bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological evidence that inducible nitric oxide synthase is a mediator of delayed preconditioning
Authors: Imagawa J , Yellon D M , Baxter G F 
Published: January 2005

Brief periods of myocardial ischaemia preceding a subsequent more prolonged ischaemic period 24–72 h later confer protection against myocardial infarction (‘delayed preconditioning’ or the ‘second window’ of preconditioning). In the present study, we examined the effects of pharmacological modifiers of inducible nitric oxide synthase (iNOS) induction and activity on delayed protection conferred by ischaemic preconditioning 48 h later in an anaesthetized rabbit model of myocardial infarction.
Rabbits underwent a myocardial preconditioning protocol (four 5 min coronary artery occlusions) or were sham‐operated. Forty‐eight hours later they were subjected to a sustained 30 min coronary occlusion and 120 min reperfusion. Infarct size was determined with triphenyltetrazolium staining. In rabbits receiving no pharmacological intervention, the percentage of myocardium infarcted within the risk zone was 43.9±5.0% in sham‐operated animals and this was significantly reduced 48 h after ischaemic preconditioning with four 5 min coronary occlusions to 18.5±5.6% (P<0.01).
Administration of the iNOS expression inhibitor dexamethasone (4 mg kg−1 i.v) 60 min before ischaemic preconditioning completely blocked the infarct‐limiting effect of ischaemic preconditioning (infarct size 48.6±6.1%). Furthermore, administration of aminoguanidine (300 mg kg−1, s.c.), a relatively selective inhibitor of iNOS activity, 60 min before sustained ischaemia also abolished the delayed protection afforded by ischaemic preconditioning (infarct size 40.0±6.0%).
Neither aminoguanidine nor dexamethasone per se had significant effect on myocardial infarct size. Myocardial risk zone volume during coronary ligation, a primary determinant of infarct size in this non‐collateralized species, was not significantly different between intervention groups. There were no differences in systolic blood pressure, heart rate, arterial blood pH or rectal temperature between groups throughout the experimental period.
These data provide pharmacological evidence that the induction of iNOS, following brief periods of coronary occlusion, is associated with increased myocardial tolerance to infarction 48 h later.

British Journal of Pharmacology (1999) 126, 701–708; doi:10.1038/sj.bjp.0702368
Effects of nicorandil as compared to mixtures of sodium nitroprusside and levcromakalim in isolated rat aorta
Authors: Cogolludo Angel L , Pérez‐Vizcaíno Francisco , Fajardo Susan , Ibarra Manuel , Tamargo Juan 
Published: January 2005

The contribution of the relaxant mechanisms of nicorandil (NIC) were analysed by comparing its effects with those of sodium nitroprusside (SNP), levcromakalim (LEM) and mixtures (1:10, 1:30 and 1:100) of SNP:LEM in isolated endothelium‐denuded rat aorta.
In rings precontracted with KCl (25 mM), the relative inhibitory potency of the soluble guanylate cyclase inhibitor ODQ and the KATP channel inhibitor glibenclamide (GLI) on SNP:LEM mixtures showed a good correlation with the relative proportion of SNP and LEM in the mixtures. Furthermore, the degree of the inhibition by ODQ and GLI of the effects of the 1:30 SNP:LEM mixture varied as a function of the relative potency of SNP and LEM in KCl‐, noradrenaline‐ (NA) or NA plus nifedipine‐treated arteries.
The inhibitory effects of ODQ, GLI and ODQ plus GLI on NIC‐induced relaxation was similar to that for the 1:30 SNP:LEM mixture in NA plus nifedipine‐contracted arteries, but the inhibition of GLI or ODQ plus GLI was smaller in KCl‐contracted arteries.
In conclusion, the relative importance of activation of the cyclic GMP pathway and KATP channel opening in mixtures of SNP and LEM could be predicted by the proportion of the drugs in the mixtures and by the relative potency of SNP vs LEM in different experimental conditions. Furthermore, the present results suggest that besides these two mechanisms, a third ODQ‐ and GLI‐insensitive mechanism, possibly involving Ca2+ channel blockade, also participates in the relaxant effects of NIC in KCl‐induced contractions.

