bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nociceptin inhibits cough in the guinea‐pig by activation of ORL1 receptors
Authors: McLeod Robbie L , Parra Leonard E , Mutter Jennifer C , Erickson Christine H , Carey Galen J , Tulshian Deen B , Fawzi Ahmad B , Smith‐Torhan April , Egan Robert W , Cuss Francis M , Hey John A 
Published: January 2005

We studied the central and peripheral antitussive effect of ORL1 receptor activation with nociceptin/orphanin FQ in conscious guinea‐pigs. In guinea‐pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 μg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 μg, i.c.v.) was blocked by the selective ORL1 antagonist [Phe1γ(CH2‐NH)Gly2]nociceptin‐(1‐13)‐NH2 (180 μg, i.c.v.) and J113397 (10 mg kg−1, i.p.) but not by the opioid antagonist, naltrexone (3 mg kg−1, i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg−1) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL1 agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.British Journal of Pharmacology (2001) 132, 1175–1178; doi:10.1038/sj.bjp.0703954
Effects of specific inhibition of cyclo‐oxygenase‐1 and cyclo‐oxygenase‐2 in the rat stomach with normal mucosa and after acid challenge
Authors: Gretzer Britta , Maricic Nenad , Respondek Michael , Schuligoi Rufina , Peskar Brigitta M 
Published: January 2005

Effects of the cyclo‐oxygenase (COX)‐1 inhibitor SC‐560 and the COX‐2 inhibitors rofecoxib and DFU were investigated in the normal stomach and after acid challenge.
In healthy rats, neither SC‐560 nor rofecoxib (20 mg kg−1 each) given alone damaged the mucosa. Co‐treatment with SC‐560 and rofecoxib, however, induced severe lesions comparable to indomethacin (20 mg kg−1) whereas co‐administration of SC‐560 and DFU (20 mg kg−1 each) had no comparable ulcerogenic effect 5 h after dosing.
SC‐560 (20 mg kg−1) inhibited gastric 6‐keto‐prostaglandin (PG) F1α by 86±5% and platelet thromboxane (TX) B2 formation by 89±4% comparable to indomethacin (20 mg kg−1). Rofecoxib (20 mg kg−1) did not inhibit gastric and platelet eicosanoids.
Intragastric HCl elevated mucosal mRNA levels of COX‐2 but not COX‐1. Dexamethasone (2 mg kg−1) prevented the up‐regulation of COX‐2.
After acid challenge, SC‐560 (5 and 20 mg kg−1) induced dose‐dependent injury. Rofecoxib (20 mg kg−1), DFU (5 mg kg−1) and dexamethasone (2 mg kg−1) given alone were not ulcerogenic but aggravated SC‐560‐induced damage. DFU augmented SC‐560 damage 1 but not 5 h after administration whereas rofecoxib increased injury after both treatment periods suggesting different time courses.
Gastric injurious effects of rofecoxib and DFU correlated with inhibition of inflammatory PGE2.
The findings show that in the normal stomach lesions only develop when both COX‐1 and COX‐2 are inhibited. In contrast, during acid challenge inhibition of COX‐1 renders the mucosa more vulnerable suggesting an important role of COX‐1 in mucosal defence in the presence of a potentially noxious agent. In this function COX‐1 is supported by COX‐2. In the face of pending injury, however, COX‐2 cannot maintain mucosal integrity when the activity of COX‐1 is suppressed.

British Journal of Pharmacology (2001) 132, 1565–1573; doi:10.1038/sj.bjp.0703955
Role of endothelin and vasopressin in DOCA‐salt hypertension
Authors: Yu Ming , Gopalakrishnan V , Robert McNeill J 
Published: January 2005

