bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anti‐emetic effects of CP‐99,994 in the ferret and the dog: role of the NK1 receptor
Authors: Watson J.W. , Gonsalves S.F. , Fossa A.A. , McLean S. , Seeger T. , Obach S. , Andrews P.L.R. 
Published: July 2012

The selective NK1 receptor antagonist, CP‐99,994, produced dose‐related (0.1‐1.0 mg kg−1, s.c.) inhibition of vomiting and retching in ferrets challenged with central (loperamide and apomorphine), peripheral (CuSO4) and mixed central and peripheral (ipecac, cisplatin) emetic stimuli.
Parallel studies with the enantiomer, CP‐100,263 (1 mgkg−1, s.c), which is > 1 000 fold less potent as a NK1 antagonist, indicated that it was without significant effect against CuSO4, loperamide, cisplatin and apomorphine‐induced emesis. Against ipecac, it inhibited both retching and vomiting, expressing approximately l/10th the potency of CP‐99,994.
The 5‐HT3 receptor antagonist, tropisetron (lmgkg−1, s.c.) inhibited retching and vomiting to cisplatin and ipecac, but not CuSO4 or loperamide.
CP‐99,994 (lmgkg−1, i.v.) blocked retching induced by electrical stimulation of the ventral abdominal vagus without affecting the cardiovascular response, the apnoeic response to central vagal stimulation or the guarding and hypertensive response to stimulation of the greater splanchnic nerves. CP‐99,994 (1 mg kg−1, i.v.) did not alter baseline cardiovascular and respiratory parameters and it failed to block the characteristic heart rate, blood pressure and respiratory rate/depth changes in response to i.v. 2‐methyl‐5‐HT challenge (von Bezold‐Jarisch reflex).
Using in vitro autoradiography, [3H]‐substance P was shown to bind to several regions of the ferret brainstem with the density of binding in the nucleus tractus solitarius being much greater than in the area postrema. This binding was displaced by CP‐99,994 in a concentration‐related manner.
In dogs, CP‐99,994 (40 μg kg−1 bolus and 300 μg kg−1 h−1, i.v.) produced statistically significant reductions in vomiting to CuSO4 and apomorphine as well as retching to CuSO4.
Together, these studies support the hypothesis that the NK1 receptor antagonist properties of CP‐99,994 are responsible for its broad spectrum anti‐emetic effects. They also suggest that CP‐99,994 acts within the brainstem, most probably within the nucleus tractus solitarius although the involvement of the area postrema could not be excluded.
Interaction of the antiarrhythmic agents SR 33589 and amiodarone with the β‐adrenoceptor and adenylate cyclase in rat heart
Authors: Chatelain P. , Meysmans L. , Mattéazzi J.R. , Beaufort Ph. , Clinet M. 
Published: July 2012

