bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of endogenous nitric oxide on tumour necrosis factor‐α‐induced leukosequestration and IL‐8 release in guinea‐pigs airways in vivo
Authors: Kuo H.‐P. , Hwang K.‐H. , Lin H.‐C. , Wang C.‐H. , Lu L.‐C. 
Published: January 2005

Tumour necrosis factor‐α (TNF‐α) is implicated in the pathogenesis of many pulmonary and airway diseases. TNF‐α stimulation may release interleukin‐8 (IL‐8) in airways mediated via an increase in intracellular oxidant stress. In the present study, we have assessed leukosequestration and IL‐8 release in the airways in response to intratracheal administration of human recombinant TNF‐α, and examined the modulatory role of endogenous NO by pretreatment with a NO synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME).
TNF‐α (102–104 u) was administered intratracheally in male guinea‐pigs which were anaesthetized with urethane and were ventilated artificially. TNF‐α induced a time‐ and dose‐related increase in neutrophil numbers and a concomitant increase in human IL‐8 equivalent level retrieved from bronchoalveolar lavage (BAL) with the peak effect at 103 u at 6 h of TNF‐α injection (late phase). Intratracheal administration of recombinant human (rh)IL‐8 (0.025, 0.25, 2.5 ng) producing a similar range of human IL‐8 equivalent levels in BAL as measured in our results induced neutrophil recovery in BAL fluid to a similar extent. Administration of anti‐IL‐8 antibody prevented the late phase of neutrophil recruitment induced by TNF‐α or rhIL‐8.
Pretreatment with L‐NAME significantly enhanced the TNF‐α (103 u)‐induced neutrophil recruitment and human IL‐8 equivalents production at 6 h, but not at 1 h of TNF‐α administration (early phase). L‐Arginine reversed the responses to L‐NAME. Pretreatment with 0.2% DMSO (i.v.) significantly inhibited TNF‐α‐induced neutrophil recruitment and human IL‐8 equivalents release both in the early and late phase of the responses. Pretreatment with DMSO also inhibited the enhancement effect of L‐NAME on the late phase of TNF‐α‐induced responses. DMSO failed to modify exogenous rhIL‐8‐induced neutrophil recruitment. Neither L‐NAME nor DMSO alone induced any significant change in neutrophil numbers or human IL‐8 equivalent level in BAL fluid.
Neutrophil depletion by cyclophosphamide pretreatment failed to modify TNF‐α‐induced human IL‐8 equivalent release.
The expression of β2‐integrin, CD11b/CD18 on neutrophils was increased only in the late but not early phase of TNF‐α stimulation. L‐NAME failed to modify these responses.
In conclusion, we demonstrated that NO may be an important endogenous inhibitor of TNF‐α‐induced leukocyte chemotaxis via inhibition of IL‐8 production. Thus, the production of NO in airway inflammatory diseases may play a negative feedback role in self‐limiting the magnitude of inflammatory responses.

British Journal of Pharmacology (1997) 122, 103–111; doi:10.1038/sj.bjp.0701338
G protein‐independent stimulation of human myocardial phospholipase C by mastoparan
Authors: Schnabel Petra , Gäs Heidi , Nohr Theo , Böhm Michael 
Published: January 2005

