bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the α subunit on imidacloprid sensitivity of recombinant nicotinic acetylcholine receptors
Authors: Matsuda K. , Buckingham S D. , Freeman J C. , Squire M D. , Baylis H A. , Sattelle D B. 
Published: January 2005

Imidacloprid is a new insecticide with selective toxicity for insects over vertebrates. Recombinant (α4β2) chicken neuronal nicotinic acetylcholine receptors (AChRs) and a hybrid nicotinic AChR formed by co‐expression of a Drosophila melanogaster neuronal α subunit (SAD) with the chicken β2 subunit were heterologously expressed in Xenopus oocytes by nuclear injection of cDNAs. The agonist actions of imidacloprid and other nicotinic AChR ligands ((+)‐epibatidine, (−)‐nicotine and acetylcholine) were compared on both recombinant nicotinic AChRs by use of two‐electrode, voltage‐clamp electrophysiology.
Imidacloprid alone of the 4 agonists behaved as a partial agonist on the α4β2 receptor; (+)‐epibatidine, (−)‐nicotine and acetylcholine were all full, or near full, agonists. Imidacloprid was also a partial agonist of the hybrid Drosophila SAD chicken β2 receptor, as was (−)‐nicotine, whereas (+)‐epibatidine and acetylcholine were full agonists.
The EC50 of imidacloprid was decreased by replacing the chicken α4 subunit with the Drosophila SAD α subunit. This α subunit substitution also resulted in an increase in the EC50 for (+)‐epibatidine, (−)‐nicotine and acetylcholine. Thus, the Drosophila (SAD) α subunit contributes to the greater apparent affinity of imidacloprid for recombinant insect/vertebrate nicotinic AChRs.
Imidacloprid acted as a weak antagonist of ACh‐mediated responses mediated by SADβ2 hybrid receptors and as a weak potentiator of ACh responses mediated by α4β2 receptors. This suggests that imidacloprid has complex effects upon these recombinant receptors, determined at least in part by the α subunit.

British Journal of Pharmacology (1998) 123, 518–524; doi:10.1038/sj.bjp.0701618
Effects of clozapine on the δ‐ and κ‐opioid receptors and the G‐protein‐activated K+ (GIRK) channel expressed in Xenopus oocytes
Authors: Kobayashi Toru , Ikeda Kazutaka , Kumanishi Toshiro 
Published: January 2005

To investigate the effects of clozapine, an atypical antipsychotic, on the cloned μ‐, Δ‐ and κ‐opioid receptors and G‐protein‐activated inwardly rectifying K+ (GIRK) channel, we performed the Xenopus oocyte functional assay with each of the three opioid receptor mRNAs and/or the GIRK1 mRNA.
In the oocytes co‐injected with either the Δ‐ or κ‐opioid receptor mRNA and the GIRK1 mRNA, application of clozapine induced inward currents which were attenuated by naloxone, an opioid‐receptor antagonist, and blocked by Ba2+, which blocks the GIRK channel. Since the opioid receptors functionally couple to the GIRK channel, these results indicate that clozapine activates the Δ‐ and κ‐opioid receptors and that the inward‐current responses are mediated by the GIRK channel. The action of clozapine at the Δ‐opioid receptor was more potent and efficacious than that at the κ‐opioid receptor. In the oocytes co‐injected with the μ‐opioid receptor and GIRK1 mRNAs, application of clozapine (100 μM) did not induce an inward current, suggesting that clozapine could not activate the μ‐opioid receptor.
Application of clozapine caused a reduction of the basal inward current in the oocytes injected with the GIRK1 mRNA alone, but caused no current response in the uninjected oocytes. These results indicate that clozapine blocks the GIRK channel.
To test the antagonism of clozapine for the μ‐ and κ‐opioid receptors, we applied clozapine together with each selective opioid agonist to the oocytes co‐injected with either the μ‐ or κ‐opioid receptor mRNA and the GIRK1 mRNA. Each of the peak currents induced by each selective opioid agonist together with clozapine was almost equal to the responses to a selective opioid agonist alone. These results indicate that clozapine has no significant antagonist effect on the μ‐ and κ‐opioid receptors.
We conclude that clozapine acts as a Δ‐ and κ‐agonist and as a GIRK channel blocker. Our results suggest that the efficacy and side effects of clozapine under clinical conditions may be partly due to activation of the Δ‐opioid receptor and blockade of the GIRK channel.

