bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrophysiological effects of activating the peptidergic primary afferent innervation of rat mesenteric arteries
Authors: Dunn W R , Hardy T A , Brock J A 
Published: September 2003

Intracellular recording was used to investigate the electrophysiological effects of activating peptidergic primary afferent axons with capsaicin in the smooth muscle of rat mesenteric arteries in vitro. In addition, continuous amperometry was used to monitor the effects of capsaicin on noradrenaline release from the sympathetic nerves.
Capsaicin (1 μM) produced a hyperpolarization (−11±2 mV) and a reduction in the time constant of decay of excitatory junction potentials (e.j.p.'s) evoked by electrical stimulation of the perivascular sympathetic nerves. These effects of capsaicin were mimicked by calcitonin gene‐related peptide (CGRP; 1 and 10 nM) but not by substance P (50 nM), which produced a small hyperpolarization (maximum −3±1 mV) but did not change excitatory junction potential (e.j.p.) time course.
The hyperpolarization produced by capsaicin and CGRP was blocked by glibenclamide (10 μM) but was not changed by the CGRP antagonist, CGRP8–37 (0.5 μM). Mechanical denudation of the endothelium also did not reduce the effect of capsaicin on membrane potential.
Capsaicin (1 μM) increased the amplitude of e.j.p.'s. This effect was not mimicked by CGRP or substance P nor blocked by glibenclamide or CGRP8–37.
All effects of capsaicin desensitized.
Capsaicin (1 μM) had no effect on noradrenaline‐induced oxidation currents evoked by electrical stimulation, indicating that noradrenaline release was unchanged.
These results suggest that CGRP released from primary afferent axons hyperpolarizes vascular smooth muscle by activating glibenclamide‐sensitive K+ channels. The findings also indicate that an unknown factor released by the primary afferent axons increases e.j.p. amplitude.

British Journal of Pharmacology (2003) 140, 231–238. doi:10.1038/sj.bjp.0705417
Cannabinoid receptor activation in the rostral ventrolateral medulla oblongata evokes cardiorespiratory effects in anaesthetised rats
Authors: Padley James R , Li Qun , Pilowsky Paul M , Goodchild Ann K 
Published: September 2003

The nature of the cardiorespiratory effects mediated by cannabinoids in the hindbrain is poorly understood. In the present study we investigated whether cannabinoid receptor activation in the rostral ventrolateral medulla oblongata (RVLM) affects cardiovascular and/or respiratory function.
Initially, we looked for evidence of CB1 receptor gene expression in rostral and caudal sections of the rat ventrolateral medulla (VLM) using reverse transcription–polymerase chain reaction. Second, the potent cannabinoid receptor agonists WIN55,212‐2 (0.05, 0.5 or 5 pmol per 50 nl) and HU‐210 (0.5 pmol per 50 nl) or the CB1 receptor antagonist/inverse agonist AM281 (1 pmol per 100 nl) were microinjected into the RVLM of urethane‐anaesthetised, immobilised and mechanically ventilated male Sprague–Dawley rats (n=22). Changes in splanchnic nerve activity (sSNA), phrenic nerve activity (PNA), mean arterial pressure (MAP) and heart rate (HR) in response to cannabinoid administration were recorded.
The CB1 receptor gene was expressed throughout the VLM. Unilateral microinjection of WIN55,212‐2 into the RVLM evoked short‐latency, dose‐dependent increases in sSNA (0.5 pmol; 175±8%, n=5) and MAP (0.5 pmol; 26±3%, n=8) and abolished PNA (0.5 pmol; duration of apnoea: 5.4±0.4 s, n=8), with little change in HR (P<0.005). HU‐210, structurally related to Δ9‐tetrahydrocannabinol (THC), evoked similar effects when microinjected into the RVLM (n=4). Surprisingly, prior microinjection of AM281 produced agonist‐like effects, as well as significantly attenuated the response to subsequent injection of WIN55,212‐2 (0.5 pmol, n=4).
The present study reveals CB1 receptor gene expression in the rat VLM and demonstrates sympathoexcitation, hypertension and respiratory inhibition in response to RVLM‐administered cannabinoids. These findings suggest a novel link between CB1 receptors in this region of the hindbrain and the central cardiorespiratory effects of cannabinoids. The extent to which these central effects contribute to the cardiovascular and respiratory outcomes of cannabis use remains to be investigated.

