bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of two pharmacologically predicted endothelin B receptor subtypes by using the endothelin B receptor gene knockout mouse
Authors: Mizuguchi Tadahiko , Nishiyama Mariko , Moroi Kayoko , Tanaka Hirokazu , Saito Toshihiro , Masuda Yoshiaki , Masaki Tomoh , De Wit Damiane , Yanagisawa Masashi , Kimura Sadao 
Published: August 2006

This study was performed to clarify whether the endothelin (ET) receptor subtypes mediating two pharmacologically heterogeneous response to ETB receptor agonists in normal mice are the product(s) of a single ETB receptor gene.
Vasodilator responses to sarafotoxin S6c (S6c) in the thoracic aorta and contractile responses to ET‐1 and IRL1620 in the stomach were examined in tissues from normal and ETB receptor gene knockout mice, in the absence and presence of an ETA receptor antagonist, BQ‐123, or an ETA/ETB receptor antagonist, PD142893.
In the normal mouse aorta precontracted with phenylephrine, S6c (0.1100 nm) caused concentration‐dependent relaxations (pD2=8.4). BQ‐123 had no effect on these responses. However, PD142893 almost abolished the relaxations induced by 0.1300 nm S6c.
In aortae taken from ETB receptor gene knockout mice, S6c up to 1 μm failed to cause relaxations, confirming that ETB receptors are involved in mediating this response.
In normal mouse gastric fundus, 0.1 nm1 μm ET‐1, S6c or IRL1620 caused dose‐dependent, BQ‐123‐insensitive contractions, which were much more resistant to PD142893 than S6c‐induced relaxations of the aorta. The pD2 values for S6c in the absence and presence of PD142893 (10 μm) were 8.12±0.11 and 7.70±0.11, respectively.
In the gastric fundus of the ETB receptor gene knockout mouse, S6c and IRL1620 caused no contractions. ET‐1 (0.1 nm1 μm) caused contractions sensitive to both BQ‐123 and PD142893, indicating that only ETA receptors mediate ET‐1‐induced contractions of the knockout mouse gastric fundus.
Since both the PD142893‐sensitive vasodilator response of the aorta and the PD142893‐resistant contractile response of the gastric fundus to S6c were completely absent in the ETB receptor gene knockout mouse, we conclude that the two pharmacologically heterogeneous responses to S6c are mediated by receptors derived from the same ETB receptor gene.

British Journal of Pharmacology (1997) 120, 1427–1430; doi:10.1038/sj.bjp.0701054
Role of intracellular calcium in fast and slow desensitization of P2‐receptors in PC12 cells
Authors: Khiroug L. , Giniatullin R. , Talantova M. , Nistri A. 
Published: August 2006

Combined whole‐cell patch clamp recording and confocal laser scanning microscopy of [Ca2+]i transients were performed on single PC12 cells to study any correlation between membrane currents induced by ATP and elevation in [Ca2+]i. ATP was applied by pressure from micropipettes near the recorded PC12 cells continuously superfused at a fast rate.
Brief (20 ms) pulses of ATP elicited monophasic inward currents and [Ca2+]i increases. Long applications (2 s) of ATP (5 mm) evoked peak currents which rapidly faded during the pulse and were followed by a large rebound current, interpreted as due to rapid desensitization and recovery of P2‐ receptors. The associated [Ca2+]i increase grew monotonically to a peak reached only after the occurrence of the current rebound, indicating that it is unlikely this cation has a role in fast desensitization.
Both membrane currents and [Ca2+]i transients were linearly dependent on holding membrane potential, suggesting that Ca2+ influx is the predominant cause of [Ca2+]i elevation. This view was supported by experiments carried out in Ca2+‐free solution.
Brief pulses of ATP applied after a desensitizing pulse (2 s) of the same elicited smaller inward currents and [Ca2+]i rises indicating a role for [Ca2+]i in controlling slow desensitization of P2‐receptors.
This notion was confirmed in experiments with various [Ca2+]i chelators which differentially affected slow desensitization in relation to their buffering capacity, while sparing fast receptor desensitization.
These results suggest a role for [Ca2+]i in slow rather than fast desensitization of P2‐receptors, thus proposing this divalent cation as an intracellular factor able to provide an efficient and reversible control over receptor activity induced by ATP.