British Journal of Pharmacology (1998) 123, 421–426; doi:10.1038/sj.bjp.0701621
Effects of the antihypertensive agent, cicletanine, on noradrenaline release and vasoconstriction in perfused mesenteric artery of SHR
Authors: Nasa Yoshihisa , Yoshida Hiroyuki , Urata Maki , Uchibayashi Kumiko , Tsunoda Yumi , Kamigata Keiko , Takeo Satoshi 
Published: January 2005

The mechanism by which cicletanine (CIC) exerts its antihypertensive effects has not been fully elucidated. The present study was undertaken to examine the effects of in vivo and in vitro treatment with CIC on the pressor response and noradrenaline (NA) overflow during periarterial nerve stimulation (PNS) in perfused mesenteric arterial beds isolated from spontaneously hypertensive rats (SHR).
CIC at a dose of 50 mg kg−1 day−1 was administered orally to both SHR and normotensive Wistar‐Kyoto rats (WKY) from the 6th to 10th week of age. At the 10th week, the isolated mesenteric arterial bed was perfused with Krebs‐Henseleit buffer and changes in perfusion pressure and NA overflow during PNS were measured.
Chronic treatment with CIC suppressed the age‐related elevation of systemic blood pressure in SHR but not in WKY.
The PNS (20 Hz)‐induced mesenteric vasoconstrictor response and NA overflow were greater in SHR than in WKY. In the vasculature of SHR chronic treatment with CIC resulted in a significant attenuation of the vasoconstriction and the NA overflow during PNS, whereas it did not alter vasoconstrictor responses to bolus injections of KCl and phenylephrine.
Treatment with 30 μM CIC in vitro diminished the PNS‐induced vasoconstriction and NA overflow but not the NA‐ and KCl‐induced vasoconstriction in the vasculature of untreated SHR.
In the vasculature of SHR PNS‐induced NA overflow was attenuated by prostaglandin E2 (0.05 μM), whereas it was augmented by the cyclo‐oxygenase inhibitor diclofenac‐Na (30 μM). In the presence of diclofenac, in vitro treatment with CIC did not attenuate the NA overflow during PNS.
The results suggest that the antihypertensive effect of CIC in SHR is partially due to the presynaptic inhibition of NA release during sympathetic nerve activation. Transjunctional inhibition of NA release by prostaglandins may contribute to the inhibitory action of CIC on NA release in the vasculature of SHR.

British Journal of Pharmacology (1998) 123, 427–434; doi:10.1038/sj.bjp.0701622
The role of lipocortin‐1 in the inhibitory action of dexamethasone on eosinophil trafficking in cutaneous inflammatory reactions in the mouse
Authors: Teixeira Mauro M. , Das Anuk M. , Miotla Jadwiga M. , Perretti Mauro , Hellewell Paul G. 
Published: January 2005

