bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuation of the antiarrhythmic effects of ischaemic preconditioning by blockade of bradykinin B2 receptors
Authors: Vegh Agnes , Papp Julius Gy , Parratt James 
Published: July 2012

The possibility that bradykinin is involved in the pronounced antiarrhythmic effects of ischaemic preconditioning in anaesthetized mongrel dogs was examined with the use of the selective B2 antagonist, icatibant (Hoe‐140).
Preconditioning, achieved by two 5 min occlusions of the left anterior descending coronary artery, followed 20 min later by a 25 min occlusion of the same artery resulted, during this prolonged occlusion, in less severe arrhythmias (VF 0% versus 47% in control non‐preconditioned dogs), reductions in the incidence and number of episodes of ventricular tachycardia (VT) and in the number of ventricular premature beats and increased survival following reperfusion (50% versus 0% in the controls).
Hoe‐140 was given in a dose of 300μg kg−1 either before the preconditioning procedure or after preconditioning but before the prolonged occlusion. This dose of Hoe‐140 had insignificant haemodynamic effects and failed to modify the increase in coronary blood flow that occurred in the circumflex coronary artery when the anterior descending branch was occluded.
It was difficult to precondition dogs in the presence of Hoe–140. There were more ventricular arrhythmias during the initial 5 min occlusion (44 ± 12 versus 10 ± 3) and a higher incidence of ventricular fibrillation (50% versus 21%) during the preconditioning procedure. There was also a more pronounced ST‐elevation (recorded from epicardial electrodes) during the preconditioning occlusions in those dogs given Hoe‐140.
In those dogs that survived to the long (25 min) occlusion, Hoe‐140 prevented the antiarrhythmic effects of preconditioning (reduction in ventricular premature beats and in VT) although all the dogs survived the occlusion period. However on reperfusion, survival in the preconditioned dogs given Hoe‐140 was less than in those dogs preconditioned without the B2 antagonist.
Changes in the degree of inhomogeneity of conduction within the ischaemic area, which were markedly suppressed by preconditioning, were attenuated in those dogs preconditioned in the presence of Hoe–140.
These results suggest that bradykinin acts as both a ‘trigger’ for preconditioning and as one of the mediator protective (antiarrhythmic) substances generated by the myocardium under these conditions. Since the protection afforded both by preconditioning and by local intracoronary infusions of bradykinin is markedly attenuated by an inhibitor of the 1‐arginine nitric oxide pathway, we suggest that much of the protection afforded by ischaemic preconditioning results from the generation of nitric oxide, and that bradykinin, released early during ischaemia, acts as a stimulant for this generation.
The relative importance of nitric oxide and nitric oxide‐independent mechanisms in acetylcholine‐evoked dilatation of the rat mesenteric bed
Authors: Parsons Sarah J.W. , Hill Anthony , Waldron Gareth J. , Plane Trances , Garland Christopher J. 
Published: July 2012