British Journal of Pharmacology (1997) 120, 1552–1560; doi:10.1038/sj.bjp.0701060
The effect of ketotifen on nitric oxide synthase activity
Authors: Heyman Samuel N. , Karmeli Fanny , Brezis Mayer , Rachmilewitz Daniel 
Published: August 2006

We studied the effect of ketotifen, a second generation H1‐receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo.
Ketotifen (100 μg ml−1) increased human colonic NOS activity from 3.7±0.6 to 14.5±1.3 nmol g−1 min−1 (P<0.005, ANOVA). In rat renal cortical and medullary tissues ketotifen increased NOS activity by 55% and 86%, respectively (P<0.001). The stimulation of NOS activity was attenuated by NADPH deletion and by the addition of Nω nitro‐l‐arginine methyl ester (l‐NAME) or aminoguanidine, but not by [Ca2+] deprivation. NOS activity was unaffected by two other H1‐antagonists, diphenhydramine and astemizole, or by the structurally related cyproheptadine. Renal cortical NOS activity was also significantly stimulated 90 min after intravenous administration of ketotifen to anaesthetized rats.
Ketotifen administration to anaesthetized rats induced modest declines in blood pressure and reduced total renal, cortical and outer medullary vascular resistance. This is in contrast to diphenhydramine, which did not induce renal vasodilatation.
We conclude that ketotifen stimulates NOS activity by mechanisms other than H1‐receptor antagonism. The association of this effect with therapeutic characteristics of ketotifen and the clinical implications of these findings are yet to be defined.

British Journal of Pharmacology (1997) 120, 1545–1551; doi:10.1038/sj.bjp.0701063
Absence of prostaglandin E2‐induced hyperalgesia in NMDA receptor ε subunit knockout mice
Authors: Minami Toshiaki , Sugatani Junko , Sakimura Kenji , Abe Manabu , Mishina Masayoshi , Ito Seiji 
Published: August 2006

We have previously found that intrathecal administration of prostaglandins E2 (PGE2) and D2 (PGD2) into conscious mice induced hyperalgesia by the hot plate test. The present study investigated the involvement of N‐methyl‐d‐aspartate (NMDA) receptor in the prostaglandin‐induced hyperalgesia by use of mice lacking NMDA receptor ε1, ε4, or ε1/ε4 subunits.
PGE2 induced hyperalgesia over a wide range of doses from 50 pg to 500 ng kg−1 in wild‐type mice. But PGE2 could not induce hyperalgesia in ε1, ε4, or ε1/ε4 subunit knockout mice.
The NMDA receptor antagonist d‐(−)‐2‐amino‐5‐phosphonovaleric acid (d‐AP5), the non‐NMDA receptor antagonist γ‐d‐glutamylaminomethyl sulphonic acid (GAMS), and the nitric oxide synthase inhibitor Nω‐nitro‐l‐arginine methyl ester (l‐NAME) inhibited the PGE2‐induced hyperalgesia in wild‐type mice.
PGD2 induced hyperalgesia at doses of 25 ng to 250 ng kg−1 in both wild‐type and ε1/ε4 subunit knockout mice. The substance P receptor antagonist CP 96,345 blocked the PGD2‐induced hyperalgesia in wild‐type and ε1/ε4 subunit knockout mice.
These results demonstrate that the pathways leading to hyperalgesia are different between PGD2 and PGE2 and that both ε1 and ε4 subunits of the NMDA receptor are involved in the PGE2‐induced hyperalgesia.

