bluuebunny/crossref_metadata_2025_split huggingface dataset:
The gastric H,K‐ATPase blocker lansoprazole is an inhibitor of chloride channels
Authors: Schmarda Andreas , Dinkhauser Patrick , Gschwentner Martin , Ritter Markus , Fürst Johannes , Scandella Elke , Wöll Ewald , Laich Andreas , Rossmann Heidi , Seidler Ursula , Lang Florian , Paulmichl Markus 
Published: January 2005

It was postulated that swelling dependent chloride channels are involved in the proton secretion of parietal cells. Since omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are structurally related to phenol derivatives known to block swelling dependent chloride channels, we set out to test, whether these substances – which are known to block the H,K‐ATPase – could also lead to an inhibition of swelling‐dependent chloride channels. Swelling‐dependent chloride channels – characterized in many different cell types – show highly conserved biophysical and pharmacological features, therefore we investigated the effect of omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 on swelling‐dependent chloride channels elicited in fibroblasts, after the reduction of the extracellular osmolarity.
Omeprazole, lansoprazole and its acid activated sulphenamide form AG2000 are able to block swelling‐dependent chloride channels (IClswell).
Lansoprazole and its protonated metabolite AG2000 act on at least two different sites of the IClswell protein: on an extracellular site which seems to be in a functional proximity to the nucleotide binding site, and on an intracellular site which allows the formation of disulfide‐bridges.
The inhibition of the proton pump and the simultaneous blocking of chloride channels by omeprazole, lansoprazole and its acid activated sulphenamide form AG2000, as described here could be an effective mode to restrict proton secretion in parietal cells.

British Journal of Pharmacology (2000) 129, 598–604; doi:10.1038/sj.bjp.0703070
Protein phosphatase‐protein kinase interplay modulates α1b‐adrenoceptor phosphorylation: effects of okadaic acid
Authors: Alcántara‐Hernández Rocío , Vázquez‐Prado José , García‐Sáinz J Adolfo 
Published: January 2005

In the present work we studied the effect of protein phosphatase inhibitors on the phosphorylation state and function of α1b‐adrenoceptors.
Okadaic acid increased receptor phosphorylation in a time‐ and concentration‐dependent fashion (maximum at 30 min, EC50 of 30 nM). Other inhibitors of protein phosphatases (calyculin A, tautomycin and cypermethrin) mimicked this effect.
Staurosporine and Ro 31‐8220, inhibitors of protein kinase C, blocked the effect of okadaic acid on receptor phosphorylation. Neither genistein nor wortmannin altered the effect of okadaic acid.
The intense adrenoceptor phosphorylation induced by okadaic acid altered the adrenoceptor‐G protein coupling, as evidenced by a small decreased noradrenaline‐stimulated [35S]GTPγS binding. Okadaic acid did not alter the noradrenaline‐stimulated increases in intracellular calcium or the production of inositol trisphosphate.
Our data indicate that inhibition of protein phosphatases increases the phosphorylation state of α1b‐adrenoceptors; this effect seems to involve protein kinase C. In spite of inducing an intense receptor phosphorylation, okadaic acid alters α1b‐adrenergic actions to a much lesser extent than the direct activation of protein kinase C by phorbol myristate acetate.

British Journal of Pharmacology (2000) 129, 724–730; doi:10.1038/sj.bjp.0703073
Participation of mitogen‐activated protein kinase in thapsigargin‐ and TPA‐induced histamine production in murine macrophage RAW 264.7 cells
Authors: Shiraishi Muneshige , Hirasawa Noriyasu , Kobayashi Yuriko , Oikawa Shinji , Murakami Akira , Ohuchi Kazuo 
Published: January 2005