The relative roles of endothelin (ET) and vasopressin (AVP) in the regulation of blood pressure (BP), cardiac output (CO) and total peripheral resistance (TPR) were investigated in the early stages (24 – 31 days) of development of hypertension in the conscious deoxycorticosterone acetate (DOCA)‐salt hypertensive rat model.
BP was recorded with radiotelemetry devices and CO with ultrasonic transit‐time probes. TPR was calculated from the BP and CO recordings. The contributions of endogenous ET and AVP were studied by infusing [d(CH2)51,O‐Me_Tyr2,Arg8]‐vasopressin, a V1‐receptor antagonist, and bosentan, a mixed ETA/ETB receptor antagonist (Study 1). Vascular responsiveness was estimated from the changes in TPR evoked by i.v. infusions of ET‐1 and AVP (Study 2).
In study 1, infusion of bosentan reduced TPR and BP dramatically in DOCA‐salt hypertensive rats but not in SHAM control rats, and this effect was greater when the AVP system had been blocked. In contrast, the V1 receptor antagonist alone failed to change TPR and BP in DOCA‐salt hypertensive rats. However, subsequent infusion of the V1 receptor antagonist during the plateau phase of the response in bosentan pretreated DOCA‐salt hypertensive rats led to significant decreases in both BP and TPR.
In study 2, TPR and BP responses to ET‐1, but not AVP, were greater in DOCA‐salt rats than in control rats. CO responses to ET‐1 or AVP were similar in the two groups.
The results suggest that both ET and AVP play a role in the maintenance of TPR and BP; when one system is blocked the other compensates. However, the magnitude of the contribution to the hypertensive state appears greater for ET than for AVP. Enhanced vascular responses to ET appear to contribute to this greater role.

British Journal of Pharmacology (2001) 132, 1447–1454; doi:10.1038/sj.bjp.0703958
Chronic vascular toxicity of doxorubicin in an organ‐cultured artery
Authors: Murata Takahisa , Yamawaki Hideyuki , Hori Masatoshi , Sato Koichi , Ozaki Hiroshi , Karaki Hideaki 
Published: January 2005

We investigated the chronic effects of doxorubicin (DXR) on morphological and functional changes in the rabbit mesenteric artery using an organ culture system.
In arteries cultured with 0.3 μM DXR for 7 days, the contractions induced by noradrenaline, but not those induced by endothelin‐1 or high K+, were strongly inhibited. This reaction was followed by a decrease in the induction of the α1A‐adrenoceptor without any change in the mRNA level. Inhibition of noradrenaline‐induced contractions by DXR was attenuated by superoxide dismutase, and α1A‐adrenoceptor protein expression recovered.
In the arteries cultured with 1 μM DXR for 7 days, contractions induced by endothelin‐1 or high K+ and absolute force in the permeabilized muscles were also inhibited. Morphological examinations revealed the existence of concentrated nuclei and terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labelling (TUNEL)‐positive smooth muscle cells, and internucleosomal DNA fragmentation was also detected, indicating the induction of apoptosis.
In the arteries cultured with 10 μM DXR for 7 days, nuclear swelling, karyolysis and random DNA fragmentation indicative of necrosis were observed, and muscle contractility was abolished.
These results suggest that 0.3 μM DXR selectively down‐regulates the α1A‐adrenoceptor protein expression, resulting in a decrease in the noradrenaline‐induced contraction. This down‐regulation may be at least partly due to the production of a superoxide radical. DXR also caused a decrease in muscle contractility followed by apoptotic changes at 1 μM and necrotic changes at 10 μM. These changes might be responsible for the disturbance of the circulatory system that is often observed during the course of repetitive chemotherapy.

British Journal of Pharmacology (2001) 132, 1365–1373; doi:10.1038/sj.bjp.0703959
Mechanism of airway hyperresponsiveness to adenosine induced by allergen challenge in actively sensitized Brown Norway rats
Authors: Hannon J P , Tigani B , Williams I , Mazzoni L , Fozard J R 
Published: January 2005