British Journal of Pharmacology (1999) 126, 1025–1033; doi:10.1038/sj.bjp.0702375
Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries
Authors: Chan Elsa C H , Woodman Owen L 
Published: January 2005

Anaesthetized dogs were subjected to 1 h occlusion of the left circumflex coronary artery followed by 2 h of reperfusion. Relaxant responses were examined in coronary artery rings removed proximal (nonischaemic) or distal (ischaemic) to the site of occlusion.
Relaxant responses to acetylcholine (ACh) were similar in nonischaemic and ischaemic artery rings. In addition ACh‐induced relaxation of nonischaemic and ischaemic artery rings was equally susceptible to inhibition of nitric oxide (NO) synthase using L‐NG‐nitroarginine (L‐NOARG, 10−4 M), or to inhibition of soluble guanylate cyclase using 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxaline‐1‐one (ODQ, 10−5 M).
In nonischaemic arteries, the relaxation to ACh was unaffected by high K+ (67 mM) but in ischaemic arteries, the maximum relaxation to ACh was significantly reduced from 113±6 to 60±2% (ANOVA, P<0.05). Tetraethylammonium (TEA, 10−3 M), an inhibitor of large conductance calcium activated potassium (BKCa) channels did not inhibit the response to ACh in nonischaemic arteries but in ischaemic arteries TEA significantly shifted the concentration response curve to ACh to the right (pEC50; nonischaemic, 7.07±0.25; ischaemic, 6.54±0.21, P<0.01, ANOVA) without decreasing the maximum relaxation. TEA did not affect the responses to sodium nitroprusside in either nonischaemic or ischaemic arteries.
In conclusion, ischaemia/reperfusion did not change the sensitivity of endothelium‐dependent relaxation to L‐NOARG or ODQ indicating that ischaemia did not affect the contribution of NO or cyclic GMP to ACh‐induced relaxation. However, in ischaemic arteries the opening of the BKCa channels contributed to relaxation caused by ACh whereas TEA had no effect in nonischaemic arteries. The factor responsible for the opening of this potassium channel was a factor other than NO and may be endothelium derived hyperpolarizing factor (EDHF).

British Journal of Pharmacology (1999) 126, 925–932; doi:10.1038/sj.bjp.0702376
Decreased vascular permeability response to substance P in airways of genetically hypertensive rats
Authors: Bakhle Y S , Brogan Juliet D , Bell C 
Published: January 2005

The inbred genetically hypertensive strain (GH) of the Otago Wistar rat possesses more sensory neurons containing the neuropeptide substance P (SP) than does its genetically related control normotensive strain.
As SP contributes to airway inflammation by increasing microvascular permeability, we assessed the extravasation of Evans Blue dye in trachea and main bronchus of anaesthetized GH and control rats, in the presence of endogenous (capsaicin‐liberated) or exogenous SP.
Following intravenous administration of either capsaicin (75 μg kg−1) or SP (3.3 nmol kg−1), extravasation of Evans Blue in airways from GH rats was only about 60% of that in airways of control rats. This difference was not gender‐specific and responses to capsaicin were abolished by pretreatment with a selective NK1 receptor antagonist SR 140333 (360 nmol kg−1).
By contrast, the extravasation of dye caused by intravenous 5‐hydroxytryptamine (0.5 μmol kg−1) was similar in magnitude in both GH and control strains.
Falls in systemic arterial blood pressure in response to exogenous SP (0.1–3 nmol kg−1) or acetylcholine (0.2–2 nmol kg−1) were also very similar between strains, but those in response to capsaicin (75 μg kg−1) in the GH rats were about double those in control rats. The hypotensive response to SP was abolished by SR 140333, but that to capsaicin was unaffected.
Our results indicate that the increased peripheral innervation density by SP nerves in GH rats is accompanied by reduced inflammatory responses to SP. This does not involve decreased vasodilator potency of SP and is therefore probably related to altered endothelial responsiveness.