British Journal of Pharmacology (1997) 120, 1522–1526; doi:10.1038/sj.bjp.0701067
Species‐dependent differences in inotropic effects and phosphoinositide hydrolysis induced by endothelin‐3 in mammalian ventricular myocardium
Authors: Yang Huang‐Tian , Zhu Yi , Endoh Masao 
Published: August 2006

Species‐dependent variations in the positive inotropic effect (PIE) of endothelin‐3 (ET‐3), and the relationships between the PIE and specific binding sites for [125I]‐ET‐3 and the PIE and the acceleration of phosphoinositide hydrolysis by ET‐3, were studied in ventricular muscles from the rat, guinea‐pig, rabbit, ferret and dog.
ET‐3 in the presence of (±)‐bupranolol (0.3 μm) and prazosin (0.3 μm) elicited a concentration‐dependent PIE in the ventricular muscle from the rat, guinea‐pig, rabbit and ferret. The potency of ET‐3 and its efficacy in inducing a PIE were highest in the rabbit, intermediate in the rat and guinea‐pig and lowest in the ferret. ET‐3 did not have any inotropic effect on ventricular muscle from the dog.
Specific high‐affinity binding of [125I]‐ET‐3 was observed with membrane fractions derived from the ventricular muscle of the five species. The maximal specific binding (Bmax) of ET‐3 was highest in the rat and guinea‐pig, intermediate in the rabbit and ferret and lowest in the dog. The values of KD in the rabbit and dog (33 and 52 pm) were lower than those in the rat, guinea‐pig and ferret (141221 pm).
In slices of ventricular muscle from all five species, ET‐3 increased the accumulation of [3H]‐inositol monophosphate (IP1) in a concentration‐dependent manner. The extent of accumulation of IP1 was highest in the rat, intermediate in the guinea‐pig and rabbit and lowest in the ferret and dog.
The results demonstrate the wide range of variations in the PIE of ET‐3 on mammalian ventricular muscles. The variations in the coupling processes subsequent to the acceleration of the hydrolysis of PI, triggered by the binding of ET‐3 to its receptor, might be important in these species‐dependent differences in the PIE of ET‐3.

British Journal of Pharmacology (1997) 120, 1497–1504; doi:10.1038/sj.bjp.0701085
Suppressive effect of melatonin administration on ethanol‐induced gastroduodenal injury in rats in vivo
Authors: Melchiorri Daniela , Sewerynek Ewa , Reiter Russel J , Ortiz Genaro G , Poeggeler Burkhard , Nisticò Giuseppe 
Published: August 2006

Melatonin protection against ethanol‐induced gastroduodenal injury was investigated in duodenum‐ligated rats.
Melatonin, injected i.p. 30 min before administration of 1 ml of absolute ethanol, given by gavage, significantly decreased ethanol‐induced macroscopic, histological and biochemical changes in the gastroduodenal mucosa.
Ethanol‐induced lesions were detectable as haemorrhagic streaks. Ethanol administration damaged 36% and 25% of the total gastric and duodenal surface, respectively. Melatonin treatment reduced ethanol‐induced gastric and duodenal damage to 14% and 8%, respectively. When indomethacin was given together with ethanol, the gastric damaged area was 44% of the total surface, while the duodenal damaged area was 35%; melatonin administration reduced the damage to only 13% of the total gastric surface and to 12% of total duodenal surface.
Both stomach and duodenum of ethanol‐treated animals showed polymorphonuclear leukocyte (PMN) infiltration. The number of PMN increased more than 600 and 200 times in stomach and duodenum, respectively, following ethanol administration. Melatonin treatment reduced ethanol‐induced PMN infiltration by 38% in the stomach and 20% in the duodenum. In indomethacin‐ethanol‐treated rats, the number of PMN increased by 875% compared to control group in the stomach and by 264% in duodenum. Melatonin administration reduced the indomethacin‐ethanol‐induced PMN rise by 57% in the stomach and 40% in the duodenum.
Gastroduodenal total glutathione (tGSH) concentration and glutathione reductase (GSSG‐Rd) activity were significantly reduced following ethanol and indomethacin‐ethanol administration. Melatonin ameliorated both the decrease in tGSH concentration as well as the reduction of GSSG‐Rd activity elicited by ethanol both in the stomach and duodenum; melatonin was effective against indomethacin‐ethanol‐induced damage only in the stomach.
Ethanol‐induced gastroduodenal damage is believed to be mediated by the generation of free radicals. Recently, a number of in vivo and in vitro experiments have shown melatonin to be an effective antioxidant and free radical scavenger; thus, we conclude that the protection by melatonin against ethanol‐induced gastroduodenal injury is due, at least in part, to its radical scavenging activity.