We have explored the role of allergen sensitization and challenge in defining the response of the airways of the Brown Norway (BN) rat to adenosine.
In naïve animals or in rats sensitized to ovalbumin (OA) adenosine induced only weak bronchoconstrictor responses. Challenge of sensitized animals with OA induced a marked airway hyperresponsiveness to adenosine which was not seen with methacholine or bradykinin.
The augmented bronchoconstrictor response to adenosine was not affected by acute bivagotomy or atropine nor mimicked by an i.v. injection of capsaicin. It was, however, blocked selectively by disodium cromoglycate methysergide or ketanserin and reduced in animals treated sub‐chronically with compound 48/80.
The augmented response to adenosine was associated with increases in the plasma concentrations of both histamine and 5‐hydroxytryptamine (5‐HT), which were attenuated by pretreatment with disodium cromoglycate, and degranulation of mast cells in the lung.
Parenchymal strips from lungs removed from sensitized rats challenged with OA gave augmented bronchoconstrictor responses to adenosine relative to strips from sensitized animals challenged with saline. Responses were inhibited by methysergide and disodium cromoglycate.
These data demonstrate a marked augmentation of the bronchoconstrictor response to adenosine in actively sensitized BN rats challenged with OA. The augmented response is primarily a consequence of mast cell activation, leading to the release of 5‐HT, which in turn induces bronchoconstriction. Our data further suggest the involvement of a discrete lung‐based population of mast cells containing and releasing mainly 5‐HT and brought into play by prior exposure to allergen.

British Journal of Pharmacology (2001) 132, 1509–1523; doi:10.1038/sj.bjp.0703961
Effects of mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP‐sensitive potassium channel
Authors: Reimann Frank , Proks Peter , Ashcroft Frances M 
Published: January 2005

We have investigated the mechanism of action of the novel anti‐diabetic agent mitiglinide (S 21403) on Kir6.2/SUR1, Kir6.2/SUR2A and Kir6.2/SUR2B types of ATP‐sensitive potassium (KATP) channel. These possess a common pore‐forming subunit, Kir6.2, and different regulatory sulphonylurea receptor (SUR) subunits. It is believed that they correspond to native KATP channels in pancreatic β‐cells, heart and non‐vascular smooth muscle, respectively.
Kir6.2 was coexpressed with SUR1, SUR2A or SUR2B in Xenopus oocytes and macroscopic currents were recorded in giant inside‐out membrane patches. Mitiglinide was added to the intracellular membrane surface.
Mitiglinide inhibited Kir6.2/SUR currents at two sites: a low‐affinity site on Kir6.2 and a high‐affinity site on SUR. Low‐affinity inhibition was similar for all three types of KATP channel but high‐affinity inhibition was greater for Kir6.2/SUR1 currents (IC50, 4 nM) than for Kir6.2/SUR2A or Kir6.2/SUR2B currents (IC50, 3 and 5 μM, respectively).
Inhibition of Kir6.2/SUR1 currents was only slowly reversible on the time scale of electrophysiological experiments.
Kir6.2/SUR1‐S1237Y currents, which previously have been shown to lack high affinity tolbutamide inhibition, resembled Kir6.2/SUR2 currents in being unaffected by 100 nM but blocked by 10 μM mitiglinide.
Our results show that mitiglinide is a high‐affinity drug that shows a 1000 fold greater affinity for the β‐cell type than the cardiac and smooth muscle types of KATP channel, when measured in excised patches.

British Journal of Pharmacology (2001) 132, 1542–1548; doi:10.1038/sj.bjp.0703962
Endothelium‐dependent vasorelaxation independent of nitric oxide and K+ release in isolated renal arteries of rats
Authors: Jiang Fan , Dusting Gregory J 
Published: January 2005

