bluuebunny/crossref_metadata_2025_split huggingface dataset:
Roles of calcium‐activated and voltage‐gated delayed rectifier potassium channels in endothelium‐dependent vasorelaxation of the rabbit middle cerebral artery
Authors: Dong Hui , Waldron Gareth J. , Cole William C. , Triggle Christopher R. 
Published: January 2005

The cellular mechanism(s) of action of endothelium‐derived vasodilator substances in the rabbit middle cerebral artery (RMCA) were investigated. Specifically, the subtypes of potassium channels involved in the effects of endothelium‐derived relaxing factors (EDRFs) in acetylcholine (ACh)‐induced endothelium‐dependent vasorelaxation in this vessel were systematically compared.
In the endothelium‐intact RMCA precontracted with histamine (3 μM), ACh induced a concentration‐dependent vasorelaxation, which was sensitive to indomethacin (10 μM) or NG‐nitro‐L‐arginine (L‐NOARG; 100 μM); pD2 values 8.36 vs 7.40 and 6.38, P<0.01 for both, n=6 and abolished by a combination of both agents. ACh caused relaxation in the presence of high K+ PSS (40 mM KCl), which was not affected by indomethacin, but abolished by L‐NOARG and a combination of indomethacin and L‐NOARG.
In the presence of indomethacin, relaxation to ACh in the endothelium‐intact RMCA precontracted with histamine was unaffected by either glibenclamide (10 μM), an ATP‐sensitive K+ channel (KATP) blocker, 4‐aminopyridine (4‐AP, 1 mM) or dendrotoxin (DTX, 0.1 μM), delayed rectifier K+ channel (KV) blockers. However, relaxation responses to ACh were significantly inhibited by either LY83583 (10 μM) and 1H‐[1,2,4]oxadiazolo[4,3,‐a]quinoxalin‐1‐one (ODQ, 10 μM), guanylyl cyclase inhibitors, or charybdotoxin (CTX; 0.1 μM), iberiotoxin (ITX, 0.1 μM) and apamin (APA, 0.1 μM), large conductance Ca2+ ‐activated K+ channels (BKCa) blocker and small conductance Ca2+ ‐activated K+ channel (SKCa) blocker, respectively.
In the presence of L‐NOARG, relaxation to ACh was unaffected by glibenclamide or the cytochrome P450 mono‐oxygenase inhibitor, clotrimazole (1 μM), but was significantly inhibited by either 9‐(tetrahydro‐2‐furanyl)‐9H‐purin‐6‐amine (SQ  22,536, 10 μM) and 2′,3′‐dideoxyadenosine (2′,3′‐DDA, 30 μM), adenylyl cyclase inhibitors, or 4‐AP, DTX, CTX, ITX and APA.
In the endothelium‐denuded RMCA precontracted with histamine, authentic NO‐induced relaxation was unaffected by glibenclamide, 4‐AP and DTX, but significantly reduced by ODQ, ITX and APA. Authentic prostaglandin I2 (PGI2)‐induced relaxation was unaffected by glibenclamide, but significantly reduced by 2′,3′‐DDA, 4‐AP, DTX, ITX and APA. Forskolin‐induced relaxation was significantly inhibited by high K+, CTX and 4‐AP.
These results indicate that: (1) in the RMCA the EDRFs released by ACh are NO and a prostanoid (presumably PGI2), and there is no evidence for the release of a non‐NO/PGI2 endothelium‐derived hyperpolarizing factor (EDHF), (2) KCa channels are involved in NO‐mediated relaxation of the RMCA but both KCa and Kv channels are involved in PGI2‐mediated relaxation.