Phosphoinositide‐specific phospholipase C (PLC) is involved in the regulation of many cellular functions. In the myocardium, PLC‐generated second messengers play a role in the regulation of contractile function and in the pathophysiology of myocardial hypertrophy.
In the present study, the effect of mastoparan, a tetradecapeptide which is capable of activating heterotrimeric G proteins by mimicking the action of an activated receptor, on membrane‐bound human myocardial PLC, was investigated in a cell‐free assay with exogenous phospholipids as a substrate.
Mastoparan stimulated human myocardial PLC approximately two fold with a half‐maximal effect at approximately 2 μM and a maximal effect at 10 μM. The peptide did not alter the dependence of PLC on free calcium ions. In order to exclude non‐specific effects of mastoparan due to its amphiphilic properties, different mastoparan derivatives were used as positive and negative controls. Mas17, an inactive mastoparan analogue with phsyical properties very similar to mastoparan, did not induce substantial PLC stimulation in human myocardial membranes. In contrast, Mas7, the most active mastoparan derivative known, caused a more pronounced PLC activation compared with the mother compound indicating that the effect was sequence‐specific. Human myocardial PLC stimulation was pertussis toxin‐insensitive and could not be abolished by addition of excess α‐subunits from purified retinal transducin or by excess GDP or GDPβS. In order to investigate whether mastoparan stimulated PLC via pertussis toxin‐insensitive αq, a deletion mutant of PLCβ2 deficient of the site of interaction with αq‐subunits was expressed in COS‐1 cells. Both wild‐type and mutant PLCβ2 were similarly sensitive to stimulation by mastoparan.
It is concluded that mastoparan stimulates human myocardial PLC by a mechanism distinct from heterotrimeric G proteins.

British Journal of Pharmacology (1997) 122, 31–36; doi:10.1038/sj.bjp.0701341
Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats
Authors: Matsuura Takeshi , Miura Katsuyuki , Ebara Tsuneyuki , Yukimura Tokihito , Yamanaka Shinya , Kim Shokei , Iwao Hiroshi 
Published: January 2005

Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats.
Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 μmol kg−1, for 20 min) induced a very small fall in blood pressure. Similarly, a non‐selective ETA/ETB receptor antagonist, TAK‐044 (12.5 μmol kg−1, for 20 min) slightly decreased blood pressure. A selective ETB receptor antagonist, BQ‐788 (0.5 μmol kg−1, for 20 min) had no effect on blood pressure.
FR139317 and TAK‐044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ‐788 significantly reduced renal blood flow by 18.2±2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ‐788 was not observed when combined with FR139317.
Pretreatment with a nitric oxide (NO) synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 37 μmol kg−1, i.v.) and a cyclo‐oxygenase inhibitor ibuprofen (44 μmol kg−1, i.v.) completely abolished the BQ‐788‐mediated renal vasoconstriction.
These results indicate that activation of ETB receptors by endogenous ET acts as a physiological brake for the ETA‐mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.

British Journal of Pharmacology (1997) 122, 81–86; doi:10.1038/sj.bjp.0701349
Role of Na+‐K+ ATPase in cyclic GMP‐mediated relaxation of canine pulmonary artery smooth muscle cells
Authors: Tamaoki J. , Tagaya E. , Nishimura K. , Isono K. , Nagai A. 
Published: January 2005

Sodium‐potassium adenosine triphosphatase (Na+‐K+ ATPase) plays a role in the regulation of vascular tone, but contribution of this enzyme to nitrovasodilator‐induced pulmonary vasodilatation remains uncertain. We thus studied the interaction between guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) and Na+‐K+ ATPase in smooth muscle cells isolated from canine pulmonary artery.
To assess the contractile properties, changes in smooth muscle cell length were determined microscopically. Application of potassium chloride (KCl) shortened the cell length, an effect which was reduced by sodium nitroprusside and 8‐bromo‐cyclic GMP in a concentration‐dependent manner. Pretreatment of cells with the cyclic GMP‐dependent kinase inhibitor KT 5823 (2 μM) abolished the effects of sodium nitroprusside and 8‐bromo‐cyclic GMP.
Ouabain (0.3 μM) did not alter the KCl‐induced muscle shortening, but inhibited the relaxant responses to sodium nitroprusside and 8‐bromo‐cyclic GMP.
Incubation of smooth muscle cells with sodium nitroprusside concentration‐dependently increased intracellular cyclic GMP levels and ouabain‐sensitive 86Rb uptake, and these values were significantly correlated. In the presence of KT 5823, sodium nitroprusside increased cyclic GMP levels but did not alter ouabain‐sensitive 86Rb uptake.
These results suggest that there is a link between accumulation of intracellular cyclic GMP and activation of sarcolemmal Na+‐K+ ATPase in pulmonary artery smooth muscle cells and that this link may be involved in the sodium nitroprusside‐induced pulmonary vasodilatation.