We investigated whether K+ can act as an endothelium‐derived hyperpolarizing factor (EDHF) in isolated small renal arteries of Wistar‐Kyoto rats.
Acetylcholine (0.001 – 3 μM) caused relaxations that were abolished by removal of the endothelium. However, acetylcholine‐induced relaxations were not affected by the nitric oxide (NO) synthase inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 100 μM), by L‐NAME plus the soluble guanylate cyclase inhibitor 1H‐[1,2,4]oxadiazolo[4,3,‐a]quinoxalin‐1‐one (ODQ, 1 μM) or by L‐NAME plus the cyclo‐oxygenase inhibitor indomethacin (10 μM). In rings precontracted with high‐K+(60 mM) physiological salt solution in the presence of L‐NAME, acetylcholine‐induced relaxations were abolished.
L‐NAME‐resistant relaxations were abolished by the large‐conductance Ca2+‐activated K+ channel inhibitor charybdotoxin plus the small‐conductance Ca2+‐activated K+ channel inhibitor apamin, while the inward rectifier K+ channel inhibitor Ba2+ or the gap junction inhibitor 18α‐glycyrrhetinic acid had no effect. Acetylcholine‐induced relaxation was unchanged by ouabain (10 μM) but was partially inhibited by a higher concentration (100 μM).
In half of the tissues tested, K+(10 mM) itself produced L‐NAME‐resistant relaxations that were blocked by ouabain (10 μM) and partially reduced by charybdotoxin plus apamin, but not affected by 18α‐glycyrrhetinic acid or Ba2+. However, K+ did not induce relaxations in endothelium‐denuded tissues.
In conclusion, acetylcholine‐induced relaxations in this tissue are largely dependent upon hyperpolarization mechanisms that are initiated in the endothelium but do not depend upon NO release. K+ release cannot account for endothelium‐dependent relaxation and cannot be an EDHF in this artery. However, K+ itself can initiate endothelium‐dependent relaxations via a different pathway from acetylcholine, but the mechanisms of K+‐induced relaxations remain to be clarified.

British Journal of Pharmacology (2001) 132, 1558–1564; doi:10.1038/sj.bjp.0703965
Tedisamil and dofetilide‐induced torsades de pointes, rate and potassium dependence
Authors: Barrett Terrance D , Hennan James K , Fischbach Peter S , O'Neill Brian P , Driscoll Edward M , Lucchesi Benedict R 
Published: January 2005

Tedisamil is a bradycardiac agent that prolongs the QT interval of the ECG and prevents cardiac arrhythmias. Given this profile, tedisamil might be expected to have proarrhythmic actions similar to Class III antiarrhythmic drugs. To address this question, the actions of dofetilide and tedisamil were examined in rabbit isolated hearts in which bradycardia was induced by AV ablation.
The QT interval was prolonged in a reverse rate‐dependent fashion by dofetilide (3 and 30 nM) and tedisamil (0.3 and 3 μM).
Torsades de pointes was observed in 1/7 hearts treated with 3 nM dofetilide and 0/7 hearts treated with 0.3 μM tedisamil. The incidence of torsades de pointes was increased to 5/7 in hearts treated with 30 nM dofetilide and to 7/7 in hearts treated with 3 μM tedisamil (both P<0.05 vs control).
The actions of 30 nM dofetilide and 3 μM tedisamil were also examined in hearts paced at 50, 100, 200 and 50 beats min−1 successively. Both drugs caused torsades de pointes in 5/5 hearts paced at 50 beats min−1; however, the incidence was reduced to 0/5 during pacing at 200 beats min−1. Thus, drug‐induced proarrhythmia was bradycardia‐dependent.
Drug‐induced prolongation of the interval between the peak and end of the T‐wave (QTa‐e) was reverse rate‐dependent and was associated with the occurrence of torsades de pointes (r=0.91, P<0.01).
The results suggest that tedisamil, like dofetilide, presents a risk for development of torsades de pointes.

British Journal of Pharmacology (2001) 132, 1493–1500; doi:10.1038/sj.bjp.0703967
Serum constituents can affect 2′‐& 3′‐O‐(4‐benzoylbenzoyl)‐ATP potency at P2X7 receptors
Authors: Michel A D , Xing M , Humphrey P P A 
Published: January 2005