British Journal of Pharmacology (1998) 123, 821–832; doi:10.1038/sj.bjp.0701680
Role of nitric oxide in regulation of gastric acid secretion in rats: effects of NO donors and NO synthase inhibitor
Authors: Kato Shinichi , Kitamura Motohiro , Korolkiewicz Roman P. , Takeuchi Koji 
Published: January 2005

The role of nitric oxide (NO) in the regulation of acid secretion was examined in the anaesthetized rat.
A rat stomach was mounted in an ex vivo chamber, instilled with 2 ml of saline every 15 min, and the recovered sample was titrated at pH 7.0 against 0.1 N NaOH by use of an automatic titrator for acid secretion. Gastric mucosal blood flow (GMBF) was measured simultaneously by laser Doppler flowmeter.
Intragastric application of NO donors such as FK409 (3 and 6 mg ml−1) and sodium nitroprusside (SNP; 6 and 12 mg  ml−1) as well as i.p. administration of cimetidine (60 mg kg−1), a histamine H2‐receptor antagonist, significantly inhibited the increase in acid secretion in response to pentagastrin (60 μg kg−1 h−1, i.v.), in doses that increased gastric mucosal blood flow (GMBF).
Intragastric application of FK409 (6 mg ml−1) increased both basal and stimulated acid secretion induced by YM‐14673 (0.3 mg kg−1, i.v.), an analogue of thyrotropin‐releasing hormone (TRH), but had no effect on the acid secretory response induced by histamine (4 mg kg−1 h−1, i.v.).
Pretreatment with NG‐nitro‐L‐arginine methyl ester (L‐NAME; 10 mg kg−1, i.v.) did not affect basal acid secretion, but significantly potentiated the increase in acid secretion induced by YM‐14673 and slightly augmented the acid secretory response to pentagastrin.
Both pentagastrin and YM‐14673 increased the release of nitrite plus nitrate (NOx), stable NO metabolites, into the gastric lumen, and these changes were completely inhibited by prior administration of L‐NAME (10 mg kg−1, i.v.).
Pentagastrin caused an increase in luminal release of histamine and this response was significantly suppressed by intragastric application of FK409 (6 mg ml−1).
These results suggest that either exogenous or endogenous NO has an inhibitory action on gastric acid secretion through suppression of histamine release from enterochromaffin‐like (ECL) cells.

British Journal of Pharmacology (1998) 123, 839–846; doi:10.1038/sj.bjp.0701691
Regulation of H1‐receptor coupling and H1‐receptor mRNA by histamine in bovine tracheal smooth muscle
Authors: Pype J L. , Dupont L J. , Mak J C W. , Barnes P J. , Verleden G M. 
Published: January 2005

Pretreatment of bovine tracheal smooth muscle (BTSM) with histamine (1–100 μM, 1 h) induced a concentration‐dependent desensitization of the contractile response to subsequently administered histamine, with a reduction of the maximum response of 72±8% (n=5) following pre‐exposure to 100 μM histamine. In contrast, concentration‐response curves to the muscarinic agonist, methacholine were not affected following histamine pretreatment, indicating a homologous desensitization. Furthermore, concentration‐response curves to NaF, a G‐protein activator, were not altered following histamine pre‐incubation.
The histamine H1‐receptor (H1R) desensitization could be antagonized by mepyramine (an H1‐receptor antagonist, 1 μM) but not by cimetidine (an H2‐receptor antagonist, 10 μM), indicating that the desensitization occurred via stimulation of histamine H1‐receptors, without evidence for the involvement of histamine H2‐receptors.
Indomethacin (10 μM) did not block the H1R desensitization, suggesting no involvement of prostaglandins. Furthermore, histamine pre‐incubation in calcium free medium still induced a functional uncoupling of H1R.
GF 109203X, a protein kinase C (PKC) inhibitor, and H‐7, a non‐selective kinase inhibitor, did not antagonize the homologous H1R desensitization.
The steady‐state level of H1R mRNA, assessed by Northern blot analysis, was not affected by prolonged histamine exposure (100 μM, 0.5, 1, 2, 4, 16 and 24 h).
These results suggest that histamine induces desensitization of the H1R at the level of the receptor protein, which involves a mechanism independent of PKC, PKA, PKG and calcium influx, suggesting the involvement of a receptor‐specific kinase.