The effects of SR 33589 and amiodarone on the cardiac β‐adrenoceptor were studied in vitro and after chronic treatment by means of [125I]‐(−)−iodocyanopindolol ([125I]‐(−)−CYP) binding and measurement of adenylate cyclase activity.
Binding of [125I]‐(−)−CYP was inhibited in a dose‐dependent manner by SR 33589 (IC50 = 1.8 ± 0.4 μM, nH = 0.93 ± 0.06) and amiodarone (IC50 = 8.7 ± 2.0 μM, nH = 0.92 ± 0.03). Saturation binding experiments indicated a non‐competitive interaction such that SR 33589 (1 and 3 μm) and amiodarone (5 and 10 μm) reduced the Bmax of [125I]‐(−)−CYP binding without any effect on the KD. Kinetic studies showed that the rate of association of [125I]‐(−)−CYP was unchanged while the rate of dissociation was increased both in the presence of SR 33589 (10 μm) and amiodarone (30 μM).
Under the same conditions, the receptor stimulated adenylate cyclase activity was inhibited in a dose‐dependent, but non‐competitive manner, by SR 33589 (isoprenaline‐, glucagon‐ and secretin‐stimulated enzyme inhibited 50% at 6.8 ± 0.6 μM, 31 ± 10 μm and 12 ± 3 μM, respectively) while the basal, GTP‐ and Gpp(NH)p‐stimulated enzyme was inhibited by 5–10% and the NaF and forskolin‐stimulated enzyme by 50% at 500 μM. Amiodarone exhibited a similar pattern of inhibition.
After chronic oral treatment (50, 100, 150 mg kg−1 per day, 14 days), both SR 33589 and amiodarone produced a dose‐dependent decrease in Bmax without any effect on KD as determined from [125I]‐(−)−CYP saturation experiments and a decrease of the isoprenaline‐ and glucagon‐stimulated adenylate cyclase activity without any effect on basal enzyme activity or activity when stimulated by agents acting directly on regulatory catalytic units.
Unlike amiodarone, SR 33589 does not contain iodine substituents. Plasma levels of T3, T4 and rT3 were unchanged after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose‐dependently increased by amiodarone treatment.
In vitro, SR 33589 and amiodarone were characterized as non‐competitive β‐adrenoceptor antagonists. Chronic treatment led to a down‐regulation of the β‐adrenoceptor; the down‐regulation cannot be attributed to an indirect effect mediated by the thyroid hormones. To reconcile these opposing observations, we propose that SR 33589 and amiodarone interact with the β‐adrenoceptor at a site close to the intracellular loops which are involved in the coupling with Gs and contain the phosphorylable sites.
YC‐1 inhibited human platelet aggregation through NO‐independent activation of soluble guanylate cyclase
Authors: Wu Chin‐Chung , Ko Feng‐Nien , Kuo Sheng‐Chu , Lee Fang‐Yu , Teng Che‐Ming 
Published: July 2012

Our previous study demonstrated that YC‐1, a derivative of benzylindazole, is a novel activator of soluble guanylate cyclase (sGC) in rabbit platelets. This work investigated whether the antiplatelet effect of YC‐1 was mediated by a nitric oxide (NO)/sGC/cyclic GMP pathway in human platelets.
In human washed platelets, YC‐1 inhibited platelet aggregation and ATP released induced by U46619 (2 μm), collagen (10 μg ml−1) and thrombin (0.1 u ml−1) in a concentration‐dependent manner with IC50 values of (μm) 2.1 ± 0.3, 11.7 ± 2.1 and 59.3 ± 7.1, respectively.
In a 30,000 g supernatant fraction from human platelet homogenate, YC‐1 (5–100 μm) increased sGC activity in a concentration‐dependent manner. At the same concentration‐range, YC‐1 elevated cyclic GMP levels markedly, but only slightly elevated cyclic AMP levels in the intact platelets.
MY‐5445, a selective inhibitor of cyclic GMP phosphodiesterase, potentiated the increases in cyclic GMP caused by YC‐1, and shifted the concentration‐anti‐aggregation curve of YC‐1 to the left. In contrast, HL‐725, a selective inhibitor of cyclic AMP phosphodiesterase, did not affect either the increases in cyclic nucleotides or the anti‐aggregatory effect caused by YC‐1.
Methylene blue, an inhibitor of sGC, blocked the increases of cyclic GMP caused by YC‐1, and attenuated markedly the anti‐aggregatory effect of YC‐1. The adenylate cyclase inhibitor, 2′,5′‐dideoxyadenosine (DDA) did not affect YC‐1‐induced inhibition of platelet aggregation.
Haemoglobin, which binds NO, prevented the activation of sGC and anti‐aggregatory effect caused by sodium nitroprusside, but did not affect YC‐1 responses.
These results would suggest that YC‐1 activates sGC of human platelets by a NO‐independent mechanism, and exerts its antiplatelet effects through the sGC/cyclic GMP pathway.
Long‐term carbachol treatment‐induced down‐regulation of muscarinic M2‐receptors but not m2 receptor mRNA in a human lung cell line
Authors: Haddad E.‐B. , Rousell J. , Mak J.C.W. , Barnes P.J. 
Published: July 2012