Stimulation of the murine macrophage cell line RAW 264.7 with thapsigargin, an endomembrane Ca2+‐ATPase inhibitor, induced histamine production in a time‐ and concentration‐dependent manner.
The protein kinase C activator, 12‐O‐tetradecanoylphorbol 13‐acetate (TPA), also enhanced histamine production.
α‐Fluoromethylhistidine, a suicide substrate of L‐histidine decarboxylase (HDC), suppressed the thapsigargin (30 nM)‐ and TPA (30 nM)‐induced histamine production.
Both thapsigargin (30 nM) and TPA (30 nM) induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase.
PD98059, a specific inhibitor of MEK‐1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)‐ and TPA (30 nM)‐induced histamine production, whereas SB203580, a specific inhibitor of p38 MAP kinase, inhibited them only partially.
The other MEK‐1 inhibitor, U‐0126, also inhibited both the thapsigargin‐ and TPA‐induced histamine production in a concentration‐dependent manner.
Thapsigargin (30 nM) and TPA (30 nM) increased the levels of HDC mRNA at 4 h, but PD98059 suppressed both the thapsigargin‐ and TPA‐induced increases in the HDC mRNA level.
These findings indicate that thapsigargin and TPA induce histamine production in RAW 264.7 cells by increasing the level of HDC mRNA, and that both the thapsigargin‐ and TPA‐induced histamine production are regulated largely by p44/p42 MAP kinase and partially by p38 MAP kinase.

British Journal of Pharmacology (2000) 129, 515–524; doi:10.1038/sj.bjp.0703085
The actions of ether, alcohol and alkane general anaesthetics on GABAA and glycine receptors and the effects of TM2 and TM3 mutations
Authors: Krasowski Matthew D , Harrison Neil L 
Published: January 2005

The actions of 13 general anaesthetics (diethyl ether, enflurane, isoflurane, methoxyflurane, sevoflurane, chloral hydrate, trifluoroethanol, tribromoethanol, tert‐butanol, chloretone, brometone, trichloroethylene, and α‐chloralose) were studied on agonist‐activated Cl− currents at human GABAA α2β1, glycine α1, and GABAC ρ1 receptors expressed in human embryonic kidney 293 cells.
All 13 anaesthetics enhanced responses to submaximal (EC20) concentrations of agonist at GABAA and glycine receptors, except α‐chloralose, which did not enhance responses at the glycine α1 receptor. None of the anaesthetics studied potentiated GABA responses at the GABAC ρ1 receptor.
Potentiation of submaximal agonist currents by the anaesthetics was studied at GABAA and glycine receptors harbouring mutations in putative transmembrane domains 2 and 3 within GABAA α2, β1, or glycine α1 receptor subunits: GABAA α2(S270I)β1, α2(A291W)β1, α2β1(S265I), and α2β1(M286W); glycine α1(S267I) and α1(A288W). For all anaesthetics studied except α‐chloralose, at least one of the mutations above abolished drug potentiation of agonist responses at GABAA and glycine receptors.
α‐Chloralose produced efficacious direct activation of the GABAA α2β1 receptor (a ‘GABA‐mimetic’ effect). The other 12 anaesthetics produced minimal or no direct activation of GABAA and glycine receptors. A non‐anaesthetic isomer of α‐chloralose, β‐chloralose, was inactive at GABAA and glycine receptors and did not antagonize the actions of α‐chloralose at GABAA receptors.
The implications of these findings for the molecular mechanisms of action of general anaesthetics at GABAA and glycine receptors are discussed.

British Journal of Pharmacology (2000) 129, 731–743; doi:10.1038/sj.bjp.0703087
Investigation of the interaction between nitric oxide and vasoactive intestinal polypeptide in the guinea‐pig gastric fundus
Authors: Dick J M C , Van Geldre L A , Timmermans J P , Lefebvre R A 
Published: January 2005