British Journal of Pharmacology (1998) 123, 984–990; doi:10.1038/sj.bjp.0701697
Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor
Authors: Carmen Collado M , Beleta Jorge , Martinez Ester , Miralpeix Montse , Domènech Teresa , Maria Palacios José , Hernández Jesús 
Published: January 2005

The responses of the electrically‐driven right ventricle strip of the guinea‐pig heart to diazepam were recorded in the absence and in the presence of different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors.
Diazepam, at concentrations ranging from 1 μM to 100 μM, was devoid of effect on the contractile force in this preparation.
Conversely, diazepam (5 μM–100 μM) produced a consistent positive inotropic response in the presence of a concentration (1 μM), that was without effect in the absence of diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&F 94120, but not in the presence of the selective PDE 4 inhibitor rolipram.
This effect of diazepam was not γ‐aminobutyric acid (GABA)‐dependent, since it was neither mimicked nor potentiated by GABA, and was not affected by either a high concentration (5 μM) of the antagonists of the benzodiazepine/GABA/channel chloride receptor complex, picrotoxin, flumazenil and β‐carboline‐3‐carboxylic acid methyl ester (βCCMe), or by the inverse agonists, β‐carboline‐3‐carboxylic acid N‐methylamide (βCCMa) and methyl 6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM, 0.1 μM). Furthermore, a specific antagonist of the peripheral benzodiazepine receptors, PK 11195 (5 μM), did not influence the effect of diazepam.
Biochemical studies with isolated PDEs, confirmed that diazepam selectively inhibits type 4 PDE from guinea‐pig right ventricle rather than the other PDEs present in that tissue. The compound inhibited this enzyme in a non‐competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP specific PDE absent from cardiac muscle, with a potency close to that shown for PDE 4.
Diazepam displaced the selective type 4 PDE inhibitor, rolipram from its high affinity binding site in rat brain cortex membranes, and also potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea‐pig eosinophils, where only type 4 PDE is present.
The PDE inhibitory properties of diazepam were shared, although with lower potency, by other structurally‐related benzodiazepines, that also displaced [3H]‐rolipram from its high affinity binding site. The order of potency found for these compounds in these assays was not related to their potencies as modulators of the GABA receptor through its benzodiazepine binding site.
The pharmacological and biochemical data presented in this study indicate that diazepam behaves as a selective type 4 PDE inhibitor in cardiac tissue and this effect seems neither to be mediated by the benzodiazepine/GABA/channel chloride receptor complex nor by peripheral type benzodiazepine receptors.

British Journal of Pharmacology (1998) 123, 1047–1054; doi:10.1038/sj.bjp.0701698
Receptor mechanisms involved in the 5‐HT‐induced inotropic action in the rat isolated atrium
Authors: Läer Stephanie , Remmers Freerk , Scholz Hasso , Stein Birgitt , Ulrich Müller Frank , Neumann Joachim 
Published: January 2005

The effects of 5‐hydroxytryptamine (5‐HT) in rat cardiac preparations were studied. 5‐HT up to 10 μM failed to affect contractility in papillary muscles. However, in electrically driven (1 Hz) left atria 5‐HT exerted a positive inotropic effect that started at 1 μM and attained its maximum at 10 μM (312±50% of predrug value, n=8).
5‐HT 10 μM stimulated the content of inositol‐1,4,5‐trisphosphate but not of cyclic AMP in rat left atria.
Plasma and serum levels of 5‐HT amounted to about 0.3 μM and 15 μM, respectively.
The selective 5‐HT4 receptor antagonists GR 125487 (10 nM and 1 μM) and SB 203186 (1 μM) did not attenuate the positive inotropic effect of 5‐HT in rat left atria. In contrast, the 5‐HT2 receptor antagonist ketanserin (5 nM, 50 nM, 1 μM) resulted in a concentration‐dependent diminution of the positive inotropic effect of 5‐HT in rat left atria.
Reverse transcriptase polymerase chain reaction with specific primers detected mRNA of the 5‐HT2A receptor in rat atria and ventricles, while expression of the 5‐HT4 receptor was confined to atria.
It is suggested that the positive inotropic effect of 5‐HT in electrically driven rat left atria is mediated by ketanserin‐sensitive 5‐HT2A receptors and not through 5‐HT4 receptors.