British Journal of Pharmacology (1997) 122, 112–116; doi:10.1038/sj.bjp.0701351
Regulation of apical and basolateral K+ conductances in the rat colon
Authors: Schultheiß G. , Diener M. 
Published: January 2005

Apical administration of an ionophore, nystatin, and basolateral depolarization by K+ were used to investigate the regulation of apical and basolateral electrogenic transport pathways for K+ in the rat proximal and distal colon.
Administration of nystatin (100 μg ml−1 at the mucosal side), in the presence of Na+ and in the presence of a serosally directed K+ gradient, stimulate a large increase in short‐circuit current (ISC) and tissue conductance in both colonic segments. This response was composed of a pump current generated by the Na+‐K+‐ATPase and of a current across a quinine‐sensitive basolateral K+ conductance.
The pump current, measured as Na+‐dependent or scilliroside‐sensitive current in the absence of a K+ gradient, was significantly greater in the distal than in the proximal colon. The pump current was unaltered by pretreatment of the tissue with forskolin (5×10−6 mol l−1).
The current across the basolateral K+ conductance, measured as current in the presence of a serosally directed K+ gradient either in the absence of Na+ or in the presence of scilliroside, was increased by the cholinoreceptor agonist, carbachol (5×10−5 mol l−1), but inhibited by forskolin (5×10−6 mol l−1).
Basolateral K+ depolarization induced a negative ISC in both colonic segments, which was inhibited by the K+ channel blocker quinine (10−3 mol l−1 at the mucosal side), but was resistant to tetraethylammonium (5×10−3 mol l−1 at the mucosal side). This K+ current across an apical K+ conductance was stimulated in both colonic segments by carbachol, whereas forskolin had no effect, although control experiments revealed that forskolin was still able to open an apical Cl− conductance under these conditions.
These results demonstrate that an increase in intracellular Ca2+ concentration induced by carbachol causes an increase in the basolateral and the apical K+ conductance, thereby inducing K+ secretion in parallel with an indirect support for Cl− secretion due to the hyperpolarization of the cell membrane. In contrast, the dominating effect of an increase in the intracellular cyclic AMP concentration is inhibition of a basolateral K+ conductance; a mechanism which might contribute to the inhibition of K+ absorption.

British Journal of Pharmacology (1997) 122, 87–94; doi:10.1038/sj.bjp.0701353
Response of normoxic pulmonary arteries of the rat in the resting and contracted state to NO synthase blockade
Authors: Steeds R. P. , Thompson J. S. , Channer K. S. , Morice A. H. 
Published: January 2005

The pulmonary vasculature is normally in a low resting state of tone. It has been hypothesized that this basal tone is actively maintained by the continuous release of a vasodilator in the resting state. However, evidence for basal release of nitric oxide (NO) is inconclusive.
We studied the release of NO in arteries from the pulmonary circulation of male Wistar‐Kyoto rats by examining the effects of the L‐arginine analogue NG‐nitro‐L‐arginine methyl ester (L‐NAME) on resting pulmonary arteries and on vessels pre‐contracted with prostaglandin F2α (PGF2α).
Rats (n=21) were killed by an overdose with pentobarbitone. Pulmonary arteries were dissected (mean internal diameter 459±11 μm) and mounted in a small vessel wire myograph. Resting tensions were set to simulate transmural pressures of 17.5 mmHg.
L‐NAME (100 μM) was found to produce a contraction of 0.64±0.09 mN mm−1 in resting pulmonary arteries when added alone to the myograph bath. This contraction was not produced following removal of the endothelium. Vessel contraction to PGF2α (100 μM) was found to be significantly greater when carried out in the presence of L‐NAME (100 μM)–1.37±0.15 mN mm−1 compared with 1.96±0.17 mN mm−1. Dilatation following acetylcholine (ACh) (1 μM) was abolished in the presence of L‐NAME (100 μM).
Rat pulmonary artery contraction in response to the addition of L‐NAME and the absence of contraction upon removal of the endothelium provides supportive evidence of the active release of nitric oxide for the maintenance of resting tone.