The ability of glucocorticosteroids to inhibit tissue eosinophilia may be an important feature of their anti‐inflammatory action in allergic diseases. Our previous work showed that an effect of dexamethasone on the release of eosinophils from the bone marrow could explain its inhibitory action on eosinophil accumulation in a mouse air‐pouch model. Thus, it was unclear from that study whether dexamethasone could interfere with the process of eosinophil trafficking. In the present study, therefore, we used a newly developed mouse model to evaluate the effects of systemic treatment with dexamethasone on the recruitment of 111In‐labelled blood eosinophils to sites of cutaneous inflammation in the mouse and whether lipocortin‐1 (LC‐1) was involved.
The i.d. injection of ovalbumin (OVA) in sensitized mice induced a dose‐dependent recruitment of 111In‐labelled blood eosinophils which peaked at 4 to 8 h after antigen challenge. Systemic treatment with dexamethasone (50 μg per mouse, 3 h after antigen) effectively inhibited 111In‐eosinophil recruitment in this reaction by 70 to 85%. Similarly, a 1 h pretreatment with dexamethasone significantly suppressed 111In‐eosinophil induced by platelet‐activating factor (PAF), leukotriene B4(LTB4) and the chemokine macrophage inflammatory protein‐1α (MIP‐1α) by 40 to 70%.
Two experimental approaches were used to evaluate the role of LC‐1: treatment with LC‐1 fragment Ac2‐26 and use of an anti‐LC‐1 antiserum. LC‐1 fragment Ac2 ‐26 (100 μg per mouse) failed to affect 111In‐eosinophil recruitment. Moreover, pretreatment of animals with an anti‐LC‐1 antiserum failed to reverse the inhibitory effects of dexamethasone on 111In‐eosinophil recruitment induced by MIP‐1α and by antigen in sensitized mice.
In contrast, the LC‐1 fragment significantly inhibited glycogen‐induced neutrophil recruitment into the peritoneal cavity of mice. Furthermore, the anti‐LC‐1 antiserum reversed the inhibitory effects of dexamethasone on the glycogen‐induced neutrophil recruitment.
Thus, our results suggest that dexamethasone can inhibit the recruitment of eosinophils in mouse skin independent of an action on the bone marrow. However, by use of two different approaches, we showed that LC‐1 does not play a role in mediating the inhibitory action of dexamethasone on eosinophil migration into cutaneous inflammatory reactions in the mouse. These data add further support to a LC‐1‐independent action of dexamethasone on eosinophils in vivo.

British Journal of Pharmacology (1998) 123, 538–544; doi:10.1038/sj.bjp.0701625
Regulation by tolbutamide and diazoxide of the electrical activity in mouse pancreaticβ‐cells recordedin vivo
Authors: Gomis Ana , Valdeolmillos Miguel 
Published: January 2005

The glucose‐dependence of β‐cell electrical activity and the effects of tolbutamide and diazoxide were studied in anaesthetized mice.In untreated animals there was a direct relationship between glycaemia and the burst pattern of electrical activity. Animals with high glucose concentration showed continuous electrical activity. The application of insulin led to a steady decrease in blood glucose concentration and a transition from continuous to oscillatory activity at 7.7±0.1 mMglucose (mean±s.d.) and a subsequent transition from oscillatory to silent at 4.7±0.6 mMglucose.At physiological blood glucose concentrations the electrical activity was oscillatory. The injection of tolbutamide (1800 mg kg−1) transformed this oscillatory pattern into one of continuous electrical activity. The increased electrical activity was associated with a decrease in blood glucose concentration from 7.1±0.9 (control) to 5.5±1.0 mM(10 min after tolbutamide injection). The effects of tolbutamide are consistent with a direct blocking effect on the KATPchannel that leads to membrane depolarization.The injection of diazoxide (6000 mg kg−1) hyperpolarized the cells and transformed the oscillatory pattern into a silent one. This is consistent with a direct stimulant effect by diazoxide on the KATPchannel. The use of tolbutamide or diazoxide correspondingly led to the lengthening or shortening of the active phase of electrical activity, respectively. This indicates thatin vivo, such activity can be modulated by the relative degree of activation or inhibition of the KATPchannel.These results indicate that under physiological conditions, tolbutamide and diazoxide have direct and opposite effects on the electrical activity of pancreatic β‐cells, most likely through their action on KATPchannels. This is consistent with previous work carried out onin vitromodels and explains the drugs hypo‐ and hyperglycaemic effects.British Journal of Pharmacology(1998)123, 443–448; doi:10.1038/sj.bjp.0701628
Epoxyeicosatrienoic acids, potassium channel blockers and endothelium‐dependent hyperpolarization in the guinea‐pig carotid artery
Authors: Chataigneau Thierry , Félétou Michel , Duhault Jacques , Vanhoutte Paul M. 
Published: January 2005

