher doses at least in part by a cardiac effect. This phenomenon is more pronounced in rats pretreated with vitamin D3 and nicotine.
S‐12967‐(+) resembles a calcium channel activator in this model.
Chloride channels and anion fluxes in a human colonic epithelium (HCA‐7)
Authors: Henderson R.M. , Ashford M.L.J. , MacVinish L.J. , Cuthbert A.W. 
Published: July 2012

Colonic epithelial cells, derived from a human adenocarcinoma (HCA‐7), were examined by the patch clamp technique.
Outwardly rectifying anion (Cl−) channels were identified in the apical membrane. The conductance was gin ≅ 26 pS, gout ≅ 40 pS. The open state probability of the channels increased with depolarization and the selectivity for Cl− over K+ (PCl/PK) was ≅ 7.5.
The channels were sensitive to intracellular adenosine 3′:5′‐cyclic monophosphate (cyclic AMP, 0.1 mm), but not to Ca2+ (at concentrations up to 1 mm). At depolarized potentials the channels were blocked by pirentanide (1–5 μm) applied intracellularly.
HCA‐7 monolayers loaded with 125I− (as a marker for Cl−) were used to measure I− efflux and converted to instantaneous rate constants.
The rate constant for I− efflux was increased by forskolin and lysylbradykinin (LBK). The effects of forskolin were not effected by BAPTA (an intracellular calcium chelator). The effects of LBK were inhibited by BAPTA and by Ba2+, indicating that LBK raised intracellular Ca2+ (Cai) which activates Ca2+‐sensitive K‐channels, the latter being blocked by Ba2+.
Although it cannot be conclusively proved that the outwardly rectifying chloride channels described here are solely or partially responsible for the increased anion efflux or transepithelial chloride secretion, the channels are likely to be more relevant for cyclic AMP‐requiring rather than Ca2+‐requiring secretagogues.
Contractions induced by potassium‐free solution and potassium relaxation in vascular smooth muscle of hypertensive and normotensive rats
Authors: Arvola Pertti , Pörsti Ilkka , Vuorinen Pauli , Pekki Anu , Vapaatalo Heikki 
Published: July 2012

Vascular contractions induced by K+‐free solution and relaxation responses following the return of K+ to the organ bath were studied in mesenteric arterial rings from spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY) with particular focus on the role of vascular adrenergic nerve‐endings and endothelium.
In endothelium‐denuded rings the omission of K+ from the incubation medium resulted in gradual contractions, the rate of which was slower in SHR than WKY. Nifedipine (1 μm) inhibited the contractions more effectively in SHR than WKY.
Adrenergic denervation in vitro with 6‐hydroxydopamine reduced the contractions induced by the K+‐free medium in endothelium‐denuded rings. The remaining contractions after denervation were markedly greater in SHR than WKY.
The presence of intact vascular endothelium attenuated the K+‐free contractions in both strains, the attenuation being smaller in SHR than WKY. NG‐nitro‐l‐arginine methyl ester (l‐NAME, 0.1 mm) and methylene blue (10 μm), but not indomethacin (10 μm), abolished the attenuating effect of endothelium on the K+‐free contractions. l‐Arginine (1 mm) reversed the effect of l‐NAME in WKY but not in SHR.
The re‐addition of K+ after full K+‐free contractions dose‐dependently relaxed the rings. The rate of this K+‐induced relaxation was significantly slower in SHR than WKY at all K+ concentrations (0.1–5.9 mm) studied, whether the endothelium or functioning adrenergic nerve‐endings were present or not. Ouabain (1 mm) totally inhibited the K+ relaxation in SHR but only partially in WKY.
Vascular smooth muscle contractions induced by high concentrations of potassium were comparable between the strains. The EC50 for noradrenaline‐induced contractions was lower in SHR than WKY, but the maximal forces did not differ significantly.
In conclusion, the contractile response in K+‐free solution more clearly differentiates vascular rings from SHR and WKY than the responses induced by the classical contractile agents noradrenaline and high concentrations of potassium. The depressant effect of the presence of intact endothelium on the K+‐free contractions, which was smaller in SHR than WKY, is mediated via the endothelium‐derived relaxing factor. Neurotransmitter release from vascular adrenergic nerve‐endings participates less in the K+‐free contractile response in SHR than WKY. Moreover, the contractile response is more dependent on calcium entry through nifedipine‐sensitive calcium channels in SHR than WKY. The greater K+‐free contractions of denervated endothelium‐denuded rings and the reduced K+ relaxation rate in SHR when compared to WKY suggest increased cell membrane permeability and decreased activity of vascular Na+, K+‐ATPase, respectively, in this type of genetic hypertension.
Influence of NG‐nitro‐L‐arginine on non‐adrenergic non‐cholinergic relaxation in the guinea‐pig gastric fundus
Authors: Lefebvre R.A. , Baert E. , Barbier A.J. 
Published: July 2012