The relative contribution of nitric oxide (NO) to acetylcholine‐induced smooth muscle relaxation was investigated in the rat perfused mesenteric vasculature and in isolated segments of second, third and fourth order arterial branches.
The EC50 values and maximal relaxation to acetylcholine were not significantly different in the sequential arterial branches, being approximately 0.05 μm and 85%, respectively.
The NO synthase inhibitor L‐NG‐nitro‐L‐arginine methyl ester (L‐NAME; 100 μm) reduced acetylcholine‐evoked endothelium‐dependent dilatation and relaxation in the perfused mesenteric bed and in isolated arterial segments. The maximum response to acetylcholine in both preparations was reduced by between 35% to 40% while the EC50 values were increased by 5–6 fold. L‐NAME had no effect on basal smooth muscle tone in either case.
In contrast, endothelium‐dependent dilatation of the perfused mesenteric bed evoked by A23187 (0.002–20 nmol), was unaffected by exposure to L‐NAME. The EC50 values and maximal responses elicited by A23187 (20 nmol) before and after exposure to L‐NAME were 0.96 ± 0.5 nmol and 67.0 ± 7.0% (n = 4), and 0.7 ± 0.4 nmol and 70.0 ± 5.0% (n = 4; P > 0.01), respectively.
Perfusion of the isolated mesenteric bed with raised K+‐Krebs buffer (25 μm) had no effect on basal tone, but reduced the amplitude of both acetylcholine‐ and A23187‐evoked dilatation. The maximum responses to acetylcholine (2 μmol) and A23187 (20 nmol) were reduced from 67.5 ± 7.3% and 65.4 ± 8.2% to 18.9 ± 11.0% (n = 5; P < 0.01) and 13.5 ± 12.0% (n = 4; P < 0.01), respectively.
Exposure of the mesenteric bed to L‐NAME in the presence of raised K+‐Krebs further reduced the maximal response elicited by acetylcholine to only 8.9 ± 2.8% (n = 4; P < 0.01).
These results indicate that acetylcholine‐evoked vasodilatation of the rat mesenteric vasculature is mediated by both NO‐dependent and ‐independent mechanisms. The relative contribution made by these mechanisms does not appear to differ in sequential branches of the mesenteric artery. In contrast, A23187‐evoked vasodilatation appears to be mediated predominantly by a NO‐independent mechanism which is sensitive to increases in the extracellular potassium concentration and may reflect the action of endothelium‐derived hyperpolarizing factor (EDHF).
[125I]‐PD151242: a selective ligand for endothelin ETA receptors in human kidney which localizes to renal vasculature
Authors: Davenport Anthony P. , Kuc Rhoda E. , Hoskins Sarah L. , Karet Fiona E. , Fitzgerald Fiona 
Published: July 2012

The linear tetrapeptide radioligand, [125I]‐PD151242 was used to characterize ETA receptors in human kidney which is an ETB‐rich tissue. Saturation binding assays with [125I]‐PD151242 revealed a single population of high affinity endothelin receptors: KD = 0.75 ± 0.07 nm and Bmax = 48.4 ± 1.6 fmol mg−1 protein (n = 3 individuals ± s.e.mean). Hill slopes were close to unity and a one site fit was preferred to a two site model.
ETA‐receptor‐selective ligands competed for [125I]‐PD151242 binding with sub‐nanomolar affinity: BQ123 KD = 0.43 ± 0.10 nm, Bmax = 46.6 ± 7.9 fmol mg−1 protein; FR139317, KD = 0.37 ± 0.06nM, Bmax = 39.5 ± 6.5 fmol mg−1 protein (n = 3 individuals ± s.e.mean). In each case, monophasic inhibition curves were obtained and a one site fit was preferred to a two site model. The ETB‐selective agonist, BQ3020 at the highest concentration tested (10 μm) inhibited binding by only 50%. The non‐selective RO462005 competed for the binding of [125I]‐PD151242: KD = 1.31 ± 1.38 μm, Bmax = 33.0 ± 9.7 fmol mg−1 protein. Endothelin‐2 and sarafotoxin S6B inhibited [125I]‐PD151242 binding to renal tissue whereas ET‐3 and sarafotoxin S6C were less effective. Non‐endothelin and non‐sarafotoxin peptides did not compete.
No degradation of [125I]‐PD151242 was detected following incubation of the ligand with renal tissue under the conditions of the binding assay.
Polymerase chain reaction products corresponding to the expected size for mRNA encoding ETA and ETB receptor sub‐types were detected in cortex and medulla in each of the five individuals examined.
Autoradiographical studies showed that ETA receptors visualised with [125I]‐PD151242 were mainly localized to blood vessels including interlobular and arcuate arteries, arterioles and adjacent arcuate veins. ETB receptors localized with [125I]‐BQ3020 were concentrated in the medulla and the density of binding to vessels was low.
These data suggest [125I]‐PD151242 is selective for ETA receptors in human kidney and this sub‐type is mainly localized to the renal vasculature. The results provide further evidence that the human vasculature mainly expresses the ETA receptor.
Differences in the distribution and characteristics of tachykinin NK1 binding sites between human and guinea pig lung
Authors: Walsh David A. , Salmon Michael , Featherstone Roland , Wharton John , Church Martin K. , Polak Julia M. 
Published: July 2012