Using intracellular microelectrodes, we investigated the effects of 17‐octadecynoic acid (17‐ODYA) on the endothelium‐dependent hyperpolarization induced by acetylcholine in the guinea‐pig isolated internal carotid artery with endothelium.
In the presence of Nω‐nitro‐L‐arginine (L‐NOARG, 100 μM) and indomethacin (5 μM) to inhibit nitric oxide synthase and cyclo‐oxygenase, acetylcholine (1 μM) evoked an endothelium‐dependent hyperpolarization which averaged −16.4 mV starting from a resting membrane potential of −56.8 mV. There was a negative correlation between the amplitude of the hyperpolarization and the absolute values of the resting membrane potential.
The acetylcholine‐induced endothelium‐dependent hyperpolarization was not altered by charybdotoxin (0.1 μM) or iberiotoxin (30 nM). It was partially but significantly reduced by apamin (0.5 μM) to −12.8±1.2 mV (n=10) or the combination of apamin plus iberiotoxin (−14.3±3.4 mV, n=4). However, the combination of charybdotoxin and apamin abolished the hyperpolarization and under these conditions, acetylcholine evoked a depolarization (+7.1±3.7 mV, n=8).
17‐ODYA (10 μM) produced a significant hyperpolarization of the resting membrane potential which averaged −59.6 mV and a partial but significant inhibition of the acetylcholine‐induced endothelium‐dependent hyperpolarization (−10.9 mV).
Apamin did not modify the effects of 17‐ODYA but in the presence of charybdotoxin or iberiotoxin, 17‐ODYA no longer influenced the resting membrane potential or the acetylcholine‐induced hyperpolarization.
When compared to solvent (ethanol, 1% v/v), epoxyeicosatrienoic acids (EpETrEs) (5,6‐, 8,9‐, 11,12‐ and 14,15‐EpETrE, 3 μM) did not affect the cell membrane potential and did not relax the guinea‐pig isolated internal carotid artery.
These results indicate that, in the guinea‐pig internal carotid artery, the involvement of metabolites of arachidonic acid through the cytochrome P450 pathway in endothelium‐dependent hyperpolarization is unlikely. Furthermore, the hyperpolarization mediated by the endothelium‐derived hyperpolarizing factor (EDHF) is probably not due to the opening of BKCa channels.

British Journal of Pharmacology (1998) 123, 574–580; doi:10.1038/sj.bjp.0701629
The effect of chronic treatment with trandolapril on cyclic AMP‐ and cyclic GMP‐dependent relaxations in aortic segments of rats with chronic heart failure
Authors: Toyoshima Hiroko , Nasa Yoshihisa , Kohsaka Yumi , Isayama Yoko , Yamaguchi Fuminari , Sanbe Atsushi , Takeo Satoshi 
Published: January 2005