British Journal of Pharmacology (1997) 121, 264–270; doi:10.1038/sj.bjp.0701104
Central antitussive activity of the NK1 and NK2 tachykinin receptor antagonists, CP‐99,994 and SR 48968, in the guinea‐pig and cat
Authors: Bolser Donald C , DeGennaro Frances C , O'Reilly Sandra , McLeod Robbie L , Hey John A 
Published: August 2006

The purpose of this study was to investigate the antitussive activity and sites of action of the NK1 and NK2 tachykinin receptor antagonists, CP‐99,994, SR 48968, and the racemate of SR 48968, SR 48212A in the cat and guinea‐pig.
Guinea‐pigs were dosed subcutaneously (s.c.) with CP‐99,994, SR 48212A or SR 48968 one hour before exposure to aerosols of capsaicin (0.3 mM) to elicit coughing. Coughs were detected with a microphone and counted.
Intracerebroventricular (i.c.v.) cannulae were placed in the lateral cerebral ventricles of anaesthetized guinea‐pigs. Approximately one week later, the animals were dosed with CP‐99,994 or SR 48212A (i.c.v.) and exposed to aerosols of capsaicin (0.3 mM) to elicit coughing.
Cough was produced in anaesthetized cats by mechanical stimulation of the intrathoracic trachea and was monitored from electromyograms of respiratory muscle activity. Cannulae were placed for intravenous (i.v.) or, in separate groups of animals, intravertebral arterial (i.a.) administration of CP‐99,994, SR 48212A or SR 48968. Dose‐response relationships for i.v. and i.a. administration of each drug were generated to determine a ratio of i.v. ED50 to i.a. ED50, known as the effective dose ratio (EDR). The EDR will be 20 or greater for a centrally active drug and less than 20 for a peripherally active drug.
In the guinea‐pig, CP‐99,994 (0.1–30 mg kg−1, s.c.), SR 48212A (1.0–30 mg kg−1, s.c.), and SR 48968 (0.3–3.0 mg kg−1, s.c.) inhibited capsaicin‐induced cough in a dose‐dependent manner. Capsaicin‐induced cough was also inhibited by i.c.v. administration of CP‐99,994 (10 and 100 μg) or SR 48212A (100 μg).
In the cat, both CP‐99,994 (0.0001–0.3 mg kg−1, i.a., n=5; 0.003–3.0 mg kg−1, i.v., n=5) and SR 48212A (0.003–1.0 mg kg−1, i.a., n=5; 0.01–3.0 mg kg−1, i.v., n=5) inhibited mechanically induced cough by either the i.v. or i.a. routes in a dose‐dependent manner. SR 48968 (0.001–0.3 mg kg−1, i.a., n=5; 0.03–1.0 mg kg−1, i.v., n=5) inhibited cough when administered by the i.a. route in a dose‐dependent manner, but had no effect by the i.v. route up to a dose of 1.0 mg kg−1. Intravenous antitussive potencies (ED50, 95% confidence interval (CI)) of these compounds were: CP‐99,994 (0.082 mg kg−1, 95% CI 0.047–0.126), SR 48212A (2.3 mg kg−1, 95% CI 0.5–20), and SR 48968 (>1.0 mg kg−1, 95% CI not determined). The intra‐arterial potencies of these compounds were: CP‐99,994 (1.0 μg kg−1, 95% CI 0.4–1.8), SR 48212A (25 μg kg−1, 95% CI 13–52), and SR 48968 (8.0 μg kg−1, 95% CI 1–32). The derived EDRs for each compound were: CP‐99,994, 82; SR 48212A, 92; and SR 48968, >125.
We concluded that CP‐99,994 and SR 48968 inhibit cough in the guinea‐pig and cat by a central site of action. In the cat, the antitussive action of these compounds appears to be solely by a central site.