British Journal of Pharmacology (1999) 126, 933–938; doi:10.1038/sj.bjp.0702377
Characterization of high affinity neurotensin receptor NTR1 in HL‐60 cells and its down regulation during granulocytic differentiation
Authors: Choi Se‐Young , Chae Hee‐Don , Park Tae‐Ju , Ha Hyunjung , Kim Kyong‐Tai 
Published: January 2005

We investigated responses to neurotensin in human promyelocytic leukaemia HL‐60 cells.
Neurotensin increased the cytosolic calcium concentration ([Ca2+]i) in a concentration‐dependent manner and also produced inositol 1,4,5‐trisphosphate (InsP3).
Among the tested neurotensin analogues, neurotensin 8–13, neuromedin‐N, and xenopsin also increased [Ca2+]i, whereas neurotensin 1–11 and neurotensin 1–8 did not elicit detectable responses.
SR48692, an antagonist of NTR1 neurotensin receptors, blocked the neurotensin‐induced [Ca2+]i increase, whereas levocabastine, which is known as an NTR2 neurotensin receptor antagonist, did not attenuate the neurotensin‐evoked effect.
The expression of NTR1 neurotensin receptors was confirmed by Northern blot analysis and reverse transcriptase‐polymerase chain reaction (RT–PCR).
During 1.25% dimethylsulfoxide (DMSO)‐triggered granulocytic differentiation of HL‐60 cells, the neurotensin‐induced [Ca2+]i rise became gradually smaller and completely disappeared 4 days after treatment with DMSO. The mRNA level for neurotensin receptors was also decreased after differentiation.
The results show that HL‐60 cells express NTR1 neurotensin receptors and suggest that granulocytic differentiation involves transcriptional regulation of the receptors resulting in down‐regulation of the neurotensin‐induced signalling.

British Journal of Pharmacology (1999) 126, 1050–1056; doi:10.1038/sj.bjp.0702378
Effects of the adenylyl cyclase inhibitor SQ22536 on iloprost‐induced vasorelaxation and cyclic AMP elevation in isolated guinea‐pig aorta
Authors: Turcato Sally , Clapp Lucie H 
Published: January 2005

The stable prostacyclin analogue, iloprost relaxes a variety of blood vessels and increases cyclic AMP, although the relationship between adenosine 3′ : 5′‐cyclic monophosphate (cyclic AMP) and vasorelaxation remains unclear. We therefore investigated the effect of the adenylyl cyclase inhibitor, 9‐(tetrahydro‐2‐furanyl)‐9H‐purin‐6‐amine (SQ22536) on iloprost‐mediated relaxation and cyclic AMP elevation in endothelium‐denuded aortic strips. Iloprost (1–1000 nM) caused a concentration‐dependent inhibition of phenylephrine (1–6 μM) contractions, the responses being unaffected by pre‐incubation with SQ22536 (100 μM) for 30 min. In other experiments 60 nM iloprost caused a 64% inhibition of phenylephrine contractions concomitant with a 3 fold rise in cyclic AMP. SQ22536 completely abolished the iloprost‐induced elevation in cyclic AMP while having no significant effect on relaxation. Our results therefore strongly suggest that cyclic AMP‐independent pathways are responsible for the vasorelaxant effects of iloprost in guinea‐pig aorta.British Journal of Pharmacology (1999) 126, 845–847; doi:10.1038/sj.bjp.0702383
Influence of TASP‐V, a novel neuropeptide Y (NPY) Y2 agonist, on nasal and bronchial responses evoked by histamine in anaesthetized pigs and in humans
Authors: Malis Didier‐David , Grouzmann Eric , Morel Denis R , Mutter Manfred , Lacroix Jean‐Silvain 
Published: January 2005