2′‐& 3′‐O‐(4‐benzoylbenzoyl)‐ATP (BzATP) is the prototypic agonist for P2X7 receptors. In this study we demonstrate that bovine serum albumin (BSA) can affect the potency of BzATP at P2X receptors.
BzATP potency (pEC50) to stimulate ethidium accumulation in cells expressing recombinant P2X7 receptors varied between 6.5 and 4, depending upon the species orthologue studied and ionic conditions employed. BSA (0.1 – 1 mg ml−1) and foetal bovine serum (FBS, 1 – 10% v v−1) inhibited responses to BzATP but only when the BzATP pEC50 exceeded 5.
BSA did not block ATP‐stimulated ethidium accumulation, suggesting its effects were independent of P2X7 receptor blockade.
BSA did not cause breakdown of nucleotides, although FBS (10% v v−1) exhibited appreciable nucleotidase activity and caused significant breakdown of ATP.
In the presence of BSA, lipids such as 11‐((5‐dimethylaminonaphthalene‐1‐sulphonyl)amino)undecanoic acid (DAUDA) and arachidonic acid (AA) markedly increased BzATP potency. Lipids had no affect on ATP potency in the presence of BSA and had little effect on responses to BzATP in the absence of BSA.
These results suggested that the reduction in BzATP potency by BSA was due to BzATP binding to BSA and that lipids prevented this binding. Consistent with this hypothesis, BzATP inhibited binding of the fluorescent lipid, DAUDA, to BSA.
In conclusion, BSA and lipids can markedly affect BzATP potency at P2X7 receptors but this is probably a consequence of BzATP binding to BSA. This finding has important implications when using BzATP in vivo or in the presence of albumin.

British Journal of Pharmacology (2001) 132, 1501–1508; doi:10.1038/sj.bjp.0703968
The effect of ABT‐702, a novel adenosine kinase inhibitor, on the responses of spinal neurones following carrageenan inflammation and peripheral nerve injury
Authors: Suzuki Rie , Stanfa Louise C , Kowaluk Elizabeth A , Williams Michael , Jarvis Michael F , Dickenson Anthony H 
Published: January 2005

Adenosine (ADO) receptor activation modulates sensory transmission in the dorsal horn. Little is known about the circumstances underlying release of the purine. The present study was conducted to investigate the effect of a novel and potent non‐nucleoside adenosine kinase (AK) inhibitor, ABT‐702, on the responses of dorsal horn neurones to selected peripheral stimuli. ABT‐702 is orally effective to reduce behavioural signs of nociception in models of acute, inflammatory, and neuropathic pain.
Electrophysiological recordings were made from wide dynamic range (WDR) neurones in halothane‐anaesthetized rats. ABT‐702 was given subcutaneously following either carrageenan inflammation or peripheral nerve injury (L5/L6 spinal nerve ligation). Comparisons were made between carrageenan and uninjected control animals, and similarly between spinal nerve ligated (SNL) and sham operated animals.
ABT‐702 produced inhibition of the postdischarge, wind‐up and C‐fibre evoked responses in both carrageenan and nerve‐injured animals. Furthermore, the mechanical and thermal evoked responses were similarly reduced in SNL rats. Overall, ABT‐702 produced a significantly greater inhibition of these responses in SNL rats as compared to sham controls. Similarly ABT‐702 tended to produce greater effects after carrageenan inflammation, however this did not reach significance.
Protection of endogenous adenosine by ABT‐702 therefore produces a marked inhibition of the noxious evoked neuronal activity in inflamed and neuropathic rats. Our results demonstrate a plasticity in the endogenous adenosine‐mediated inhibitory system following SNL and provide a possible basis for the use of this compound for the treatment of neuropathic and other persistent pain states.

British Journal of Pharmacology (2001) 132, 1615–1623; doi:10.1038/sj.bjp.0703972
Tetrapentylammonium block of chloramine‐T and veratridine modified rat brain type IIA sodium channels
Authors: Ghatpande A S , Rao S , Sikdar S K 
Published: January 2005

Tetrapentylammonium (TPeA) block of rat brain type IIA sodium channel α subunit was studied using whole cell patch clamp. Results indicate that TPeA blocks the inactivating brain sodium channel in a potential and use‐dependent manner similar to that of the cardiac sodium channel. Removal of inactivation using chloramine‐T (CT) unmasks a time‐dependent block by TPeA consistent with slow blocking kinetics. On the other hand, no time dependence is observed when inactivation is abolished by modification with veratridine. TPeA does not bind in a potential‐dependent fashion to veratridine‐modified channels and does not significantly affect gating of veratridine‐modified channels suggesting that high affinity binding of TPeA to the brain sodium channel is lost after veratridine modification.British Journal of Pharmacology (2001) 132, 1755–1760; doi:10.1038/sj.bjp.0703973
Heterogeneity of neuronal nicotinic acetylcholine receptors in 5‐HT‐containing chemoreceptor cells of the chicken aorta
Authors: Ito Shigeo , Ohta Toshio , Kasai Yohei , Yonekubo Kazuki , Nakazato Yoshikazu 
Published: January 2005