British Journal of Pharmacology (1997) 121, 165–170; doi:10.1038/sj.bjp.0701111
The stimulation of human neutrophil migration by angiotensin II: its dependence on Ca2+and the involvement of cyclic GMP
Authors: Elferink Jan G. R. , de Koster Ben M. 
Published: August 2006

Angiotensin II had a bimodal effect on human neutrophil migration. Low concentrations of angiotensin II stimulated random migration. At a concentration of 10−10Mit caused a maximal increase of migration; migration increased from 47.2±2.1 μm in the absence of angiotensin II, to 73.1±2.2 μm with 10−10Mangiotensin II present in the lower compartment of the Boyden chamber (n=5,P<0.001). Stimulation of migration by angiotensin II was partly chemotactic and partly chemokinetic. Angiotensin II concentrations of 10−8Mand higher inhibited chemotactic peptide‐stimulated chemotaxis.The stimulant effect of angiotensin II on migration was completely dependent on extracellular Ca2+. In the presence of 1 mMCa2+, angiotensin II stimulated migration to 76.1±1.7 μm, while migration in the absence of Ca2+was 42.2±1.9 μm (n=4,P<0.001). Different types of calcium channel blockers either moderately or strongly inhibited angiotensin II‐activated migration. Stimulation of migration by angiotensin II in intact cells required higher concentrations of Ca2+than in electroporated cells. This supports the view that there is an influx of Ca2+through the plasma membrane, and a requirement of calcium for an intracellular target.Angiotensin II‐stimulated migration was inhibited by pertussis toxin; from 71.6±2.0 μm in the absence, to 43.6±1.5 μm in the presence of pertussis toxin (n=4,P<0.001). Migration of electroporated neutrophils stimulated by angiotensin II was synergistically enhanced by GTPγS. This suggests that one or more G‐proteins are involved in the activating effect of angiotensin II.Inhibitors of soluble guanylate cyclase and antagonists of cyclic GMP‐dependent kinase strongly inhibited the activating effect of angiotensin II. The results suggest that the activating effect of angiotensin II is mediated by cyclic GMP and by cyclic GMP‐dependent kinase.British Journal of Pharmacology(1997)121, 643–648; doi:10.1038/sj.bjp.0701167
Suppression by cyclosporin A of interleukin 1β‐induced expression of group II phospholipase A2 in rat renal mesangial cells
Authors: Walker Gaby , Kunz Dieter , Pignat Werner , van den Bosch Henk , Pfeilschifter Josef 
Published: August 2006

We investigated whether cyclosporin A, a potent immunosuppressive drug, affects group II phospholipase A2 (PLA2; EC 3.1.1.4) induction in rat renal mesangial cells.
Previously we showed that the expression of group II PLA2 in rat renal mesangial cells is triggered by exposure of the cells to inflammatory cytokines such as interleukin 1β (IL‐1β) or tumour necrosis factor α and agents that elevate cellular levels of cyclic AMP. Treatment of mesangial cells with IL‐1β for 24 h induced PLA2 activity secreted into cell culture supernatants by about 16 fold. Incubation of mesangial cells with cyclosporin A inhibited IL‐1β‐induced PLA2 section in a dose‐dependent fashion, with an IC50 value of 4.3 μM. Cyclosporin A did not directly inhibit enzymatic activity of PLA2.
Immunoprecipitation of radioactively labelled PLA2 protein from mesangial cell supernatants revealed that the inhibition of PLA2 activity is due to a suppression of PLA2 protein levels. This effect was preceded by a reduction of PLA2 mRNA steady state levels, as demonstrated by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells.
In order to evaluate whether cyclosporin A would affect the transcriptional activity of the PLA2 gene, we performed nuclear run on transcription experiments and provided evidence that the transcription rate of the PLA2 gene is reduced by cyclosporin A.
Previously we found that the nuclear transcription factor κB (NFκB) is an essential component of the IL‐1β‐dependent upregulation of PLA2 gene transcription. By electrophoretic mobility shift analysis, we demonstrated that cyclosporin A diminishes the formation of NFκB DNA‐binding complexes, thus suggesting that this transcription factor is a target for cyclosporin A‐mediated repression of PLA2 gene transcription.
The data presented in this study strongly suggest that the cellular mechanism involved in the IL1β ‐ dependent transcriptional upregulation of the PLA2 gene in mesangial cells is a target for the action of cyclosporin A.