British Journal of Pharmacology (1998) 123, 1182–1188; doi:10.1038/sj.bjp.0701702
Salmeterol inhibition of mediator release from human lung mast cells by β‐adrenoceptor‐dependent and independent mechanisms
Authors: Chong Lee K. , Cooper Elizabeth , Vardey Christopher J. , Peachell Peter T. 
Published: January 2005

The long‐acting β2‐adrenoceptor agonist, salmeterol (10−9–10−5 M), inhibited the IgE‐mediated release of histamine from human lung mast cells (HLMC) in a dose‐dependent fashion. Additional β‐adrenoceptor agonists were studied and the rank order of potency for the inhibition of histamine release from HLMC was isoprenaline>salmeterol>salbutamol. Approximate EC50 values for the inhibition of histamine release were 10 nM for isoprenaline and 100 nM for salbutamol. An EC50 value for salmeterol could not be calculated because maximal responses to salmeterol were not observed over the concentration range employed.
Both salmeterol and isoprenaline inhibited the generation of sulphopeptidoleukotrienes (sLT) more potently and more efficaciously than the release of histamine from immunologically‐activated HLMC. Salmeterol (EC50<0.1 nM) was more potent than isoprenaline (EC50 0.4 nM) at attenuating sLT generation.
The β‐adrenoceptor antagonist, propranolol (1 μM), and the selective β2‐adrenoceptor antagonist, ICI 118,551 (0.1 μM), both caused rightward shifts in the dose‐response curve for the inhibition of histamine release by isoprenaline. The antagonism of salmeterol effects by propranolol and ICI 118,551 was more complex. At lower concentrations (<1 μM) of salmeterol, both antagonists shifted the dose‐reponse curve to salmeterol rightward. At a higher concentration (10 μM) of salmeterol, neither ICI 118,551 nor propranolol was an effective antagonist of the salmeterol‐mediated inhibition of histamine release.
Prolonged exposure (4 h) of HLMC to isoprenaline (1 μM) caused an approximately 50% reduction in the effectiveness of a second exposure to isoprenaline (10 μM) at inhibiting the release of histamine, whereas this pretreatment did not affect the salmeterol (10 μM) inhibition of histamine release.
Isoprenaline (10−9–10−5 M) caused a dose‐dependent increase in total cell cyclicAMP levels in purified HLMC which paralleled the inhibition of histamine release. Salmeterol (10−9–10−5 M) was considerably less potent than isoprenaline at increasing HLMC cyclicAMP levels.
In summary, these data indicate that salmeterol is an effective inhibitor of the stimulated release of mediators from HLMC. The present data also suggest that salmeterol may act to inhibit mediator release from HLMC by β‐adrenoceptor‐dependent and independent mechanisms.

British Journal of Pharmacology (1998) 123, 1009–1015; doi:10.1038/sj.bjp.0701703
Resistance to myocardial infarction induced by heat stress and the effect of ATP‐sensitive potassium channel blockade in the rat isolated heart
Authors: Joyeux Marie , Godin‐Ribuot Diane , Ribuot Christophe 
Published: January 2005