The distribution and characteristics of tachykinin NK1 binding sites have been compared in human and guinea pig lung using quantitative in vitro receptor autoradiography with [125I]‐Bolton Hunter‐labelled substance P ([125I]‐BH‐SP). In addition, the effects on these sites of ovalbumin sensitization and challenge have been determined in guinea pig lung.
[125I]‐BH‐SP bound specifically and with high affinity to microvascular endothelium in both human and guinea pig lung, but to bronchial smooth muscle and pulmonary artery media in only guinea pig lung.
Specific binding of [125I]‐BH‐SP to guinea pig bronchial smooth muscle was positively correlated with airway diameter in the range 150–800 μm and was less dense in trachea than in main bronchi.
[125I]‐BH‐SP binding was inhibited by tachykinins with rank orders of affinity of SP > NKA > NKB (human microvessels) and SP > NKA = NKB (guinea pig bronchi and pulmonary arteries). NKA displayed a higher affinity for [125]‐BH‐SP binding sites in human microvessels than in guinea pig tissues (P < 0.0001), indicating differences in selectivity for tachykinins between human and guinea pig NK1 receptors.
In both human and guinea pig lung, [125I]‐BH‐SP binding was inhibited by the specific tachykinin receptor antagonists FK888 (NK1 selective antagonist) and FK224 (mixed NK1/NK2 antagonist), with FK888 displaying equal affinity to SP and > 500 times higher affinity than FK224. SP, NKA, NKB and FK888 exhibited similar affinities for [125I]‐BH‐SP binding sites in both guinea pig arteries and bronchi.
Similar distributions, densities and characteristics of [125I]‐BH‐SP binding sites were demonstrated in ovalbumin‐sensitized and ‐challenged guinea‐pig lung and in naive animals.
Differences in the distribution and characteristics of NK1 binding sites labelled with [125I]‐BH‐SP between guinea pig and human lung suggest limitations in the use of guinea pig models for studying roles of tachykinins in pulmonary disease. However, the similar microvascular distributions of NKj binding sites in human and guinea pig lung suggest that the selective tachykinin receptor antagonists FK888 and FK224 may be useful in the management of airway inflammation in man.
Dexamethasone‐induced selective inhibition of the central μ opioid receptor: functional in vivo and in vitro evidence in rodents
Authors: Pieretti S. , Di Giannuario A. , Domenici M.R. , Sagratella S. , Capasso A. , Sorrentino L. , Loizzo A. 
Published: July 2012

Endogenous corticosteroids and opioids are involved in many functions of the organism, including analgesia, cerebral excitability, stress and others. Therefore, we considered it important to gain information on the functional interaction between corticosteroids and specific opioid receptor subpopulations.
We have found that systemic administration (i.p.) of the potent synthetic corticosteroid, dexamethasone, reduced the antinociception induced by the highly selective μ agonist, DAMGO or by less selective μ agonists morphine and β‐endorphin administered i.e.v., On the contrary dexamethasone exerted little or no influence on the antinociception induced by a δ1 agonist, DPDPE and a δ2 agonist deltorphin II. Dexamethasone potentiated the antinociception induced by the k agonist, U50,488.
In experiments performed in an in vitro model of cerebral excitability in the rat hippocampal slice, dexamethasone strongly prevented both the increase of the duration of the field potential recorded in CA1, and the appearance and number of additional population spikes induced by μ receptor agonists.
In both models pretreatment with cycloheximide, a protein synthesis inhibitor, prevented the antagonism by dexamethasone of responses to the μ opioid agonists.
Our data indicate that in the rodent brain there is an important functional interaction between the corticosteroid and the opioid systems at least at the μ receptor level, while δ and k receptors are modulated in different ways.
Antimuscarinic action of liriodenine, isolated from Fissistigma glaucescens, in canine tracheal smooth muscle
Authors: Lin Chien‐Huang , Yang Chuen‐Mao , Ko Feng‐Nien , Wu Yang‐Chang , Teng Che‐Ming 
Published: July 2012