The interaction between nitric oxide (NO) and vasoactive intestinal polypeptide (VIP) was investigated in isolated circular smooth muscle cells and strips of the guinea‐pig gastric fundus.
VIP induced a concentration‐dependent inhibition of carbachol‐induced contraction in smooth muscle cells with a maximum at 10−6 M. The relaxation by 10−6 M VIP was inhibited for 79.1±5.8% (mean±s.e.mean) by the NO‐synthase (NOS) inhibitor L‐NG‐nitroarginine (L‐NOARG; 10−4 M) in a L‐arginine reversible way. Also the inducible NOS (iNOS) selective inhibitor N‐(3‐(acetaminomethyl)‐benzyl)acetamide (1400 W; 10−6 M) inhibited the VIP‐induced relaxation, but its inhibitory effect was not reversed by L‐arginine.
When cells were incubated with the guanylyl cyclase inhibitor 1H‐(1,2,4)oxadiazolo(4,3‐a)quinoxalin‐1‐one (ODQ, 10−6 M), the protein kinase A‐inhibitor (R)‐p‐cyclic adenosine‐3′,5′‐monophosphothioate ((R)‐p‐cAMPS, 10−6 M) and the glucocorticoid dexamethasone (10−5 M), the relaxant effect of VIP was decreased by respectively 80.9±7.6, 77.0±11.6 and 87.1±4.5%.
In circular smooth muscle strips of the guinea‐pig gastric fundus, the VIP (10−9–10−7 M)‐induced relaxations were not significantly influenced by 10−4 M L‐NOARG, 10−6 M 1400 W, 10−6 M ODQ and 10−5 M dexamethasone.
These results suggest that iNOS, possibly induced by the procedure to prepare the smooth muscle cells, is involved in the relaxant effect of VIP in isolated smooth muscle cells but not in smooth muscle strips of the guinea‐pig gastric fundus. This study illustrates the importance of the experimental method when studying the influence of NOS inhibitors on the relaxation induced by VIP in gastrointestinal smooth muscle preparations.

British Journal of Pharmacology (2000) 129, 751–763; doi:10.1038/sj.bjp.0703089
β1‐, β2‐ and atypical β‐adrenoceptor‐mediated relaxation in rat isolated aorta
Authors: Brawley L , Shaw A M , MacDonald A 
Published: January 2005

β‐adrenoceptor‐mediated relaxation was investigated in ring preparations of rat isolated thoracic aorta. Rings were pre‐constricted with a sub‐maximal concentration of noradrenaline (1 μM) and relaxant responses to cumulative concentrations of β‐adrenoceptor agonists obtained.
The concentration‐response curve (CRC) to isoprenaline was shifted to the right by propranolol (0.3 μM) with a steepening of the slope. Estimation of the magnitude of the shift from EC50 values gave a pA2 of 7.6. Selective β1‐ and β2‐adrenoceptor antagonists, CGP 20712A (0.1 μM) and ICI 118551 (0.1 μM), respectively, produced 4 and 14 fold shifts of the isoprenaline CRC.
Atypical β‐adrenoceptor agonists also produced concentration‐dependent relaxation of aortic rings. The order of potency of the β‐adrenoceptor agonists was (−log EC50): isoprenaline (6.25)>cyanopindolol (5.59)>isoprenaline+propranolol (5.11)>CGP 12177A (4.40)>ZD 2079 (4.24)>ZM 215001 (4.07)>BRL 37344 (3.89). Relaxation to CGP 12177A and ZM 215001 was unaffected by propranolol (0.3 μM).
SR 59230A (1 μM) and cyanopindolol (1 μM), β3‐adrenoceptor antagonists, had no effect on the isoprenaline (in the presence of propranolol) or CGP 12177A CRCs. Bupranolol and CGP 20712A, at μM concentrations (β4‐adrenceptor antagonists), inhibited responses to isoprenaline (in the presence of propranolol) and CGP 12177A.
In conclusion, atypical β‐adrenoceptors co‐exist with β1‐ and β2‐adrenoceptors in rat aorta. Although non‐conventional partial agonists and selective β3‐adrenoceptor agonist cause relaxation, the vascular atypical β‐adrenoceptor does not appear to correspond to the β3‐adrenoceptor. There are, however, similarities with the putative β4‐adrenoceptor.