The influence of NG‐nitro‐l‐Arginine (l‐NNA) on non‐adrenergic non‐cholinergic (NANC) relaxations induced by electrical field stimulation was investigated in circular muscle strips of the guinea‐pig gastric fundus.
In the presence of 10−6 m. atropine and 4 × 10−6 m guanethidine, electrical field stimulation (40 V, 1 ms, 0.125–16 Hz) with 10 s trains at 5 min intervals induced short‐lasting, frequency‐dependent relaxations. Continuous stimulation, with cumulative increase of the stimulation frequency, induced sustained frequency‐dependent relaxations. Both types of response were abolished by 3 × 10−6 m tetrodotoxin.
l‐NNA (10−5 m and 10−4 m) concentration‐dependently reduced both types of NANC response. Pre‐incubation with 2 × 10−3 m l‐arginine prevented the inhibitory action of 10−5 m l‐NNA and partially antagonized that of 10−4 m l‐NNA. d‐arginine (2 × 10−3 m) did not protect against the inhibitory effect of l‐NNA.
l‐NNA did not consistently influence the basal tone of the tissues. l‐Arginine and d‐arginine likewise did not influence basal tone; they also had no influence on the electrically‐induced NANC relaxations.
NO (10−6−10−4 m) induced short‐lasting concentration‐dependent relaxations, while vasoactive intestinal polypeptide (VIP, (10−9−10−7 m) induced more sustained relaxations, that developed at a slower rate. The NO‐ and VIP‐induced relaxations were not influenced by 10−4 m l‐NNA.
These results suggest that NO is involved in NANC neurotransmission of the guinea‐pig gastric fundus; its contribution to sustained NANC relaxation in the guinea‐pig gastric fundus is much more important than in the rat.
Effects of cyclopiazonic acid, a novel Ca2+‐ATPase inhibitor, on contractile responses in skinned ileal smooth muscle
Authors: Uyama Yoshiaki , Imaizumi Yuji , Watanabe Minoru 
Published: July 2012

Effects of cyclopiazonic acid (CPA), a specific inhibitor of the Ca2+‐ATPase in sarcoplasmic reticulum (SR) of skeletal and cardiac muscles, on contractile responses induced by Ca2+‐release from intracellular storage sites were examined in the longitudinal smooth muscle strip of the guinea‐pig ileum skinned with β‐escin.
Ca2+‐loading of storage sites (Ca2+‐uptake) was performed in pCa 6.3 solution. The amount of Ca2+ taken up was monitored by use of the amplitude of contraction following application of 25 mm caffeine or 25 μm inositol 1,4,5‐trisphosphate (IP3).
Contractile responses to caffeine or IP3 were reduced or abolished when the preceding Ca2+‐uptake was performed in the presence of 0.1–10 μm CPA. The dose of CPA required to inhibit the contraction induced by caffeine or IP3 by 50% was approximately 0.6 μm. The CPA‐sensitive Ca2+‐uptake completely depended upon the presence of ATP in the solution during Ca2+‐uptake.
When 1 μm CPA was added after Ca2+‐uptake, the subsequent caffeine‐ or IP3‐induced contraction was not significantly affected by the presence of CPA.
Acetylcholine‐induced contraction was also almost abolished when the preceding Ca2+‐uptake was performed in the presence of 10 μm CPA.
The relationship between pCa and contraction was not affected by the presence of 10 μm CPA in skinned fibres where Ca2+ storage sites had been destroyed by treatment with A23187. The enhancement of contraction in pCa 6.0 solution by calmodulin was not affected by 10 μm CPA.
These results suggest that CPA selectively inhibits ATP‐dependent Ca2+‐uptake into intracellular storage sites in skinned ileal smooth muscle strips. CPA appears to be a potent, reversible, and very specific inhibitor of the Ca2+‐pump in the storage sites of smooth muscle, and is an extremely valuable pharmacological tool.
Functional comparisons of gastrin/cholecystokinin receptors in isolated preparations of gastric mucosa and ileum
Authors: Patel Mina , Spraggs Colin F. 
Published: July 2012