The effects of nicotinic agonists and antagonists on whole‐cell currents and 5‐hydroxytryptamine (5‐HT) release were studied in order to characterize nicotinic ACh receptors on the 5‐HT‐containing chemoreceptor cells of the chicken aorta.
ACh, nicotine and dimethylphenylpiperazinium (DMPP) evoked concentration‐dependent inward currents accompanied by increases in current noise at a holding potential of −70 mV. The peak amplitude of the current response to DMPP was 50% larger than that to either nicotine or ACh.
Hexamethonium, α – bungarotoxin (α – BTX) and methyllycaconitine decreased nicotine‐induced inward currents in a concentration‐dependent manner. Although hexamethonium (0.1 mM) abolished the current response to nicotine (30 μM), a high concentration (1 μM) of α – BTX decreased it only by about 30% of the control response. Methyllycaconitine (0.1 μM) decreased the current response to nicotine to the same extent as did α – BTX whilst a high concentration (10 μM) abolished the response.
ACh, nicotine and DMPP caused concentration‐dependent increases in 5‐HT output from the thoracic aorta which effect was blocked by hexamethonium (0.1 mM). Pre‐treatment with α – BTX (1 μM) for 30 min reduced the output of 5‐HT induced by ACh to 70% of the control response.
It is suggested that neuronal nicotinic ACh receptors, sensitive and insensitive to α – BTX, are present on the chemoreceptor cells of the chicken aorta, the activation of which causes the release of 5‐HT.

British Journal of Pharmacology (2001) 132, 1934–1940; doi:10.1038/sj.bjp.0703978
Involvement of PACAP receptor in primary afferent fibre‐evoked responses of ventral roots in the neonatal rat spinal cord
Authors: Sakashita Yoshihiko , Kurihara Takashi , Uchida Daigaku , Tatsuno Ichiro , Yamamoto Tatsuo 
Published: January 2005

The role of PACAP receptor in nociceptive transmission was investigated in vitro using maxadilan, a PACAP receptor selective agonist and max.d.4, a PACAP receptor selective antagonist.
Potentials, from a ventral root (L3 – L5) of an isolated spinal cord preparation or a spinal cord – saphenous nerve – skin preparation from 0 – 3‐day‐old rats, were recorded extracellularly.
In the isolated spinal cord preparation, single shock stimulation of a dorsal root at C‐fibre strength induced a slow depolarizing response lasting about 30 s (slow ventral root potential; slow VRP) in the ipsilateral ventral root of the same segment. Bath‐application of max.d.4 (0.01 – 3 μM) inhibited the slow VRP in a concentration‐dependent manner.
In the spinal cord – saphenous nerve – skin preparation, application of capsaicin (0.1 μM) to the skin evoked a depolarization of the ventral root. This response was also depressed by max.d.4 (1 μM).
Application of maxadilan evoked a long‐lasting depolarization in a concentration‐dependent manner in the spinal cord preparation. In the presence of max.d.4 (0.3 μM), the concentration response curve of maxadilan was shifted to the right.
Reverse transcription‐polymerase chain reaction (RT – PCR) experiments demonstrated the existence of PACAP receptor and VPAC2 receptor in the neonatal rat spinal cord and [125I]‐PACAP27 binding was displaced almost completely by maxadilan and max.d.4, but not by vasoactive intestinal peptide (VIP). These data indicate that PACAP receptor is dominantly distributed in the neonatal rat spinal cord.
The present study suggests that PACAP receptor may play an excitatory role in nociceptive transmission in the neonatal rat spinal cord.

British Journal of Pharmacology (2001) 132, 1769–1776; doi:10.1038/sj.bjp.0703980