The antimuscarinic properties of liriodenine, isolated from Fissistigma glaucescens, were compared with methoctramine (cardioselective M2 antagonist) and 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP, smooth muscle selective M3 antagonist) by radioligand binding tests, functional tests and measurements of second messenger generation in canine cultured tracheal smooth muscle cells.
Liriodenine, pirenzepine, methoctramine and 4‐DAMP displaced [3H]‐N‐methyl scopolamine ([3H]‐NMS) binding in a concentration‐dependent manner with Ki values of 2.2 ± 0.4 × 10−6, 3.3 ± 0.7 × 10−7, 8.9 ± 2.3 × 10−8 and 2.3 ± 0.6 × 10−9 m, respectively. The curves for competitive inhibition of [3H]‐NMS with liriodenine, methoctramine and 4‐DAMP were best fitted according to a two site model of binding, but pirenzepine was best fitted according to a model with one site.
Liriodenine and 4‐DAMP displayed a high affinity for blocking tracheal contraction (pKB = 5.9 and 9.1, respectively) and inositol phosphate formation (pKh = 6.0 and 8.9, respectively), but a low affinity for antagonism of cyclic AMP inhibition (pKB = 4.7 and 7.8, respectively).
Methoctramine blocked cyclic AMP inhibition with a high affinity (pKB = 7.4), but it antagonized tracheal contraction and inositol phosphate formation with a low affinity (pKh = 6.1 and 6.0, respectively).
In conclusion, both M2 and M3 muscarinic receptor subtypes coexist in canine tracheal smooth muscle and are coupled to the inhibition of cyclic AMP formation and phosphoinositide breakdown, respectively. The antimuscarinic characteristics of liriodenine are similar to those of 4‐DAMP. It may act as a selective M3 receptor antagonist in canine tracheal smooth muscle.
Involvement of tyrosine kinase in the induction of cyclo‐oxygenase and nitric oxide synthase by endotoxin in cultured cells
Authors: Akarasereenont P. , Mitchell J.A. , Appleton I. , Thiemermann C. , Vane J.R. 
Published: July 2012

Cyclo‐oxygenase (COX) and nitric oxide synthase (NOS) are two enzymes which have distinct cytokine‐inducible isoforms (COX‐2 and iNOS). Many cytokine receptors have an intracellular tyrosine kinase domain. Here we have used the tyrosine kinase inhibitors, erbstatin and genistein, to investigate the potential role of tyrosine kinase activation in the induction on COX‐2 and iNOS caused by endotoxin (lipopolysaccharide; LPS) in bovine aortic endothelial cells (BAEC) and J774.2 macrophages.
The main COX metabolites, 6‐oxo‐prostaglandin F1α (6‐oxo‐PGF1α) (for BAEC) and PGF2α (for 774.2 macrophages) were measured by radioimmunossay: (i) accumulation of COX metabolites from endogenous arachidonic acid was measured at 24 h after addition of LPS (1 μg ml−1); (ii) in experiments designed to measure ‘COX activity’, COX metabolites generated by BAEC or J774.2 macrophages activated with LPS were assayed (at 12 h after LPS administration) after incubation of the washed cells with exogenous arachidonic acid (30 μg for 15min). Western blot analysis with a specific antibody to COX‐2 was used to determine the expression of COX‐2 protein caused by LPS in cell extracts. Accumulation of nitrite (measured by the Griess reaction) was used as an indicator of NO formation and, hence, iNOS activity.
Erbstatin (0.05 to 5 μg ml−1) or genistein (0.5 to 50 μg ml−1) caused a dose‐dependent inhibition of the accumulation of COX metabolites in the supernatant of BAEC or J774.2 macrophages activated with LPS. Erbstatin or genistein also caused a dose‐dependent inhibition of ‘COX activity’ in both cell types. Western blot analysis showed that erbstatin (5 μg ml−1) or genistein (50μg ml−1) inhibited the expression of COX‐2 protein in BAEC and J774.2 macrophages activated with LPS (1 μg ml−1 for 24 h).
Erbstatin or genistein also caused a dose‐dependent inhibition of nitrite accumulation in J774.2 macrophages activated with LPS (1 μg ml−1 for 24 h). In contrast to J774.2 macrophages, BAEC stimulated with LPS (1 μg ml−1 for 24 h) did not produce detectable amounts (> 1μm) of nitrite.
These results suggest that tyrosine phosphorylation is part of the signal transduction mechanism that mediates (i) the induction of COX‐2 and iNOS elicited by LPS in J774.2 macrophages, and (ii) the induction of COX‐2 by LPS in BAEC.
Two populations of muscarinic binding sites in the chick heart distinguished by affinities for ligands and selective inactivation
Authors: Jakubik Jan , Tuĉek Stanislav 
Published: July 2012