The gastrin cholecystokinin (CCK) receptors mediating stimulation of acid secretion in rat isolated gastric mucosa (RGM) and contraction in guinea‐pig isolated ileum longitudinal muscle‐myenteric plexus (GPI) have been characterized by use of peptide agonists and the non‐peptide antagonists, lorglumide, devazepide and L‐365,260.
In RGM, gastrin peptides (sulphated gastrin heptadecapeptide (G‐17), non‐sulphated (ns) G‐17 and pentagastrin) were potent agonists of acid secretion (EC50 values of 4.3, 16 and 27 nm respectively). Sulphated CCK octapeptide (CCK‐8) was also a potent agonist, (EC50 = 0.9 nm), but was less efficacious, producing a lower maximal response. In contrast, in GPI, CCK‐8 was a potent full agonist (EC50= 1.4 nm) and was more than 1000 times more potent than the gastrin peptides in producing a sustained contractile response.
In GPI, CCK‐8 (0.1 to 100 nm) produced sustained contractile responses, whilst CCK‐4 (3 to 1000 nm) produced transient responses. These responses had different sensitivities to atropine (1 μm), suggesting that more than one receptor may mediate contraction in this tissue.
In RGM, L‐365,260 was the most potent antagonist of pentagastrin‐stimulated acid secretion (pA2 = 7.6). This functional affinity estimate was similar to that for L‐365,260 as an antagonist of excitatory responses in rat ventromedial hypothalamic slices (Kemp et al., 1989) but differed from binding affinity estimates in guinea‐pig cortex and gastric glands (Freidinger, 1989).
In GPI, devazepide, L‐365,260 and lorglumide yielded different affinity estimates when compared against CCK‐8 and CCK‐4 or pentagastrin respectively. These studies were consistent with the view that the sustained response produced by CCK‐8 was mediated by CCKA receptors and the transient response produced by CCK‐4 and pentagastrin was mediated by CCKB receptors.
Affinity estimates for L‐365,260 and lorglumide against CCK‐4 or pentagastrin in GPI were significantly different from corresponding estimates against pentagastrin in RGM. These studies are consistent with the view that gastrin/CCKB receptors in GPI may differ from those in RGM.
Effect of MgATP on pinacidil‐induced displacement of glibenclamide from the sulphonylurea receptor in a pancreatic β‐cell line and rat cerebral cortex
Authors: Schwanstecher Mathias , Brandt Christian , Behrends Sönke , Schaupp Ursula , Panten Uwe 
Published: July 2012

The effects of blockers and openers of K+ channels on binding of [3H]‐glibenclamide to microsomes obtained from a pancreatic β‐cell line (HIT‐T15) or rat cerebral cortex were examined.
The blockers quinine, chlorpromazine and thiopentone and the openers cromakalim [(±) 6‐cyano‐3,4‐dihydro‐2,2‐dimethyl‐trans‐4‐(2‐oxo‐1‐pyrrolidyl)‐2H‐benzo[b]pyran‐3‐ol] and minoxidil sulphate did not significantly interact with the sulphonylurea receptor of HIT‐cells both at phosphorylating (presence of MgATP) and dephosphorylating (absence of MgATP) conditions.
In the absence of MgATP, pinacidil (200‐ 500 μm) did not significantly displace [3H]‐glibenclamide binding to microsomes from HIT‐cells. The displacement of [3H]‐glibenclamide binding was strongly enhanced by MgATP and was due to a decrease in the number of high affinity binding sites for glibenclamide.
MgATP enhanced pinacidil‐induced inhibition of [3H]‐glibenclamide binding to microsomes from rat cerebral cortex.
The effect of MgATP on pinacidil‐induced inhibition of [3H]‐glibenclamide binding was maintained after solubilization of the membranes from HIT‐cells or rat cerebral cortex.
It is concluded that the sulphonylurea receptor is regulated not only by sulphonylureas but also by the K+ channel openers, diazoxide and pinacidil, and by protein phosphorylation. The binding sites for sulphonylureas and these K+ channel openers are not identical, but appear to be located at a single protein or at tightly associated proteins.
Pharmacological characterization of non‐NMDA subtypes of glutamate receptor in the neonatal rat hemisected spinal cord in vitro
Authors: Zeman Sophie , Lodge David 
Published: July 2012

A grease‐gap technique was used to record depolarizing responses to α‐amino‐3‐hydroxy‐5‐methyl‐isoxazole‐4‐propionate (AMPA), kainate and N‐methyl‐d‐aspartate (NMDA) in the hemisected spinal cord of the neonatal rat. The pharmacology of non‐NMDA subtypes of glutamate receptor was investigated with the novel quinoxalinedione, 2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo (F)‐quinoxaline (NBQX) and with a series of barbiturates.
NBQX antagonized AMPA‐ and kainate‐, but not NMDA‐ induced depolarizations. The near parallel shifts of the major part of the dose‐response curves for AMPA and kainate by NBQX gave pA2 values (± s.e.) of 6.7 ± 0.2 and 6.8 ± 0.2 respectively, consistent with a common site of action for these two agonists.
Below the 50% level at which these pA2 values were calculated, however, an NBQX‐resistant plateau was seen within the kainate, but not the AMPA, dose‐response curve.
In decreasing order of potency, methohexitone, secobarbitone, thiopentone, pentobarbitone and phenobarbitone preferentially reduced kainate‐, rather than AMPA‐ and NMDA‐, induced depolarizations. Methohexitone was also the most selective with IC50s against kainate, AMPA and NMDA of 31 ± 7, 172 ± 47 and >200 μm respectively.
The NBQX‐resistant plateau seen within the kainate dose‐response curve was reduced by methohexitone. Kainate antagonism by methohexitone was not reduced by 50 μm picrotoxin.
We conclude that, while mixed agonist actions may hamper demonstration of antagonist selectivity, depolarizations induced by the non‐NMDA ionotropic agonists, AMPA and kainate, are mediated in part via distinct receptors.