Heat stress (HS) is known to protect against myocardial ischaemia‐reperfusion injury by improving mechanical dysfunction and decreasing necrosis. However, the mechanisms responsible for this form of cardioprotection remain to be elucidated. ATP‐sensitive potassium (KATP) channels have been shown to be involved in the delayed phase of protection following ischaemic preconditioning, a phenomenon closely resembling the HS‐induced cardioprotection. The aim of this study was thus to investigate the role of KATP channels in HS‐induced protection of the isolated rat heart.
Twenty four hours after whole body heat stress (at 42°C for 15 min) or sham anaesthesia, isolated perfused hearts were subjected to a 15 min stabilization period followed by a 15 min infusion of either 10 μM glibenclamide (Glib), 100 μM sodium 5‐hydroxydecanoate (5HD) or vehicle (0.04% DMSO). Regional ischaemia (35 min) and reperfusion (120 min) were then performed.
Prior heat stress significantly reduced infarct‐to‐risk ratio (from 42.4±2.4% to 19.4±2.9, P<0.001). This resistance to myocardial infarction was abolished in both Glib‐treated (40.1±1.8% vs 42.3±1.8%) and 5HD‐treated (41.2±1.8% vs 41.8±1.2%) groups.
The results of this study suggest that KATP channel activation contributes to the cytoprotective response induced by heat stress.

British Journal of Pharmacology (1998) 123, 1085–1088; doi:10.1038/sj.bjp.0701710
Characterization of prejunctional 5‐HT1 receptors that mediate the inhibition of pressor effects elicited by sympathetic stimulation in the pithed rat
Authors: Morán A , Fernández M M. , Velasco C , Martín M L. , San Román L 
Published: January 2005

A study was made of the effects of 5‐carboxamidotryptamine (5‐CT) on pressor responses induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Sympathetic stimulation (0.1, 0.5, 1 and 5 Hz) resulted in frequency‐dependent increases in blood pressure. Intravenous infusion of 5‐CT at doses of 0.01, 0.1 and 1 μg kg−1 min−1 reduced the pressor effects obtained by electrical stimulation. The inhibitory effect of 5‐CT was significantly more pronounced at lower frequencies of stimulation. In the present study we characterized the pharmacological profile of the receptors mediating the above inhibitory effect of 5‐CT.
The inhibition induced by 0.01 μg kg−1 min−1 of 5‐CT on sympathetically‐induced pressor responses was partially blocked after i.v. treatment with methiothepin (10  μg kg−1), WAY‐100,635 (100 μg kg−1) or GR127935T (250 μg kg−1), but was not affected by cyanopindolol (100 μg kg−1).
The selective 5‐HT1A receptor agonist 8‐OH‐DPAT and the selective 5‐HT1B/1D receptor agonists sumatriptan and L‐694,247 inhibited the pressor response, whereas the 5‐HT1B receptor agonists CGS‐12066B and CP‐93,129 and the 5‐HT2C receptor agonist m‐CPP did not modify the pressor symapthetic responses.
The selective 5‐HT1A receptor antagonist WAY‐100,635 (100 μg kg−1) blocked the inhibition induced by 8‐OH‐DPAT and the selective 5‐HT1B/1D receptor antagonist GR127935T (250 μg kg−1) abolished the inhibition induced either by L‐694,247 or sumatriptan.
None of the 5‐HT receptor agonists used in our experiments modified the pressor responses induced by exogenous noradrenaline (NA).
These results suggest that the presynaptic inhibitory action of 5‐CT on the electrically‐induced pressor response is mediated by both r‐5‐HT1D and 5‐HT1A receptors.

British Journal of Pharmacology (1998) 123, 1205–1213; doi:10.1038/sj.bjp.0701714
Reduced sympathetic noradrenergic neurotransmission in the tail artery of Donryu rats fed with high cholesterol‐supplemented diet
Authors: Karoon Parastoo , Burnstock Geoffrey 
Published: January 2005