British Journal of Pharmacology (1997) 121, 787–793; doi:10.1038/sj.bjp.0701170
The involvement of reactive oxygen species and arachidonic acid in α1‐adrenoceptor‐induced smooth muscle cell proliferation and migration
Authors: Nishio Eisuke , Watanabe Yasuhiro 
Published: August 2006

In a previous study, we demonstrated phenylephrine‐stimulated arachidonic acid (AA) release in rabbit cultured aortic smooth muscle cells. Therefore, we have investigated the functional implications of AA which are involved in the cellular response to phenylephrine, particularly proliferation and migration of rabbit cultured aortic smooth muscle cells.
First, to determine whether AA directly modifies proliferation and mobility of vascular smooth muscle cells (VSMCs), we exposed the cells to AA. AA induced proliferation and migration of the cells in a dose‐dependent fashion. Concomitantly added catalase inhibited the proliferation and chemotaxis induced by AA of VSMCs. Conversely, aminotriazole enhanced the proliferation and migration induced by AA.
Secondly, we investigated whether the proliferation and migration of VSMCs by phenylephrine were related to AA and hydrogen peroxide (H2O2). The proliferation and chemotaxis of VSMCs by phenylephrine were inhibited by a phospholipase A2 (PLA2) inhibitor, or catalase.
Lastly, we investigated the effects of AA and phenylephrine on the content of H2O2 in VSMCs. AA and phenylephrine treatment led to an increase of H2O2 in a dose‐dependent manner.
These results suggest that the addition of phenylephrine to the cells caused the enhancement of proliferation and migration, probably by mediating AA release and reactive oxygen species (ROS) production.

British Journal of Pharmacology (1997) 121, 665–670; doi:10.1038/sj.bjp.0701171
Inhibition of Ca2+ channel current by μ‐ and κ‐opioid receptors coexpressed in Xenopus oocytes: desensitization dependence on Ca2+ channel α1 subunits
Authors: Kaneko Shuji , Yada Nobumichi , Fukuda Koichiro , Kikuwaka Masanobu , Akaike Akinori , Satoh Masamichi 
Published: August 2006

Desensitization of μ‐ and κ‐opioid receptor‐mediated inhibition of voltage‐dependent Ca2+ channels was studied in a Xenopus oocyte translation system.
In the oocytes coexpressing κ‐opioid receptors with N‐ or Q‐type Ca2+ channel α1 and β subunits, the κ‐agonist, U50488H, inhibited both neuronal Ca2+ channel current responses in a pertussis toxin‐sensitive manner and the inhibition was reduced by prolonged agonist exposure.
More than 10 min was required to halve the inhibition of Q‐type channels by the κ‐agonist. However, the half‐life for the inhibition of N‐type channels was only 6±1 min. In addition, in the oocytes coexpressing μ‐opioid receptors with N‐type or Q‐type channels, the uncoupling rate of the μ‐receptor‐mediated inhibition of N‐channels was also faster than that of Q‐type channels.
In the oocytes coexpressing both μ‐ and κ‐receptors with N‐type channels, stimulation of either receptor resulted in a cross‐desensitization of the subsequent response to the other agonist. Treatment of oocytes with either H‐8 (100 μM), staurosporine (400 nM), okadaic acid (200 nM), phorbol myristate acetate (5 nM) or forskolin (50 μM) plus phosphodiesterase inhibitor did not affect either the desensitization or the agonist‐evoked inhibition of Ca2+ channels.
These results suggest that the rate of rapid desensitization is dependent on the α1 subtype of the neuronal Ca2+ channel, and that a common phosphorylation‐independent mechanism underlies the heterologous desensitization between opioid receptor subtypes.

British Journal of Pharmacology (1997) 121, 806–812; doi:10.1038/sj.bjp.0701181