The molecular mechanisms involved in the regulation of muscarinic receptor gene expression are poorly understood. We have investigated the effect of homologous stimulation on the regulation of M2 muscarinic receptor protein and gene in human embryonic lung fibroblasts (HEL 299 cells).
Saturation studies performed with the non‐selective hydrophilic ([3H]‐N‐methyl‐scopolamine, [3H]‐NMS) and lipophilic ([3H]‐quinuchdinyl benzilate, [3H]‐QNB) muscarinic antagonists revealed a single class of high affinity binding sites.
Carbachol (1 mM) induced a rapid down‐regulation of [3H]‐NMS binding sites. Within 12 h, the process had approached steady state with 40 to 60% loss of receptors at 12 and 24 h.
The loss of [3H]‐QNB binding sites (40% reduction at 24 h) occurred at a slower rate than did loss of [3H]‐NMS binding sites as a result of receptor sequestration.
Carbachol treatment was accompanied by a functional desensitization of the receptor after 24 h of agonist treatment. In untreated cells, forskolin induced a large increase in cyclic AMP accumulation which was inhibited significantly by carbachol. The inhibitory effect of carbachol on forskolin‐induced cyclic AMP accumulation was lost following 24 h carbachol stimulation.
The steady state level of muscarinic m2 mRNA measured by Northern blot analysis was not affected by carbachol treatment over the time course investigated and half‐life studies with actinomycin D suggest that carbachol had no effect on the stability of m2 mRNA.
The rate of transcription of m2 muscarinic receptor gene as measured by nuclear RNA run‐on assay was unaltered by carbachol stimulation.
These results suggest that homologous sequestration, desensitization, and down‐regulation of M2 muscarinic receptors in HEL 299 cells does not involve transcriptional or post‐transcriptional modifications of m2 muscarinic receptor mRNAs.
Pharmacological evidence for a single bradykinin B2 receptor in the guinea‐pig
Authors: Pruneau D. , Luccarini J.M. , Defrêne E. , Paquet J.L. , Bélichard P. 
Published: July 2012

The present study addresses the possibility of the existence of different kinin B2 receptor subtypes in the guinea‐pig by evaluating the affinity of peptide and nonpeptide receptor antagonists. For this purpose, jugular vein rings, ileum segments, lung parenchymal and trachea strips were set up in organ baths for isometric tension measurements. The experiments were conducted in the presence of indomethacin (3 μm), atropine (10 μm) and captopril (10 μm).
BK contracted jugular vein (JV), ileum (GPI), parenchyma (LP) and trachea (GPT) with an EC50 of 13.2 ± 1.4 nM (n = 27), 11.2 + 2.1 (n = 26), 23.6 ± 6.3 nM (n = 26) and 33.0 ± 6.5 (n = 27), respectively. Thiorphan, a neutral endopeptidase (EC 3.4.24.11) inhibitor and MERGETPA (DL‐2‐mercaptomethyl‐3‐guanidinoethylthiopropanoic acid), a carboxypeptidase inhibitor, had no effect on the BK‐induced contractions of JV, GPI and LP. In the GPT, thiorpan potentiated the contractile response to BK and was thus added in the corresponding experiments.
The peptide B2 receptor antagonist, Hoe 140 and the nonpeptide compound, WIN 64338, behaved as noncompetitive antagonists against contractile responses to cumulative BK in the four tissues although Hoe 140 appeared as a competitive inhibitor in the GPT only. In order to compare the inhibitory potency of these compounds between tissues, pKB values were determined. Mean values of pKB for Hoe 140 were 8.05 ± 0.07, 8.43 ± 0.11, 8.13 ± 0.18 and 8.52 ± 0.25 in the JV, GPI, GPT and LP, respectively. WIN 64338 gave mean pKB values of 6.89 ± 0.10, 7.57 ± 0.12, 7.36±0.12 and 7.51 ± 0.28 in the JV, GPI, LP and GPT, respectively.
D‐Arg [Hyp3, D‐Phe7, Leu8]BK and D‐Arg [Hyp3, D‐Phe7]BK (NPC 567) inhibited in a competitive fashion the concentration‐response curves to BK. Values of pA2 for each compound were not significantly different in the four tissues and were between 5.81 and 6.31 for D‐Arg [Hyp3, D‐Phe7, Leu8]BK and between 5.55 and 5.65 for NPC 567.
We conclude that the contractile response to BK in guinea‐pig vascular, intestine and lung tissue is mediated by a unique B2 receptor. Thus, our results do not support the existence of a B3 receptor in the trachea and we suggest that the previously reported B2B receptor subtype simply represents the guinea‐pig isoform.
Anxiolytic activity of adenosine receptor activation in mice
Authors: Jain Nisha , Kemp Nicola , Adeyemo Olasumbo , Buchanan Patricia , Stone Trevor W. 
Published: July 2012