In nine anaesthetized pigs we have studied the influence of intranasal or intrabronchial pretreatment with TASP‐V, a neuropeptide Y (NPY) Y2 agonist formed by the attachment of NPY 21–36 to a template‐assembled synthetic peptide (TASP), on the functional responses to subsequent intranasal or intrabronchial histamine challenge.
In a parallel study, subjective and objective nasal airway resistance (NAR) increase following intranasal histamine challenge was evaluated in 11 healthy volunteers after TASP‐V or placebo pretreatment.
In pigs, increase in sphenopalatine blood flow induced by histamine dihydrochloride nasal spray (0.25 mg kg−1 in 3 ml of saline) was significantly reduced by 65% (P<0.05) following intranasal pretreatment with 10 μg kg−1 of TASP‐V. Bronchoconstriction induced by histamine dihydrochloride nebulization (0.5 mg kg−1 in 3 ml of saline) was significantly attenuated by 25 and 55% following aerosolized pretreatment with TASP‐V analogue at 10 and 20 μg kg−1, respectively.
In healthy volunteers, objective increase in NAR and reduction in nasal minimal cross section area (MCSA) induced by intranasal spray of histamine dihydrochloride (15 μg kg−1 in 200 μl of saline) were significantly attenuated by 50% following local pretreatment with 1.275 μg kg−1 of TASP‐V when compared with saline.
It is concluded that intranasal or intrabronchial pretreatment with TASP‐V reduced nasal obstruction and bronchoconstriction evoked by histamine challenge in the pig. In healthy human volunteers, this agent attenuated NAR increase and MCSA reduction induced by intranasal application of histamine.

British Journal of Pharmacology (1999) 126, 989–996; doi:10.1038/sj.bjp.0702388
Cell‐specific coupling of PGE2 to different transduction pathways in arginine vasopressin‐ and glucagon‐sensitive segments of the rat renal tubule
Authors: Aarab Lotfi , Siaume‐Perez Sylvie , Chabardès Danielle 
Published: January 2005

The aim of the present study was to investigate the transduction pathways elicited by prostaglandin E2 (PGE2) to inhibit hormone‐stimulated adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) accumulation in the outer medullary collecting duct (OMCD) and medullary thick ascending limb (MTAL) microdissected from the rat nephron.
In the OMCD, 0.3 μM PGE2 and low concentrations of Ca2+ ionophores (10 nM ionomycin or 50 nM A23187) inhibited by about 50% a same pool of arginine vasopressin (AVP)‐stimulated cyclic AMP content through a same process insensitive to Bordetella pertussis toxin (PTX).
Sulprostone, an agonist of the EP1/EP3 subtypes of the PGE2 receptor, decreased AVP‐dependent cyclic AMP accumulation in OMCD and MTAL samples. The concentration eliciting half‐maximal inhibition was of about 50 nM in OMCD and 0.1 nM in MTAL.
In MTAL, 1 nM sulprostone and PGE2 inhibited by about 90% a same pool of AVP‐dependent cyclic AMP content through a PTX‐sensitive, Ca2+‐independent pathway.
In the OMCD, PGE2 decreased by about 50% glucagon‐dependent cyclic AMP synthesis by a process sensitive to PTX and Ca2+‐independent. Sulprostone 1 nM induced the same level of inhibition.
These results demonstrate that PGE2 decrease hormone‐dependent cyclic AMP accumulation through a Gαi‐mediated inhibition of adenylyl cyclase activity in MTAL cells and glucagon‐sensitive cells of the OMCD or through a PTX‐insensitive increase of intracellular Ca2+ concentration in AVP‐sensitive cells of the OMCD.

British Journal of Pharmacology (1999) 126, 1041–1049; doi:10.1038/sj.bjp.0702390
Prostanoid receptors involved in the relaxation of human pulmonary vessels
Authors: Walch Laurence , Labat Carlos , Gascard Jean‐Pierre , De Montpreville Vincent , Brink Charles , Norel Xavier 
Published: January 2005