British Journal of Pharmacology (2000) 129, 637–644; doi:10.1038/sj.bjp.0703091
Differential effects of ethanol on glycine uptake mediated by the recombinant GLYT1 and GLYT2 glycine transporters
Authors: Núñez Enrique , López‐Corcuera Beatriz , Martínez‐Maza Rodrigo , Aragón Carmen 
Published: January 2005

The effects of ethanol on the function of recombinant glycine transporter 1 (GLYT1) and glycine transporter 2 (GLYT2) have been investigated.
GLYT1b and GLYT2a isoforms stably expressed in human embryonic kidney 293 (HEK 293) cells showed a differential behaviour in the presence of ethanol; only the GLYT2a isoform was acutely inhibited.
The ‘cut‐off’ (alcohols with four carbons) displayed by the n‐alkanols on GLYT2a indicates that a specific binding site for ethanol exists on GLYT2a or on a GLYT2a‐interacting protein.
The non‐competitive inhibition of GLYT2a indicates an allosteric modulation by ethanol of GLYT2a activity.
Chronic treatment with ethanol caused differential adaptive responses on the activity and the membrane expression levels of these transporters. The neuronal GLYT2a isoform decreased in activity and surface expression and the mainly glial GLYT1b isoform slightly increased in function and surface density.
These changes may be involved in some of the modifications of glycinergic or glutamatergic neurotransmitter systems produced by ethanol intoxication.

British Journal of Pharmacology (2000) 129, 802–810; doi:10.1038/sj.bjp.0703100
Effects of selective inhibitors of cyclo‐oxygenase‐1 (COX‐1) and cyclo‐oxygenase‐2 (COX‐2) on the spontaneous myogenic contractions in the upper urinary tract of the guinea‐pig and rat
Authors: Davidson M E , Lang R J 
Published: January 2005

The role of cyclo‐oxygenase‐1 (COX‐1) and cyclo‐oxygenase‐2 (COX‐2) in the upper urinary tract of the guinea‐pig and rat was examined using simultaneous tension recordings of the proximal and distal regions of the renal pelvis and the ureter.
The guinea‐pig upper urinary tract contracted at a frequency (7.52±0.3 min−1 at 35°C) significantly lower than the frequency in the proximal renal pelvis (21.6±1.3 min−1) and in the distal renal pelvis and ureter (20.2±1.4 min−1) of the rat (at 30°C).
Indomethacin (1 μM for 60 min), decreased the motility index (amplitude×frequency) (MI) in all three regions of the guinea‐pig upper urinary tract, an effect which mainly arose from a decrease in the frequency of contractions. In the rat, indomethacin (1–30 μM for 60 min) significantly decreased the MI calculated in the proximal renal pelvis (30 μM indomethacin), and in the distal renal pelvis (10 μM indomethacin), arising from a significant decrease in the amplitude of contractions.
The COX‐1 inhibitor, valeryl salicylate (VSA) (5–100 μM for 60 min), had no effect on either the amplitude or frequency of contractions in the guinea‐pig upper urinary tract. In contrast, VSA increased the force of contractions in the proximal and distal renal pelvis of the rat, whilst having little effect on the frequency of contractions.
The COX‐2 inhibitor, NS‐398 (10–100 nM for 60 min) reduced the MI in the guinea‐pig upper urinary tract in a concentration‐dependent manner. The MIs calculated for the proximal renal pelvis, distal renal pelvis and ureter, were decreased by 72, 64 and 72% respectively, in 100 nM NS‐398. NS‐398 (10–100 nM) had no effect on any of the three parameters measured in either the proximal or distal renal pelvis of the rat.
These data suggest that endogenously‐released prostaglandins (PGs) maintain the myogenic contractility of the upper urinary tract in both the guinea‐pig and rat. Moreover COX‐2 is the primary enzyme involved in synthesizing PGs in the guinea‐pig upper urinary tract, while COX‐1 appears to be the predominantly active enzyme in the rat.

British Journal of Pharmacology (2000) 129, 661–670; doi:10.1038/sj.bjp.0703104
Clotrimazole inhibits the recombinant human cardiac L‐type Ca2+channel α1Csubunit
Authors: Fearon I M , Ball S G , Peers C 
Published: January 2005