Purine analogues have been examined for anxiolytic‐ and anxiogenic‐like activity in mice, by use of the elevated plus‐maze.
The selective A1 receptor agonist, N6‐cyclopentyladenosine (CPA) had marked anxiolytic‐like activity at 10 and 50 μ kg−1, with no effect on locomotor performance at these doses.
The A1 selective adenosine receptor antagonist, 1,3‐dipropyl‐8‐cyclopentylxanthine (CPX) had no significant effect on anxiety‐related measures or locomotor behaviour, but blocked the anxiolytic‐like activity of CPA. The hydrophilk xanthine, 8‐(p‐sulphophenyl) theophylline did not prevent anxiolysis by CPA.
Caffeine had anxiogenic‐like activity at 30 mg kg−1 which was prevented by CPA at 50 μg kg−1.
The A2 receptor agonist, N6‐[2‐(3,5‐dimethoxyphenyl)‐2‐(2‐methylphenyl)‐ethyl]adenosine (DPMA) had no effect on anxiety behaviour but depressed locomotor activity at the highest dose tested of 1 mg kg−1. The A2 receptor antagonist, 1,3‐dimethyl‐l‐propargylxanthine (DMPX) had no effect on anxiety‐related measures or locomotion and did not modify the anxiolytic‐like activity of CPA.
Administration of DPMA in combination with anxiolytic doses of CPA prevented the anxiolytic‐like activity of the latter.
The results suggest that the selective activation of central A1 adenosine receptors induces anxiolytic‐like behaviour, while the activation of A2 sites causes locomotor depression and reduces the effects of A1 receptor activation. The absence of any effect of CPX alone suggests that the receptors involved in modulating behaviour in the elevated plus‐maze in mice are not activated tonically by endogenous adenosine.
Enhancement by cyclo‐oxygenase inhibitors of platelet‐activating factor production in thapsigargin‐stimulated macrophages
Authors: Watanabe Masako , Yamada Masateru , Mue Suetsugu , Ohuchi Kazuo 
Published: July 2012

Thapsigargin stimulated the accumulation of cell‐associated platelet‐activating factor (PAF) and extracellular prostaglandin E2 (PGE2) in rat peritoneal macrophages. PAF in the conditioned medium was less than the detectable amount. To obtain further insight into the mechanism of PAF accumulation, the role of PGE2 in PAF accumulation was investigated.
When macrophages were incubated in medium containing thapsigargin (30 ng ml−1, 46.1 nM) and cyclo‐oxygenase inhibitors such as indomethacin, naproxen or ibuprofen, the PAF content of the cells at 10 min was increased in a concentration‐dependent manner in accordance with inhibition of PGE2 production. The stimulation of PAF accumulation by cyclo‐oxygenase inhibitors was significant at 10 min. Without stimulation by thapsigargin, cyclo‐oxygenase inhibitors did not increase PAF accumulation.
In thapsigargin‐stimulated macrophages, when PGE2 (10−7 m) was added to the medium, the cyclo‐oxygenase inhibitor‐induced stimulation of PAF accumulation at 10 min was markedly inhibited.
The accumulation of PAF induced by thapsigargin alone at 10 min was also inhibited by exogenous PGE2 (10−8 and 10−7 m), or arachidonic acid (10−6 and 10−5 m) in accordance with the increase in PGE2 production.
The accumulation of PAF induced by thapsigargin alone or by thapsigargin and indomethacin (10−6M) was inhibited by dibutyryl cyclic AMP.
These results indicate that the concurrently produced PGE2 in thapsigargin‐stimulated macrophages down‐regulates PAF accumulation by increasing intracellular cyclic AMP levels, and that cyclo‐oxygenase inhibitors increase PAF accumulation by inhibiting PGE2 production.
Inhibition by propofol (2,6 di‐isopropylphenol) of the N‐methyl‐D‐aspartate subtype of glutamate receptor in cultured hippocampal neurones
Authors: Orser Beverley A. , Bertlik Maria , Wang Lu‐Yang , MacDonald John F. 
Published: July 2012