To characterize the prostanoid receptors on human pulmonary smooth muscle involved in vasodilatations, isolated arteries and veins were contracted with norepinephrine (10 μM) and vessels were subsequently challenged with different prostanoid‐receptor agonists in the absence or presence of selective antagonists.
Prostaglandin D2 (PGD2) and the selective DP‐receptor agonist, BW245C, induced relaxations in the contracted human pulmonary venous preparations. The pD2 values were: 6.88±0.11 (n=17) and 7.31±0.12 (n=5), respectively. The relaxant responses induced by PGD2 were reduced by the selective DP‐receptor antagonist, BWA868C, and the estimated pA2 value was 7.84±0.16 (n=4). PGD2 and BW245C did not relax contracted human pulmonary arteries.
The selective IP‐receptor agonists, iloprost and cicaprost, both induced relaxations in the contracted human vascular preparations. The pD2 values for iloprost were: 7.84±0.08 (n=6) and 8.25±0.06 (n=4) and for cicaprost: 8.06±0.12 (n=5) and 8.11±0.09 (n=5) in arteries and veins respectively.
Prostaglandin E2 (PGE2) and the EP2/EP3‐receptor agonist, misoprostol, partially relaxed the contracted venous preparations and the pD2 values were: 8.10±0.15 (n=15) and 6.24±0.33 (n=3), respectively. These relaxations suggest the presence of an EP receptor in the human pulmonary veins. The contracted human pulmonary arteries did not relax when challenged with PGE2.
In human pulmonary venous preparations, the PGE2‐induced relaxations were neither modified by treatment with TP/EP4‐receptor antagonist, AH23848B (10 and 30 μM, n=6), nor by the DP/EP1/EP2‐receptor antagonist, AH6809 (3 μM, n=6).
These data suggest that the relaxation induced by prostanoids involved DP‐, IP‐receptors and to a lesser extent an EP‐receptor on human pulmonary venous smooth muscle. In contrast, only the IP‐receptor is involved in the prostanoid induced relaxations on human pulmonary arterial smooth muscle.

British Journal of Pharmacology (1999) 126, 859–866; doi:10.1038/sj.bjp.0702393
Characterization of airway and vascular responses in murine lungs
Authors: Held Heinz‐Dieter , Martin Christian , Uhlig Stefan 
Published: January 2005

We characterized the responses of murine airways and pulmonary vessels to a variety of endogenous mediators in the isolated perfused and ventilated mouse lung (IPL) and compared them with those in precision‐cut lung slices.
Airways: The EC50 (μM) for contractions of airways in IPL/slices was methacholine (Mch), 6.1/1.5>serotonin, 0.7/2.0>U46619 (TP‐receptor agonist), 0.1/0.06>endothelin‐1, 0.1/0.05. In the IPL, maximum increase in airway resistance (RL) was 0.6, 0.4, 0.8 and 11 cmH2O s ml−1, respectively. Adenosine (1 mM), bombesin (100 μM), histamine (10 mM), LTC4 (1 μM), PAF (0.25 μM) and substance P (100 μM) had only weak effects (<5% of Mch) on RL.
Vessels: The EC50 (μM) for vasoconstriction in the IPL was LTC4, 0.06>U46619, 0.05<endothelin‐1, 0.02. The maximum increase in pulmonary artery pressure (PAP) was 11, 41 and 48 cmH2O, respectively. At 250 nM, the activity of PAF was comparable to that of LTC4. At 100 μM only, substance P caused a largely variable increase in PAP. Serotonin, adenosine, bombesin, histamine and Mch had no or only very small effects on PAP.
Hyperresponsiveness: In both the IPL and slices, U46619 in subthreshold concentrations (10 nM) reduced the EC50 to 0.6 μM. In the IPL, U46619 raised the maximum airway response to Mch 5 fold and the maximum PAF‐induced vasoconstriction 4 fold.
Conclusion: Murine precision‐cut lung slices maintain important characteristics of the whole organ. The maximum reagibility of murine airways to endogenous mediators is serotonin<Mch <U46619<ET‐1. The reagibility of the murine pulmonary vasculature is serotonin<LTC4∼PAF <U46619<ET‐1. The airway and vessel hyperreactivity induced by U46619 raises the possibility that thromboxane contributes directly to airway hyperresponsiveness in various experimental and clinical settings.