British Journal of Pharmacology (1997) 122, 99–102; doi:10.1038/sj.bjp.0701356
Effects of homocysteine on acetylcholine‐ and adenosine‐induced vasodilatation of pancreatic vascular bed in rats
Authors: Quéré I. , Hillaire‐Buys D. , Brunschwig C. , Chapal J. , Janbon C. , Blayac J. P. , Petit P. , Loubatières‐Mariani M. M. 
Published: January 2005

Epidemiological and experimental data have shown that homocysteine may provoke vascular lesions and that moderate homocysteinaemia may constitute an independent risk factor for vascular disease. It is now documented that homocysteine damages human endothelial cells in culture, possibly by producing hydrogen peroxide in an oxygen‐dependent reaction.
In this study, we have examined the direct effect of this sulphur amino acid on pancreatic vascular resistance. Experiments were performed on the vascular bed of the rat isolated pancreas perfused at constant pressure; thus, any change in pancreatic vascular resistance resulted in a change in the flow rate. D,L‐Homocysteine perfused for one hour at three different concentrations (200 μM, 2 mM, 20 mM) did not induce any significant change in the flow rate per se. Homocysteine infusion for 30 min at a concentration of 200 μM or 2 mM abolished the endothelium‐dependent vasodilatation induced by acetylcholine (0.05 μM), but did not modify adenosine (1.5 μM)‐induced vasodilatation.
The effect of D,L‐homocysteine (200 μM or 2 mM) cannot be ascribed to a direct antimuscarinic effect since 30 min pretreatment of rat ileum with these concentrations did not significantly change the contractile effect of increasing concentrations of acetylcholine (0.015–15 μM).
Preincubation of human umbilical vein endothelial cells with D,L‐homocysteine (0.2–5.0 mM) had no significant effect on overall cell number or viability during 18 h of incubation; the endothelial cells exposed to concentrations up to 5 mM exhibited a spindle‐shaped, whirled pattern. This pattern was reversed 48 h after the removal of homocysteine. A cytotoxic effect was seen after 18 h incubation in 10 mM D,L‐homocysteine.
In conclusion, an acute infusion of homocysteine altered acetylcholine endothelium‐induced vasodilatation, whereas the adenosine vasodilatator effect was insensitive to the deleterious action of homocysteine in vitro.

British Journal of Pharmacology (1997) 122, 351–357; doi:10.1038/sj.bjp.0701358
Demonstration of the existence of nitric oxide‐independent as well as nitric oxide‐dependent vasodilator mechanisms in the in situ renal circulation in near term pregnant rats
Authors: Chu Z. M. , Beilin L. J. 
Published: January 2005

We have investigated the role of endogenous nitric oxide on renal vascular reactivity in late pregnancy in in situ blood perfused kidneys of α‐chloralose anaesthetized Wistar‐Kyoto rats. Nitric oxide synthesis inhibition was achieved by intravenous administration of NG‐nitro‐L‐arginine or NG‐nitro‐L‐arginine methyl ester.
Intra‐arterial mean blood pressure was lower in pregnancy compared with nonpregnant controls. Following nitric oxide synthesis inhibition mean blood pressure increased in both pregnant and nonpregnant groups, but remained lower in pregnant animals.
Basal renal perfusion pressure was similar in pregnant and nonpregnant groups. Intravenous administration of NG‐nitro‐L‐arginine resulted in dose‐dependent increases in renal perfusion pressure but responses were substantially depressed in pregnancy.
Renal vasoconstrictor responses to regional angiotensin II (AII) were decreased in pregnancy, whereas those to noradrenaline (NA) did not differ from nonpregnant controls. NG‐nitro‐L‐arginine (5 mg kg−1) potentiated renal responses to regional AII and NA in both groups, but AII responses remained lower in pregnancy. Blunted renal AII responses in pregnancy were still evident following large doses of NG‐nitro‐L‐arginine methyl ester (100 mg kg−1).
The results demonstrate that nitric oxide synthesis inhibition increases renal perfusion pressure to a lesser extent in pregnant compared with nonpregnant rats, and that reduced renal pressor responses to AII are still evident in pregnancy after nitric oxide synthesis inhibition.
These results suggest that although endogenous nitric oxide synthesis modulates renal vasoconstrictor responses in both pregnant and nonpregnant animals, this mechanism does not fully account for the blunted renal vasoconstrictor responses to regional AII or nitric oxide inhibitors in near term pregnant rats. The nature of this important physiological vasodilator mechanism in pregnancy remains to be elucidated.