British Journal of Pharmacology (2003) 140, 384–394. doi:10.1038/sj.bjp.0705422
Benzydamine inhibits monocyte migration and MAPK activation induced by chemotactic agonists
Authors: Riboldi Elena , Frascaroli Giada , Transidico Pietro , Luini Walter , Bernasconi Sergio , Mancini Francesca , Guglielmotti Angelo , Milanese Claudio , Pinza Mario , Sozzani Silvano , Mantovani Alberto 
Published: September 2003

The present study was aimed to investigate the effect of benzydamine, an anti‐inflammatory drug devoid of activity on arachidonic acid metabolism, on monocyte chemotaxis and to define the possible biochemical correlates of activity.
Benzydamine inhibited monocyte chemotaxis in response to three classes of chemoattractants: the prototypic CC‐chemokine CCL2 (MCP‐1), the microbial product fMLP and the complement cascade component C5a. The effect was dose‐dependent with IC50's of 100, 50 and 45 μM for MCP‐1/CCL2, fMLP and C5a, respectively. At the dose of 100 μM, the effect resulted in a 50±10% inhibition of MCP‐1/CCL2‐induced chemotaxis and 53±6 and 54±5% inhibitions of chemotaxis in response of fMLP and C5a, respectively (n=3).
Receptor expression as well as calcium fluxes in response to chemoattractants were not affected by benzydamine.
Benzydamine strongly inhibited chemoattractant‐induced activation of the mitogen‐activated protein kinase (MAPK) ERK1/2, and of its upstream activator kinase MEK1/2. ERK1/12 activation in response to chemoattractants was 89–98% inhibited by a 100 μM concentration of benzydamine with an IC50 of 30 μM.
Under the same experimental conditions, pretreatment with 100 μM benzydamine caused a 75–89% inhibition of p38 activation (IC50 25 μM).
These results indicate that the anti‐inflammatory activity of benzydamine is exerted at multiple levels, including monocyte migration to chemotactic factors associated to a blockage of ERK and p38 MAPK pathways.

British Journal of Pharmacology (2003) 140, 377–383. doi:10.1038/sj.bjp.0705428
Resolution of the oedema associated with allergic pulmonary inflammation in rats assessed noninvasively by magnetic resonance imaging
Authors: Tigani Bruno , Cannet Catherine , Zurbrügg Stefen , Schaeublin Elisabeth , Mazzoni Lazzaro , Fozard John R , Beckmann Nicolau 
Published: September 2003

Magnetic resonance imaging (MRI) was used to study noninvasively the effects of compounds to resolve inflammation induced by ovalbumin (OVA) challenge in the lungs of actively sensitised rats.
Marked oedematous signals were detected between 24 and 96 h following OVA in vehicle‐treated animals. When administered 24 h after OVA, budesonide, a glucocorticosteroid, or 4‐(8‐benzo[1,2,5]oxadiazol‐5‐yl‐[1,7]naphthyridin‐6‐yl)‐benzoic acid (NVP‐ABE171), a selective phosphodiesterase 4 inhibitor, increased the rate of resolution of established oedematous signals detected by MRI. The effect was evident 3 h after drug administration and the signals were nearly fully resolved at 96 h postchallenge.
The drug‐induced rapid resolution of MRI signals was not accompanied by changes in parameters of inflammation in the bronchoalveolar lavage fluid, but was associated with perivascular oedema detected histologically.
In conclusion, the effects of anti‐inflammatory drugs on a component of allergic inflammation can be monitored by following with MRI the rate of resolution of the associated oedematous signals.