The effects of propofol (2,6 di‐isopropylphenol) on responses to the selective glutamate receptor agonists, N‐methyl‐D‐aspartate (NMDA) and kainate, were investigated in cultured hippocampal neurones of the mouse. Whole cell and single channel currents were recorded by patch‐clamp techniques. Drugs were applied with a multi‐barrel perfusion system
Propofol produced a reversible, dose‐dependent inhibition of whole cell currents activated by NMDA. The concentration of propofol which induced 50% of the maximal inhibition (IC50) was approximately 160 μm. The maximal inhibition was incomplete leaving a residual current of about 33% of the control response. This inhibitory action of propofol was neither voltage‐ nor use‐dependent
Analysis of the dose‐response relation for whole cell NMDA‐activated currents indicated that propofol caused no significant change in the apparent affinity of the receptor for NMDA
Outside‐out patch recordings of single channel currents evoked by NMDA (10 μm) revealed that propofol (100 HM) reversibly decreased the probability of channel opening but did not influence the average duration of channel opening or single channel conductance
Whole‐cell currents evoked by kainate (50 μ M) were insensitive to propofol (1 μm‐1 mM)
These results indicate that propofol inhibits the NMDA subtype of glutamate receptor, possibly through an allosteric modulation of channel gating rather than by blocking the open channel. Depression of NMDA‐mediated excitatory neurotransmission may contribute to the anaesthetic, amnesic and anticonvulsant properties of propofol.
β‐Adrenoceptor subtypes in young and old rat ventricular myocytes: a combined patch‐clamp and binding study
Authors: Cerbai E. , Guerra L. , Varani K. , Barbieri M. , Borea P.A. , Mugelli A. 
Published: July 2012

We used electrophysiological and binding techniques to assess the presence of β1 and β2‐adrenoceptors (β1AR and β2AR) in rat cardiac myocytes and to determine their ratio during aging. Experiments were performed in left ventricular myocytes enzymatically dissociated from the heart of 3‐(young) or 22‐month‐old (old) Wistar Kyoto rats
In patch‐clamp experiments, myocytes from old rats showed a prolonged action potential duration (at −20 mV: 41.7±3.6 vs 26.2±3.1 ms; at −60 mV: 154.4 ± 17.7 vs 87.1 ±6.9 ms, P < 0.05) and an augmented membrane capacitance (an index of cell size) (271.7±20.2 vs 164.3± 14.6 pF, P < 0.05) compared to young rats. β2AR stimulation, achieved by superfusing myocytes with the selective β2AR agonist, zinterol (10 μm) or with (−)‐isoprenaline (1 μm) in the presence of the selective β1 AR antagonist, CGP 20712A (0.1 μm), significantly increased L‐type calcium current (Ica,L) in rat ventricular myocytes. The percentage increase was similar in both young and old rats, either with zinterol (26.9 ±3.6% and 24.2±2.8%, respectively) or isoprenaline plus CGP 20712A (30.4±3.7% and 22.4±4.1%, respectively). Isoprenaline alone (β1AR and β2AR stimulation) caused a much smaller increase in ICa,L in old rats (58.4±12.1%) than in younger ones (95.3±8.1%) (P=0.067)
The number of βAR mg−1 protein, measured with saturation binding assays of the non selective βAR antagonist [3H]‐CGP 12177 was 1989.4± 189.5 for 3‐ and of 1580.7± 161.5 for 22‐month‐old rats. Competition for [3H]‐CGP 12177 binding by CGP 20712A gave biphasic curves which demonstrated two classes of binding sites. Densities (as percentages of total PAR density), and affinities for the two binding sites were: 80.4 ±2.2% (Ki = 6.6 ±1.3 nM) β1AR and 19.6 ±2.2% (Ki = 6.9 ±2.2 μm) β2AR in young rats and 66.1 ±1.2% (Ki = 8.3 ±1.1 nM) β1 AR and 33.9 ±1.2% (Ki = 5.2 ± 0.6 μm) β2AR in old rats. The β1AR/β2AR ratio was significantly (P<0.01) reduced in old rats with respect to the younger ones
By combining electrophysiological and binding measurements, we calculated β1AR and β2AR densities as number of receptors per μm2 of cell surface. In old rats, β1AR density was significantly decreased compared to young rats (8.4±2.0 vs 15.4±3.7 receptors μm−2, P<0.05), while β2AR density remained unchanged at both 3 and 22 months (3.8 ±0.7 and 4.2 ±1.1 receptors μm−2, respectively)
Our results demonstrate that both β1AR and β2AR are functionally present in rat ventricular myocytes of young and old rats. The decreased responsiveness to βAR stimulation during aging appears to be associated with a selective reduction in the density of β1AR.
Discrimination by the NO‐trapping agent, carboxy‐PTIO, between NO and the nitrergic transmitter but not between NO and EDRF
Authors: Rand M.J. , Li C.G. 
Published: July 2012