British Journal of Pharmacology (1997) 122, 307–315; doi:10.1038/sj.bjp.0701363
Central benzodiazepine receptor autoradiography in hippocampal sclerosis
Authors: Hand Kieran S. P. , Baird Virginia H. , Van Paesschen Wim , Koepp Matthias J. , Revesz Tamas , Thom Maria , Harkness William F. J. , Duncan John S. , Bowery Norman G. 
Published: January 2005

The γ‐aminobutyric acid (GABA)A/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. Binding of [11C]‐flumazenil to this complex in vivo is reduced in hippocampal sclerosis (HS). It has been uncertain whether reduced cBZR binding is entirely due to neuronal loss in HS.
The objective of this study was to characterize abnormalities of the cBZR in HS with a correlative autoradiographic and quantitative neuropathological study.
Saturation autoradiographic studies were performed with [†H]‐flumazenil to investigate relationships between neuronal density and receptor availability (Bmax) and affinity (Kd) in HS. Hippocampal tissue was obtained at surgery from 8 patients with intractable temporal lobe epilepsy (TLE) due to HS and autopsies of 6 neurologically normal controls. Neuronal densities were obtained by means of a 3‐D counting method.
Bmax values for [†H]‐flumazenil binding in the subiculum, CA1, CA2, CA3, hilus and dentate gyrus were all found to be significantly reduced in HS compared with controls and significant increases in affinity were observed in the subiculum, hilus and dentate gyrus. In HS, cBZR density in the CA1 region was significantly reduced (P<0.05) to a greater extent than could be attributable to neurone loss. In other regions, Bmax was reduced in parallel with neuronal density.
In HS, there is a loss of cBZR in CA1 over and above loss of neurones. This finding and increases in affinity for flumazenil in subiculum, hilus and dentate gyrus imply a functional abnormality of the GABAA/cBZR complex that may have a role in the pathophysiology of epileptogenicity in HS.

British Journal of Pharmacology (1997) 122, 358–364; doi:10.1038/sj.bjp.0701365
Ligand binding specificities of the eight types and subtypes of the mouse prostanoid receptors expressed in Chinese hamster ovary cells
Authors: Kiriyama Michitaka , Ushikubi Fumitaka , Kobayashi Takuya , Hirata Masakazu , Sugimoto Yukihiko , Narumiya Shuh 
Published: January 2005