British Journal of Pharmacology (2003) 140, 239–246. doi:10.1038/sj.bjp.0705429
NANC inhibitory neurotransmission in mouse isolated stomach: involvement of nitric oxide, ATP and vasoactive intestinal polypeptide
Authors: Mulè Flavia , Serio Rosa 
Published: September 2003

The neurotransmitters involved in NANC relaxation and their possible interactions were investigated in mouse isolated stomach, recording the motor responses as changes of endoluminal pressure from whole organ.
Field stimulation produced tetrodotoxin‐sensitive, frequency‐dependent, biphasic responses: rapid transient relaxation followed by a delayed inhibitory component.
The inhibitor of the synthesis of nitric oxide (NO), L‐NAME, abolished the rapid relaxation and significantly reduced the slow relaxation. Apamin, blocker of Ca2+‐dependent K+ channels, or ADPβS, which desensitises P2y purinoceptors, reduced the slow relaxation to 2–8 Hz, without affecting that to 16–32 Hz or the fast relaxation. α‐Chymotrypsin or vasoactive intestinal polypeptide 6–28 (VIP6–28), antagonist of VIP receptors, failed to affect the fast component or the delayed relaxation to 2–4 Hz, but antagonised the slow component to 8–32 Hz.
Relaxation to sodium nitroprusside was not affected by L‐NAME, apamin or ADPβS, but was reduced by α‐chymotrypsin or VIP6–28. Relaxation to VIP was abolished by α‐chymotrypsin, antagonised by VIP6–28, but was not affected by L‐NAME, apamin or ADPβS. Relaxation to ATP was abolished by apamin, antagonised by ADPβS, but was not affected by L‐NAME or α‐chymotrypsin.
The present results suggest that NO is responsible for the rapid relaxation and partly for the slow relaxation. ATP is involved in the slow relaxation evoked by low frequencies of stimulation. VIP is responsible for the slow relaxation evoked by high frequencies of stimulation. The different neurotransmitters appear to work in parallel, although NO could serve also as a neuromodulator that facilitates release of VIP.

British Journal of Pharmacology (2003) 140, 431–437. doi:10.1038/sj.bjp.0705431
Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats
Authors: Todorovic Slobodan M , Rastogi A J , Jevtovic‐Todorovic Vesna 
Published: September 2003

Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage‐ and ligand‐gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception.
We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage‐gated Na+ channel blockers, phenytoin and carbamazepine, and voltage‐gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose‐dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively.
Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia.
Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide.
Our data strongly suggest that cellular targets like voltage‐gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage‐gated Na+ and Ca2+ channels may be useful analgesics.

British Journal of Pharmacology (2003) 140, 255–260. doi:10.1038/sj.bjp.0705434
Inhibition of guinea‐pig and human sensory nerve activity and the cough reflex in guinea‐pigs by cannabinoid (CB2) receptor activation
Authors: Patel Hema J , Birrell Mark A , Crispino Natascia , Hele David J , Venkatesan Priya , Barnes Peter J , Yacoub Magdi H , Belvisi Maria G 
Published: September 2003

There is considerable interest in novel therapies for cough, since currently used agents such as codeine have limited beneficial value due to the associated side effects. Sensory nerves in the airways mediate the cough reflex via activation of C‐fibres and RARs. Evidence suggests that cannabinoids may inhibit sensory nerve‐mediated responses.
We have investigated the inhibitory actions of cannabinoids on sensory nerve depolarisation mediated by capsaicin, hypertonic saline and PGE2 on isolated guinea‐pig and human vagus nerve preparations, and the cough reflex in conscious guinea‐pigs.
The non‐selective cannabinoid (CB) receptor agonist, CP 55940, and the selective CB2 agonist, JWH 133 inhibited sensory nerve depolarisations of the guinea‐pig vagus nerve induced by hypertonic saline, capsaicin and PGE2. These responses were abolished by the CB2 receptor antagonist SR144528, and unaffected by the CB1 antagonist SR141716A. Similarly, JWH 133 inhibited capsaicin‐evoked nerve depolarisations in the human vagus nerve, and was prevented by SR144528.
Using a guinea‐pig in vivo model of cough, JWH 133 (10 mg kg−1, i.p., 20 min) significantly reduced citric acid‐induced cough in conscious guinea pigs compared to those treated with the vehicle control.
These data show that activation of the CB2 receptor subtype inhibits sensory nerve activation of guinea‐pig and human vagus nerve, and the cough reflex in guinea‐pigs, suggesting that the development of CB2 agonists, devoid of CB1‐mediated central effects, will provide a new and safe antitussive treatment for chronic cough.