Sympathetic neurotransmission and noradrenaline content of the tail artery of Donryu rats fed for 2 months with a cholesterol‐supplemented diet enriched with 4% cholesterol, 1% cholic acid, 0.5% thiouracil (CCT), were examined.
Total serum cholesterol level of CCT fed rats (7.05±1.77 mg ml−1, n=8) was significantly greater than lab‐chow fed controls (2.58±0.32 mg ml−1, n=8). Low density lipoprotein level was also significantly increased in CCT‐fed (1.79±0.26 mg ml−1, n=8) compared with control fed rats (1.35±0.25 mg ml−1, n=8) but plasma levels of triglyceride and high density lipoproteins did not differ significantly between the two groups.
Contractile responses of the arterial rings to transmural nerve stimulation (65 V, 0.1 ms, 4–64 Hz, 1 s), were markedly attenuated in the CCT fed animals compared with the controls. This reduction involved the noradrenergic rather than purinergic component of sympathetic transmission.
Vasoconstrictor responses to exogenous noradrenaline (0.01–300 μM) and adenosine 5′‐triphosphate (0.3–1000 μM) were unaffected by CCT diet, indicating prejunctional alteration of sympathetic neurotransmission during CCT‐induced hyperlipidaemia.
The noradrenaline content of the tail arteries of CCT fed animals (2.64±0.36 ng mg−1, n=6) was significantly lower than that of controls (3.82±0.32 ng mg−1, n=6).
These findings show that chronic treatment of Donryu rats with a cholesterol‐supplemented diet led to altered levels of circulating lipid fractions accompanied by attenuated sympathetic noradrenergic neurotransmission and reduced noradrenaline content of the rat tail artery.

British Journal of Pharmacology (1998) 123, 1016–1021; doi:10.1038/sj.bjp.0701719
Effect of PDE4 inhibitors on zymosan‐induced IL‐8 release from human neutrophils: synergism with prostanoids and salbutamol
Authors: Au B‐ T. , Teixeira M M. , Collins P D. , Williams T J. 
Published: January 2005

The activation of neutrophils with particulate stimuli such as zymosan induces the generation of the C‐X‐C chemokine interleukin (IL)‐8. There is evidence that neutrophil derived IL‐8 plays an important role in human diseases such as the adult respiratory distress syndrome. In the present study, we examined the effects of cyclic AMP elevating agents on the ability of human neutrophils to generate IL‐8 in response to zymosan particles.
The PDE4 inhibitor rolipram had limited effect on zymosan‐induced IL‐8 generation. In contrast, the PDE4 inhibitors RP 73401 and SB 207499 concentration‐dependently suppressed IL‐8 generation. The potency of these inhibitors was RP 73401 > SB 207499 > rolipram which is correlated with their rank order of potency at inhibiting the catalytic site of purified neutrophil PDE4. Pretreatment of neutrophils with the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinast had no effect on IL‐8 generation.
The prostanoids prostaglandin E1 (PGE1) and PGE2 inhibited zymosan‐induced IL‐8 release from neutrophils in a dose‐dependent manner, in response to 10−5M PGE1 and PGE2 inhibiting IL‐8 generation by 89% and 75%, respectively. Similarly, the β2‐adrenoceptor agonist salbutamol also inhibited IL‐8 generation, but it was less effective than the prostanoids.
Significant synergism between prostanoids or salbutamol and the PDE4 inhibitors to inhibit IL‐8 generation was observed. In contrast, there was no significant synergism between PGE2 and the PDE3 inhibitor ORG 9935 or the PDE5 inhibitor zaprinast.
In order to evaluate the potential role of protein kinase A in mediating the inhibitory effects of cyclic AMP‐elevating agents, we used the protein kinase A inhibitors, H 89 and KT 5720. Pretreatment of neutrophils with these drugs completely reversed the inhibitory effects of a combination treatment with rolipram and PGE2 on zymosan‐induced IL‐8 release.
Microscopic examination revealed that most neutrophils contained one or more zymosan particles and that combination treatment with rolipram and PGE2 noticeably reduced the number of ingested particles. Moreover, there was a significant reduction in the percentage of neutrophils which ingested three or more zymosan particles.
Thus, our results demonstrate that cyclic AMP‐elevating agents modulate the ability of neutrophils to generate IL‐8 in response to a particulate stimulus. However, these agents also modulate the ability of neutrophils to phagocytose zymosan particles. Whether this effect will translate into inhibition of the ability of neutrophils to deal with infectious agents needs to be investigated further.

British Journal of Pharmacology (1998) 123, 1260–1266; doi:10.1038/sj.bjp.0701723