Characteristics of cyclic GMP‐ and cyclic AMP‐mediated relaxation in aortic segments of rats with chronic heart failure (CHF) and the effects of chronic treatment with an angiotensin I converting enzyme (ACE) inhibitor, trandolapril, were examined 8 weeks after coronary artery ligation.
Cardiac output indices of coronary artery‐ligated and sham‐operated rats were 125±8 and 189±10 ml min−1 kg−1, respectively (P<0.05), indicating the development of CHF at this period.
The maximal relaxant response of aortic segments to 10 μM acetylcholine in rats with CHF and sham‐operated rats was 64.0±5.7 and 86.9±1.9%, respectively (P<0.05), whereas the relaxant response to sodium nitroprusside (SNP) remained unchanged. Tissue cyclic GMP content in rats with CHF was lower than that of sham‐operated rats.
In endothelium‐intact segments of rats with CHF, the maximal relaxant response to 10 μM isoprenaline (44.5±6.7%) was lower that sham‐operated rats (81.3±2.5%, P<0.05) and the concentration‐response curve for NKH477, a water‐soluble forskolin, was shifted to the right without a reduction in the maximal response. Isoprenaline‐induced relaxation of aortic segments was attenuated by NG‐nitro‐L‐arginine methyl ester (L‐NAME) in sham‐operated rats, but not in rats with CHF. Relaxation to 30 μM dibutyryl cyclic AMP in rats with CHF (26.8±2.7%) was lower than that in sham‐operated rats (63.4±11.8%, P<0.05).
Trandolapril (3 mg kg−1 day−1) was orally administered from the 2nd to 8th week after the operation. Aortic blood flow of rats with CHF (38.5±3.6 ml min−1) was lower than that of sham‐operated rats (55.0±3.0 ml min−1), and this reduction was reversed (54.1±3.4 ml min−1) by treatment with trandolapril. The diminished responsiveness described above was normalized in the trandolapril‐treated rat with CHF (i.e., the maximal relaxation to acetylcholine, 94.7±1.0%; that to isoprenaline, 80.5±2.8%; that to dibutyryl cyclic AMP, 54.7±6.2%). However, aortic segments of trandolapril‐treated rats with CHF, L‐NAME did not attenuate isoprenaline‐induced relaxation and the tissue cyclic GMP level was not fully restored, suggesting that the ability of the endothelium to produce NO was still partially damaged.
The results suggest that vasorelaxation in CHF, diminished mainly due to dysfunction in endothelial nitric oxide (NO) production and cyclic AMP‐mediated signal transduction, was partially restored by long‐term treatment with trandolapril. The mechanism underlying the restoration may be attributed in part to prevention of CHF‐induced endothelial dysfunction.

British Journal of Pharmacology (1998) 123, 344–352; doi:10.1038/sj.bjp.0701635
The relevance of resting tension to responsiveness and inherent tone of human bronchial smooth muscle
Authors: Watson N. , Magnussen H. , Rabe K F. 
Published: January 2005

In the present study the effects of resting tension on isometric responses of human airway smooth muscle to contractile and relaxant stimuli were investigated. Also, its effects on inherent smooth muscle tone were examined, in an effort to determine a pre‐defined resting tension which can be considered optimal for in vitro studies.
Bronchial ring preparations (2–4 mm internal diameter) were suspended in tissue baths at a range of levels of resting tension (200–1600 mg). The responses to electrical field stimulation (EFS, 30 V, 0.2 ms, 8–30 Hz), carbachol (3 μM), isoprenaline (1 μM) and the 5‐lipoxygenase inhibitor, zileuton (10 μM) were investigated along with the ability of the preparations to recover stable resting tension after 60 min of washing post challenge.
EFS induced monophasic contractions at low stimulation frequency (8 Hz). However, with increasing frequency and tension (15 and 30 Hz; > 400 mg) contractile responses were accompanied by a relaxant component. The magnitude of contractile responses increased with increasing resting tension to a plateau at between 500 and 700 mg. Relaxant responses when present, increased in magnitude with increasing resting tension.
The level of resting tension did not significantly alter responses to carbachol, but tissues at tensions 1000 mg showed poor tension recovery after washing. Isoprenaline‐induced relaxations increased with increasing resting tension (P<0.05) and tension recovery after washing was complete. The 5‐lipoxygenase sensitive portion of the tension (33±4%) was not altered by the level of resting tension.
These results suggest that in human bronchial ring preparations of 2–4 mm internal diameter, resting tensions within the range 400–1000 mg could be considered optimal for isometric tension recordings of protocols involving both contraction and relaxation procedures.

British Journal of Pharmacology (1998) 123, 694–700; doi:10.1038/sj.bjp.0701637
Mediators and mechanisms of relaxation in rabbit urethral smooth muscle
Authors: Waldeck Kristian , Ny Lars , Persson Katarina , Andersson Karl‐Erik 
Published: January 2005