British Journal of Pharmacology (2003) 140, 261–268. doi:10.1038/sj.bjp.0705435
Possible involvement of IGF‐1 receptor and IGF‐binding protein in insulin‐induced enhancement of noradrenaline response in diabetic rat aorta
Authors: Kobayashi Tsuneo , Kaneda Akihito , Kamata Katsuo 
Published: September 2003

We investigated the mechanisms underlying the changes in vascular contractile responsiveness induced by chronic treatment with insulin in controls and established streptozotocin (STZ)‐induced diabetic rats.
The aortic contractile response to noradrenaline (NA) showed no significant difference between controls and diabetics, but it was significantly greater in insulin‐treated diabetic rats than in the other groups. To investigate the mechanism, we examined the changes in NA‐induced contractility following treatment with insulin and insulin‐like growth factor‐1 (IGF‐1) in organ‐cultured control and diabetic aortas.
The contractile response to NA in organ‐cultured diabetic rat aortas treated with insulin (500 ng ml−1, 16 h) or IGF‐1 (20 ng ml−1, 16 h) was significantly greater than the corresponding values for (a) diabetic rat aortas cultured in serum‐free medium, and (b) control aortas incubated with insulin or IGF‐1. Incubating control aortas with insulin or IGF‐1 had no significant effect on the contraction induced by NA.
The expressions of the IGF‐1 receptor mRNA and protein were increased in STZ‐induced diabetic aortas and further increased in insulin‐treated diabetics. The mRNA expressions of IGF‐binding protein (IGFBP)‐2 and IGFBP‐3 were normal in diabetic aortas. In contrast, those of IGFBP‐4 and IGFBP‐5 were significantly decreased in diabetic aortas, and not restored by insulin treatment.
These results suggest that the insulin deficiency and chronic hyperinsulinemia in diabetes upregulate the IGF‐1 receptor and downregulate IGFBP‐4 and IGFBP‐5 in the aorta. This may be a major cause of the increased vascular contractility induced by insulin administration and by hyperinsulinemia in established diabetes, resulting in hypertension.

British Journal of Pharmacology (2003) 140, 285–294. doi:10.1038/sj.bjp.0705438
Molecular mechanisms of ligand–receptor interactions in transmembrane domain V of the α2A‐adrenoceptor
Authors: Peltonen Juha M , Nyrönen Tommi , Wurster Siegfried , Pihlavisto Marjo , Hoffrén Anna‐Marja , Marjamäki Anne , Xhaard Henri , Kanerva Liisa , Savola Juha‐Matti , Johnson Mark S , Scheinin Mika 
Published: September 2003