Clotrimazole (CLT) is an antimycotic agent with a potential role in the treatment of cancer. Whole‐cell patch clamp recordings and Fura‐2 AM fluorescence measurements were used to investigate the inhibition by CLT of recombinant human cardiac L‐type Ca2+channel α1Csubunits, stably expressed in human embryonic kidney (HEK 293) cells.CLT (100 nmol l−1to 25 μmol l−1) reduced Ca2+channel currents in a concentration‐dependent manner. Inhibition was neither use‐ or voltage‐dependent. The effects of CLT were rapid and maximal effects were attained within 3 min. Application of CLT also caused an acceleration of apparent Ca2+channel current inactivation.Basal current density and the degree of inhibition due to CLT were not significantly altered by pretreating cells with 3 mmol l−11‐aminobenzotriazole for 1 h, or by dialysing cells for 10 min with 2 mmol l−1α‐napthoflavoneviathe patch pipette, suggesting that the inhibitory action of CLT was not due to inhibition of cytochromeP‐450.CLT (10 μmol l−1) did not influence [Ca2+]i, as determined by Fura‐2 AM fluorescence measurements.Dialysing cells for 10 min with the non‐specific serine/threonine kinase inhibitor H‐7 (10 μmol l−1) was without effect on basal current density or on the inhibitory response to 10 μmol l−1CLT, indicating that CLT is not actingviaan indirect effect on these kinases.These data suggest that CLT exerts a direct blocking effect on the α1Csubunit at therapeutic concentrations. This effect may explain the abbreviation of the action potential duration by CLT observed in cardiac myocytes.British Journal of Pharmacology(2000)129, 547–554; doi:10.1038/sj.bjp.0703106
Apamin‐sensitive, non‐nitric oxide (NO) endothelium‐dependent relaxations to bradykinin in the bovine isolated coronary artery: no role for cytochrome P450 and K+
Authors: Drummond Grant R , Selemidis Stavros , Cocks Thomas M 
Published: January 2005

Since cytochrome P450‐derived metabolites of arachidonic acid and K+ have been implicated in endothelium‐derived hyperpolarizing factor (EDHF)‐dependent responses, the aim of this study was to determine whether such factors contribute to non‐nitric oxide (NO), endothelium‐dependent relaxation to bradykinin (BK) in bovine isolated coronary artery.
In rings of artery contracted with U46619 and treated with indomethacin (3 μM) and NG‐nitro‐L‐arginine (L‐NOARG; 100 μM), relaxation to BK (0.01 nM‐0.3 μM) was blocked by ∼60% after inhibition of K+ channels with either high extracellular K+ (high [K+]o; 15–67 mM) or apamin (0.3 μM).
Ouabain (1 μM), an inhibitor of Na+/K+‐ATPase, decreased the sensitivity to BK without affecting the maximum response. In L‐NOARG‐treated rings, ouabain had no further effect on the relaxation to BK. An inhibitor of inward‐rectifying K+ channels, Ba2+ (30 μM), had no effect on relaxations to BK in the absence or presence of either L‐NOARG or ouabain.
KCl (2.5–10 mM) elicited small relaxations (∼20%) that were abolished by nifedipine (0.3 μM) and ouabain.
Both the high [K+]o/apamin‐sensitive relaxation to BK, and the relaxation to the KATP channel‐opener, levcromakalim (0.6 μM), were unaffected by the cytochrome P450 inhibitor, 7‐ethoxyresorufin (10 μM), or by co‐treatment with a phospholipase A2 inhibitor, arachidonyl trifluoromethyl ketone (AACOCF3; 3 μM) and a diacylglycerol (DAG)‐lipase inhibitor, 1,6‐bis‐(cyclohexyloximinocarbonylamino)‐hexane (RHC 80267; 30 μM). The non‐NO/high [K+]o‐insensitive, ∼40% relaxation to BK was, however, abolished by these treatments.
Therefore, neither cytochrome P450‐derived metabolites of arachidonic acid nor K+ appear to mediate the EDHF‐like relaxation to BK (i.e the non‐NO, high [K+]o/apamin‐sensitive component) in bovine coronary arteries. Cytochrome P450‐derived metabolites may be released at higher BK concentrations to act in parallel with NO and the high [K+]o/apamin‐sensitive mechanism.