British Journal of Pharmacology (1999) 126, 1191–1199; doi:10.1038/sj.bjp.0702394
Evidence for novel caffeine and Ca2+ binding sites on the lobster skeletal ryanodine receptor
Authors: Zhang Jin Jun , Williams Alan J , Sitsapesan Rebecca 
Published: January 2005

The effects of Ca2+, ATP and caffeine on the gating of lobster skeletal muscle ryanodine receptors (RyR) was investigated after reconstitution of the channels into planar phospholipid bilayers and by using [3H]‐ryanodine binding studies.
The single channel studies reveal that the EC50 (60 μM) for activation of the lobster skeletal RyR by Ca2+ as the sole ligand is higher than for any other isoform of RyR studied.
Inactivation of the channel by Ca2+ (EC50=1 mM) occurs at concentrations slightly higher than those required to inactivate mammalian skeletal RyR (RyR1) but lower than those required to inactivate mammalian cardiac RyR (RyR2).
Lifetime analysis demonstrates that cytosolic Ca2+, as the sole activating ligand, cannot fully open the lobster skeletal RyR (maximum Po approximately 0.2). The mechanism for the increase in open probability (Po) is an increase in both the frequency and the duration of the open events.
ATP is a very effective activator of the lobster RyR and can almost fully open the channel in the presence of activating cytosolic [Ca2+]. In the presence of 700 μM Ca2+, 1 mM ATP increased Po to approximately 0.8.
Caffeine, often used as a tool to identify the presence of RyR channels, is relatively ineffective and cannot increase Po above the level that can be attained with Ca2+ alone.
The results reveal that caffeine increases Po by a different mechanism to that of cytosolic Ca2+ demonstrating that the mechanism for channel activation by caffeine is not ‘sensitization’ to cytosolic Ca2+.
By studying the mechanisms involved in the activation of the lobster RyR we have demonstrated that the channel responds in a unique manner to Ca2+ and to caffeine. The results strongly indicate that these ligand binding sites on the channel are different to those on mammalian isoforms of RyR.

British Journal of Pharmacology (1999) 126, 1066–1074; doi:10.1038/sj.bjp.0702400
Activation of adenylate cyclase by human recombinant sst5 receptors expressed in CHO‐K1 cells and involvement of Gαs proteins
Authors: Carruthers Alan M , Warner Andrea J , Michel Anton D , Feniuk Wasyl , Humphrey Patrick P A 
Published: January 2005

The coupling of the human somatostatin sst5 receptor recombinantly expressed in Chinese hamster ovary (CHO‐K1) cells to adenylate cyclase was investigated using receptor selective ligands.
Forskolin (10 μM)‐stimulated adenosine 3′ : 5′‐cyclic monophosphate (cyclic AMP) accumulation was inhibited by somatostatin‐14 and a number of receptor‐selective agonists with a rank order of agonist potency typical of the sst5 receptor. L‐362,855 and BIM‐23056 behaved as full agonists. At higher somatostatin‐14 concentrations there was sub‐maximal inhibition resulting in a bell‐shaped concentration‐effect relationship. Pertussis toxin (PTx; 100 ng ml−1, 18 h) pre‐treatment abolished agonist‐mediated inhibition of cyclic AMP accumulation and markedly enhanced stimulation of cyclic AMP at higher agonist concentrations.
The concentration of prostaglandin E2 (PGE2) in the incubation media was raised 14 fold by 1 μM somatostatin‐14 but was insufficient to stimulate adenylate cyclase activity via endogenous prostanoid receptors.
Pre‐treatment with cholera toxin (ChTx; 20 μg ml−1, 18 h) markedly inhibited sst5 receptor‐mediated increases in cyclic AMP formation in intact cells. Somatostatin‐14‐stimulated cyclic AMP accumulation was also observed in sst5 receptor containing CHO‐K1 membranes and was inhibited by the synthetic peptide Gαsacetyl‐354‐372‐amide (100 μM) by 65.9±3.5%, implicating a Gαs protein involvement in this response.
Activation of Gαs proteins by somatostatin‐14 could be demonstrated with [35S]‐guanosine 5′‐[γ‐thio]triphosphate ([35S]‐GTPγS) binding and subsequent immunoprecipitation of 35S labelled Gαs proteins with anti‐Gαs serum.
These data show that the sst5 receptor is very efficiently coupled in a negative manner to adenylate cyclase. However, at higher agonist concentrations the receptor can also mediate activation of adenylate cyclase by a mechanism apparently involving Gαs protein activation.

British Journal of Pharmacology (1999) 126, 1221–1229; doi:10.1038/sj.bjp.0702401