The structural determinants of catechol hydroxyl interactions with adrenergic receptors were examined using 12 α2‐adrenergic agonists and a panel of mutated human α2A‐adrenoceptors. The α2ASer201 mutant had a Cys → Ser201 (position 5.43) amino‐acid substitution, and α2ASer201Cys200 and α2ASer201Cys204 had Ser → Cys200 (5.42) and Ser → Cys204 (5.46) substitutions, respectively, in addition to the Cys → Ser201 substitution.
Automated docking methods were used to predict the receptor interactions of the ligands. Radioligand‐binding assays and functional [35S]GTPγS‐binding assays were performed using transfected Chinese hamster ovary cells to experimentally corroborate the predicted binding modes.
The hydroxyl groups of phenethylamines were found to have different effects on ligand affinity towards the activated and resting forms of the wild‐type α2A‐adrenoceptor. Substitution of Ser200 or Ser204 with cysteine caused a deterioration in the capability of catecholamines to activate the α2A‐adrenoceptor. The findings indicate that (i) Cys201 plays a significant role in the binding of catecholamine ligands and UK14,304 (for the latter, by a hydrophobic interaction), but Cys201 is not essential for receptor activation; (ii) Ser200 interacts with the meta‐hydroxyl group of phenethylamine ligands, affecting both catecholamine binding and receptor activation; while (iii) substituting Ser204 with a cysteine interferes both with the binding of catecholamine ligands and with receptor activation, due to an interaction between Ser204 and the para‐hydroxyl group of the catecholic ring.

British Journal of Pharmacology (2003) 140, 347–358. doi:10.1038/sj.bjp.0705439
Brief, repeated, oxygen‐glucose deprivation episodes protect neurotransmission from a longer ischemic episode in the in vitro hippocampus: role of adenosine receptors
Authors: Pugliese Anna Maria , Latini Serena , Corradetti Renato , Pedata Felicita 
Published: September 2003

Ischemic preconditioning in the brain consists of reducing the sensitivity of neuronal tissue to further, more severe, ischemic insults. We recorded field epsps (fepsps) extracellularly from hippocampal slices to develop a model of in vitro ischemic preconditioning and to evaluate the role of A1, A2A and A3 adenosine receptors in this phenomenon.
The application of an ischemic insult, obtained by glucose and oxygen deprivation for 7 min, produced an irreversible depression of synaptic transmission. Ischemic preconditioning was induced by four ischemic insults (2 min each) separated by 13 min of normoxic conditions. After 30 min, an ischemic insult of 7 min was applied. This protocol substantially protected the tissue from the irreversible depression of synaptic activity.
The selective adenosine A1 receptor antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, 100 nM), completely prevented the protective effect of preconditioning. The selective adenosine A2A receptor antagonist 4‐(2‐[7‐amino‐2‐(2‐furyl)[1,2,4]triazolo[2,3‐a][1,3,5]triazin‐5‐ylamino]ethyl)phenol (ZM 241385, 100 nM) did not modify the magnitude of fepsp recovery compared to control slices. The selective A3 adenosine receptor antagonists, 3‐propyl‐6‐ethyl‐5[ethyl(thio)carbonyl]‐2‐phenyl‐4‐propyl‐3‐pyridinecarboxylate (MRS 1523, 100 nM) significantly improved the recovery of fepsps after 7 min of ischemia.
Our results show that in vitro ischemic preconditioning allows CA1 hippocampal neurons to become resistant to prolonged exposure to ischemia. Adenosine, by stimulating A1 receptors, plays a crucial role in eliciting the cell mechanisms underlying preconditioning; A2A receptors are not involved in this phenomenon, whereas A3 receptor activation is harmful to ischemic preconditioning.

British Journal of Pharmacology (2003) 140, 305–314. doi:10.1038/sj.bjp.0705442
Protein kinase C‐mediated Ca2+ entry in HEK 293 cells transiently expressing human TRPV4
Authors: Xu Feng , Satoh Eisaku , Iijima Toshihiko 
Published: September 2003