The effects of carboxy‐PTIO, a scavenger of free radical nitric oxide (NO), were studied on endothelium‐dependent relaxations of rat aorta and nitrergic nerve stimulation‐induced relaxations of anococcygeus muscle and gastric fundus strips to test the hypothesis that endothelium‐derived relaxing factor (EDRF) and the transmitter released by nitrergic nerves is free radical NO
Carboxy‐PTIO (10–300 μm) produced concentration‐dependent reductions of relaxations elicited by exogenous NO, and relaxations mediated by EDRF released by acetylcholine and ATP in rings of rat aorta. The inhibitory effect of carboxy‐PTIO was removed by washing the tissues
In the rat anococcygeus muscle, carboxy‐PTIO (10–300 μm) produced concentration‐dependent reductions of relaxations to exogenous NO; however, in concentrations up to 2000 μm it did not reduce relaxations elicited by nitrergic nerve stimulation (1–2 Hz), in fact, concentrations of 300 μm or more slightly enhanced them
In rat gastric fundus strips, carboxy‐PTIO (100 and 300 μm) reduced relaxations to exogenous NO, but relaxations elicited by stimulation of the nitrergic component of non‐adrenergic, non‐cholinergic nerves were not affected
These results suggest that EDRF is free radical NO and may be designated EDNO, but the transmitter released from nitrergic nerves does not appear to be identical to EDNO and may not be free radical NO.
Enhanced sympathetic neurotransmission in the tail artery of 1,3‐dipropyl‐8‐sulphophenylxanthine (DPSPX)‐treated rats
Authors: Karoon Parastoo , Rubino Annalisa , Burnstock Geoffrey 
Published: July 2012

Sympathetic neurotransmission and noradrenaline content of the tail artery of Wistar rats treated for 7 days with the adenosine antagonist, 1,3‐dipropyl‐8‐sulphophenylxanthine (DPSPX), were examined
Systolic blood pressure of the DPSPX‐treated rats (164.0 ± 2.9 mmHg; n = 6) was significantly greater than saline‐treated controls (140.0 ±2.8 mmHg; n = 5) after 7 days treatment
The pressor responses of the arterial rings to transmural nerve stimulation (65 V, 0.1 ms, 4–64 Hz, for 1 s) were markedly enhanced in the DPSPX‐treated compared with the saline‐treated animals. Both noradrenergic and purinergic components of perivascular sympathetic neurotransmission were enhanced during DPSPX‐induced hypertension
Vasoconstrictor responses to exogenous noradrenaline (0.1–300 μm) and adenosine 5′‐triphosphate (0.01–3 mM) were unaffected after DPSPX treatment, indicating prejunctional alteration of sympathetic cotransmission during DPSPX‐induced hypertension
Acute exposure to DPSPX (10 μm) did not modify vasoconstrictor responses to transmural nerve stimulation, thus supporting the claim that the enhancement of sympathetic neurotransmission only results from long‐term DPSPX treatment
The noradrenaline content of the tail arteries of DPSPX‐treated (4.498 ±0.26 ng cm−1; n = 4) was significantly greater than saline‐treated (3.440 ± 0.30 ng cm−1; n = 5) animals
These findings show that chronic inhibition of the actions of endogenous adenosine by DPSPX results in an elevation of systolic blood pressure accompanied by enhanced sympathetic cotransmission and enhanced noradrenaline content of the rat tail artery.