Eight types and subtypes of the mouse prostanoid receptor, the prostaglandin D (DP) receptor, the prostaglandin F (FP) receptor, the prostaglandin I (IP) receptor, the thromboxane A (TP) receptor and the EP1, EP2, EP3 and EP4 subtypes of the prostaglandin E receptor, were stably expressed in Chinese hamster ovary cells. Their ligand binding characteristics were examined with thirty two prostanoids and their analogues by determining the Ki values from the displacement curves of radioligand binding to the respective receptors.
The DP, IP and TP receptors showed high ligand binding specificity and only bound their own putative ligands with high affinity such as PGD2, BW245C and BW868C for DP, cicaprost, iloprost and isocabacyclin for IP, and S‐145, I‐BOP and GR 32191 for TP.
The FP receptor bound PGF2α and fluprostenol with Ki values of 3–4 nM. In addition, PGD2, 17‐phenyl‐PGE2, STA2, I‐BOP, PGE2 and M&B̀‐28767 bound to this receptor with Ki values less than 100 nM.
The EP1 receptor bound 17‐phenyl‐PGE2, sulprostone and iloprost in addition to PGE2 and PGE1, with Ki values of 14–36 nM. 16,16‐dimethyl‐PGE2 and two putative EP1 antagonists, AH6809 and SC‐19220, did not show any significant binding to this receptor. M&B‐28767, a putative EP3 agonist, and misoprostol, a putative EP2/EP3 agonist, also bound to this receptor with Ki values of 120 nM.
The EP2 and EP4 receptors showed similar binding profiles. They bound 16,16‐dimethyl PGE2 and 11‐deoxy‐PGE1 in addition to PGE2 and PGE1. The two receptors were discriminated by butaprost, AH‐13205 and AH‐6809 that bound to the EP2 receptor but not to the EP4 receptor, and by 1‐OH‐PGE1 that bound to the EP4 but not to the EP2 receptor.
The EP3 receptor showed the broadest binding profile, and bound sulprostone, M&B‐28767, GR63799X, 11‐deoxy‐PGE1, 16,16‐dimethyl‐PGE2 and 17‐phenyl‐PGE2, in addition to PGE2 and PGE1, with Ki values of 0.6–3.7 nM. In addition, three IP ligands, iloprost, carbacyclin and isocarbacyclin, and one TP ligand, STA2, bound to this receptor with Ki values comparable to the Ki values of these compounds for the IP and TP receptors, respectively.
8‐Epi‐PGF2α showed only weak binding to the IP, TP, FP, EP2 and EP3 receptor at 10 μM concentration.

British Journal of Pharmacology (1997) 122, 217–224; doi:10.1038/sj.bjp.0701367
The antiarrhythmic agent bertosamil induces inactivation of the sustained outward K+ current in human atrial myocytes
Authors: Tessier Sophie , Rücker‐Martin Catherine , Macé Loïc , Coraboeuf Edouard , Mercadier Jean‐Jacques , Hatem Stéphane N. 
Published: January 2005

In whole‐cell patch‐clamped human atrial myocytes, the antiarrhythmic agent bertosamil (10 μM) inhibited the sustained component, Isus (38.6±3.1%), and enhanced the inactivating component, It (9.1±6.1%), of the outward K+ current elicited by 750 ms test pulses from −60 mV to +50 mV. Higher concentrations of bertosamil (>10 μM) inhibited both It and Isus.
Suppression of Isus and stimulation of It by 10 μM bertosamil was observed on renewed stimulation following a 2 min rest period during which the drug was applied and persisted after washout, indicating a rest‐dependent effect of bertosamil on the outward K+ current.
Cell dialysis with an internal solution containing 10 μM bertosamil increased both It (78.0±14.7%) and Itotal (26.7±8.4%) and inhibited Isus (28.9±6.3%, n=6). In the presence of intracellular bertosamil, external application of the drug inhibited It and Isus in a concentration‐dependent and use‐dependent manner.
Following the suppression of Isus by 200 μM 4‐aminopyridine (4‐AP), bertosamil (10 μM) inhibited It. Washout of 4‐AP was associated with a larger It amplitude than that observed in control conditions. In myocytes characterized by a prominent Isus and lack of It, bertosamil (10 μM) induced a rapid and partial inactivation of the current, together with inward rectification of the current measured at the end of the test pulse.
In the presence of bertosamil the activation/voltage relationships, steady‐state inactivation and recovery from inactivation of It were markedly modified, pointing to changes in the conductance underlying It.
We conclude that bertosamil induces rapid inactivation of sustained outward current which leads to an apparent increase in It and decrease in Isus. This effect, which was distinct from the use‐dependent inhibition of the outward K+ current, could represent a new antiarrhythmic mechanism.

British Journal of Pharmacology (1997) 122, 291–301; doi:10.1038/sj.bjp.0701369