We investigated whether protein kinase C (PKC) activation stimulates Ca2+ entry in HEK 293 cells transfected with human TRPV4 cDNA and loaded with fura‐2.
Phorbol 12‐myristate 13‐acetate (PMA), a PKC‐activating phorbol ester, increased the intracellular Ca2+ concentration ([Ca2+]i) in a dose‐dependent manner, with an EC50 value of 11.7 nM. Exposure to a hypotonic solution (HTS) after PMA further increased [Ca2+]i. Two other PKC‐activating phorbol esters, phorbol 12,13‐didecanoate (PDD) and phorbol 12,13‐dibutyrate, also caused [Ca2+]i to increase.
The inactive isomer 4α‐PMA was less effective and the peak [Ca2+]i increase was significantly smaller than that induced by PMA. In contrast, 4α‐PDD produced a monophasic or biphasic [Ca2+]i increase with a different latency, while 4α‐phorbol had no effect.
The PMA‐induced [Ca2+]i increase was abolished by prior exposure to bisindolylmaleimide (BIM), a PKC‐specific inhibitor, and suppressed by the nonspecific PKC inhibitor 1‐(5‐isoquinolinesulphonyl)‐2‐methylpiperazine. The [Ca2+]i increase induced by 4α‐PMA, 4α‐PDD or HTS was not significantly affected by BIM.
These results suggest that both PKC‐dependent and ‐independent mechanisms are involved in the phorbol ester‐induced activation of TRPV4, and the PKC‐independent pathway is predominant in HTS‐induced Ca2+ entry.

British Journal of Pharmacology (2003) 140, 413–421. doi:10.1038/sj.bjp.0705443
Effects of GABA agonists on body temperature regulation in GABAB(1)−/− mice
Authors: Quéva Christophe , Bremner‐Danielsen Marianne , Edlund Anders , Jonas Ekstrand A , Elg Susanne , Erickson Sven , Johansson Thore , Lehmann Anders , Mattsson Jan P 
Published: September 2003

Activation of GABAB receptors evokes hypothermia in wildtype (GABAB(1)+/+) but not in GABAB receptor knockout (GABAB(1)−/−) mice. The aim of the present study was to determine the hypothermic and behavioural effects of the putative GABAB receptor agonist γ‐hydroxybutyrate (GHB), and of the GABAA receptor agonist muscimol. In addition, basal body temperature was determined in GABAB(1)+/+, GABAB(1)+/− and GABAB(1)−/− mice.
GABAB(1)−/− mice were generated by homologous recombination in embryonic stem cells. Correct gene targeting was assessed by Southern blotting, PCR and Western blotting. GABAB receptor‐binding sites were quantified with radioligand binding. Measurement of body temperature was done using subcutaneous temperature‐sensitive chips, and behavioural changes after drug administration were scored according to a semiquantitative scale.
GABAB(1)−/− mice had a short lifespan, probably caused by generalised seizure activity. No histopathological or blood chemistry changes were seen, but the expression of GABAB(2) receptor protein was below the detection limit in brains from GABAB(1)−/− mice, in the absence of changes in mRNA levels.
GABAB receptor‐binding sites were absent in brain membranes from GABAB(1)−/− mice.
GABAB(1)−/− mice were hypothermic by approximately 1°C compared to GABAB(1)+/+ and GABAB(1)+/− mice.
Injection of baclofen (9.6 mg kg−1) produced a large reduction in body temperature and behavioural effects in GABAB(1)+/+ and in GABAB(1)+/− mice, but GABAB(1)−/− mice were unaffected. The same pattern was seen after administration of GHB (400 mg kg−1). The GABAA receptor agonist muscimol (2 mg kg−1), on the other hand, produced a more pronounced hypothermia in GABAB(1)−/−mice. In GABAB(1)+/+ and GABAB(1)+/− mice, muscimol induced sedation and reduced locomotor activity. However, when given to GABAB(1)−/− mice, muscimol triggered periods of intense jumping and wild running.
It is concluded that hypothermia should be added to the characteristics of the GABAB(1)−/−phenotype. Using this model, GHB was shown to be a selective GABAB receptor agonist. In addition, GABAB(1)−/− mice are hypersensitive to GABAA receptor stimulation, indicating that GABAB tone normally balances GABAA‐mediated effects.

British Journal of Pharmacology (2003) 140, 315–322. doi:10.1038/sj.bjp.0705447