Electrophysiological and mechanical experiments were performed to investigate whether the nitric oxide (NO)‐mediated relaxation of rabbit urethral smooth muscle is associated with a hyperpolarization of the membrane potential. In addition, a possible role for vasoactive intestinal peptide (VIP) and carbon monoxide (CO) as relaxant agents in rabbit urethra was investigated.
Immunohistochemical experiments were performed to characterize the NO‐synthase (NOS) and VIP innervation. Possible target cells for NO were studied by using antisera against cyclic GMP. The cyclic GMP‐immunoreactivity was investigated on tissues pretreated with 1 mM IBMX, 0.1 mM zaprinast and 1 mM sodium nitroprusside.
Intracellular recordings of the membrane potential in the circular smooth muscle layer revealed two types of spontaneous depolarizations, slow waves with a duration of 3–4 s and an amplitude of 30–40 mV, and faster (0.5–1 s), more irregular depolarizations with an amplitude of 5–15 mV. The resting membrane potential was 39±1 mV (n=12). Application of NO (30 μM), CO (30 μM) or VIP (1 μM) did not change the resting membrane potential.
Both NO (1–100 μM) and VIP (1 nM–1 μM) produced concentration‐dependent relaxations amounting to 87±4% and 97±2% (n=6), respectively. The relaxant effect of CO (1–30 μM) amounted to 27±4% (n=5) at the highest concentration used.
Immunohistochemical experiments revealed a rich supply of NOS‐immunoreactive nerve fibres in the smooth muscle layers. Numerous spinous cyclic GMP‐immunoreactive cells were found interspersed between the smooth muscle bundles, mainly localized in the outer layer. These cells had long processes forming a network surrounding the smooth muscle bundles. VIP‐immunoreactivity was sparse in comparison to NOS‐immunoreactive nerves.
The rich supply of NOS‐immunoreactive nerve fibres supports the view that NO is an important NANC‐mediator in the rabbit urethra. In contrast to several other tissues, the relaxant effect of NO in the rabbit urethra does not seem to be mediated by hyperpolarization. The network of cyclic GMP‐immunoreactive cells may constitute target cells for NO, but their function remains to be established.

British Journal of Pharmacology (1998) 123, 617–624; doi:10.1038/sj.bjp.0701645
Blockade of the development of morphine tolerance by U‐50,488, an AVP antagonist or MK‐801 in the rat hippocampal slice
Authors: Su Mei‐Tsu , Lin Wei‐Bin , Lue Wei‐Ming , Cheng Chen‐Yu , Tao Pao‐Luh 
Published: January 2005

In this study, we investigated the effects of different drugs (a κ‐opioid receptor agonist U‐50,488, a vasopressin receptor antagonist dPTyr(Me)AVP or an N‐methyl‐D‐aspartate (NMDA) receptor antagonist MK‐801) on the development of morphine tolerance in rat hippocampal slices.
Hippocampal slices (450 μm) of Sprague‐Dawley rats (250–300 g) were used. Slices were continuously superfused with artificial CSF or drugs at 1 ml min−1. Nichrome wire electrodes were placed in the Schaffer‐collateral pathway and used to deliver biphasic 0.2 ms pulses of 5–30 V (0.033 Hz). A glass microelectrode was placed in the CA1 area to record population spikes.
When the slices were superfused with 10 μM morphine, the amplitude of population spikes increased 2–3 fold in 30–40 min. However, this effect of morphine decreased, i.e. tolerance developed after continuous superfusion of morphine for 2–6 h.
When either U‐50,488 (200 nM) or dPTyr(Me) AVP (500 pM) or MK‐801 (500 pM) was co‐superfused with morphine (10 μM), it significantly blocked the development of morphine tolerance. Nor‐BNI (a κ‐opioid receptor antagonist, 200 nM) significantly reversed the inhibitory effect of U‐50,488 but not those of dPTyr(Me)AVP or MK‐801 on the development of morphine tolerance.
These data indicate that κ‐opioid receptors, AVP receptors and NMDA receptors are all involved in the development of morphine tolerance. The suppression of κ‐opioid receptor activity after chronic morphine may occur before the activation of AVP receptors or NMDA receptors during the development of morphine tolerance.

British Journal of Pharmacology (1998) 123, 625–630; doi:10.1038/sj.bjp.0701646