British Journal of Pharmacology (2000) 129, 811–819; doi:10.1038/sj.bjp.0703107
The effects of Z13752A, a combined ACE/NEP inhibitor, on responses to coronary artery occlusion; a primary protective role for bradykinin
Authors: Rastegar Mohamed Ali , Marchini Francesco , Morazzoni Gabrielle , Végh Agnes , Papp Julius Gy , Parratt James R 
Published: January 2005

The effects on the responses to coronary artery occlusion of a combined ACE/NEP inhibitor (Z13752A) were examined in anaesthetized dogs.
A 1 h infusion of Z13752A (128 μg kg−1 min−1 intravenously) decreased arterial blood pressure (by 11±3%; P<0.05) and increased coronary blood flow (by 12±4%, P<0.05). There were no other significant haemodynamic changes.
Z13752A inhibited both NEP and ACE enzymes both in dog plasma and in tissue (lung ACE; kidney NEP). Pressor responses to angiotensin I in vivo were inhibited and systemic vasodilator responses to bradykinin were potentiated.
When the left anterior descending coronary artery was occluded for 25 min, Z13752A markedly reduced the severity of the resultant ventricular arrhythmias. No ventricular fibrillation (VF) occurred (compared to 7/16 in the controls; P<0.05), and ventricular tachycardia (VT) was reduced (VT in 2/9 dogs treated with Z13752A cp. 16/16 of controls; episodes of VT 0.2±0.1 c.p. 10.7±3.3; P<0.05).
Reperfusion of the ischaemic myocardium led to VF in all control dogs but occurred less frequently in dogs given Z13752A (survival from the combined ischaemia‐reperfusion insult 67% c.p. 0% in controls; P<0.05).
Z13752A reduced two other indices of ischaemia severity; epicardial ST‐segment elevation and inhomogeneity of electrical activation.
These protective effects of Z13752A during ischaemia and reperfusion were abolished by the administration of icatibant (0.3 mg kg−1, i.v.) a selective antagonist of bradykinin at B2 receptors; the ischaemic changes in dogs given both icatibant and Z13752A were similar to those in the controls.
We conclude that this ACE/NEP inhibitor is effective at reducing the consequences of coronary artery occlusion in this canine model and that this protection is primarily due to potentiation of released bradykinin.

British Journal of Pharmacology (2000) 129, 671–680; doi:10.1038/sj.bjp.0703109
Hamster pancreatic beta cell lines with altered sensitivity towards apoptotic signalling by phosphatase inhibitors
Authors: Krautheim Andrea , Brechlin Peter , Becker Klaus , Winkler Monika , Steinfelder Hans Jürgen 
Published: January 2005

Specific inhibitors of serine/threonine phosphatases like okadaic acid can induce apoptotic cell death in the pancreatic beta cell line HIT. Cultivation in stepwise increased concentrations of okadaic acid enabled the isolation of HIT100R cells which proliferate at 100 nMokadaic acid (8–10 times the initially lethal concentration).These two cell lines were used to characterize the events triggered by okadaic acid that led to apoptosis. Biochemical markers, e.g. cytochrome c release from mitochondria and increase of caspase‐3‐like activity, revealed that induction of apoptosis by 100 nMokadaic acid in parental HIT cells started with the release of cytochrome c. In HIT100R cells 500 nMokadaic acid were necessary to induce alterations comparable to those observed with 100 nMokadaic acid in non‐resistant HIT cells.In contrast to okadaic acid, the potency of the structurally different phosphatase inhibitor cantharidic acid to induce cytochrome c release, increase of caspase‐3‐like activity and DNA fragmentation was comparable in HIT and HIT100R cells. Thus, no cross‐resistance between these phosphatase inhibitors seemed to exist.Phosphatase activity in extracts from HIT and HIT100R cells did not differ in its total amount or in its sensitivity for okadaic acid.Since higher concentrations of okadaic acid were needed to induce apoptosis in HIT100R cells, a compromised intracellular accumulation of the toxin appeared likely. Functional and structural analysis revealed that this was achieved by the development of the multidrug resistance phenotype in HIT100R cells. The underlying mechanism appeared to be the enhanced expression of thepgp1but not thepgp2gene.British Journal of Pharmacology(2000)129, 687–694; doi:10.1038/sj.bjp.0703113