By measuring the binding of N‐[3H‐methyl]‐scopolamine ([3H]‐NMS) and of unlabelled subtype‐specific muscarinic antagonists, two populations of muscarinic binding sites can be distinguished in the membranes of cardiac ventricles taken from 1‐day‐old chicks. One of them, corresponding to approximately 80% of [3H]‐NMS binding sites, has higher affinities for AF‐DX116 (pKi = 6.42) and methoct‐ramine (pKi = 7.33); the rate of [3H]NMS dissociation from these sites is fast. The other population, corresponding to approximately 20% of [3H]‐NMS binding sites, has lower affinities for AF‐DX116 (pKi = 5.00) and methoctramine (pKi = 6.19); the rate of [3H]‐NMS dissociation from these sites is slow. Both populations have high affinities for pirenzepine, but the affinity of the former (major) population is lower (pKi = 7.99) than that of the latter (minor) population (pKi = 10.14).
Since it has been shown earlier that two mRNAs for muscarinic receptors are expressed in the chick heart, one of them close to the genetically defined m2 and the other to the m4 subtype, we propose that the major population of binding sites with high affinities for AF‐DX116 and methoctramine and the lower affinity for pirenzepine represents the M2‐like receptors, while the minor population represents the M4‐like receptors.
It proved possible to obtain isolated samples of either population by selectively protecting the M2‐like sites with AF‐DX116 and the M4‐like sites with pirenzepine, and by inactivating the unprotected sites with benzilylcholine mustard. The properties of the isolated populations corresponded to those derived from the analysis of [3H]‐NMS binding to the original mixed population.
Alcuronium exerted positive allosteric action on the binding of [3H]‐NMS both to the M2‐like and the M4‐like population and severely slowed down [3H]‐NMS dissociation from them; its affinity for the M2‐like sites was 3–10 times higher.
Endogenous expression of histamine H1 receptors functionally coupled to phosphoinositide hydrolysis in C6 glioma cells: regulation by cyclic AMP
Authors: Peakman Marie‐Claire , Hill Stephen J. 
Published: July 2012

The effects of histamine receptor agonists and antagonists on phospholipid hydrolysis in rat‐derived C6 glioma cells have been investigated.
Histamine H1 receptor‐stimulation caused a concentration‐dependent increase in the accumulation of total [3H]‐inositol phosphates in cells prelabelled with [3H]‐myo‐inositol. The rank order of agonist potencies was histamine (EC50 = 24 μm) > Nα‐methylhistamine (EC50 = 31 μm) > 2‐thiazolylethylamine (EC50 = 91 μm).
The response to 0.1 mm histamine was antagonized in a concentration‐dependent manner by the H1‐antagonists, mepyramine (apparent Kd = 1 nm) and (+)‐chlorpheniramine (apparent Kd = 4 nm). In addition, (−)−chlorpheniramine was more than two orders of magnitude less potent than its (+)‐stereoisomer.
Elevation of intracellular cyclic AMP accumulation with forskolin (10 μm, EC50 = 0.3 μm), isoprenaline (1 μm, EC50 = 4 nm) or rolipram (0.5 μm), significantly reduced the histamine‐mediated (0.1 μm) inositol phosphate response by 37%, 43% and 26% respectively. In contrast, 1,9‐dideoxyforskolin did not increase cyclic AMP accumulation and had no effect on the phosphoinositide response to histamine.
These data indicate the presence of functionally coupled, endogenous histamine H1 receptors in C6 glioma cells. Furthermore, the results also indicate that H1 receptor‐mediated phospholipid hydrolysis is inhibited by the elevation of cyclic AMP levels in these cells.
Role of endothelin‐1 and the ETA receptor in the maintenance of deoxycorticosterone acetate‐salt‐induced hypertension
Authors: Fujita Katsuya , Matsumura Yasuo , Kita Satomi , Miyazaki Yohko , Hisaki Kazuhiro , Takaoka Masanori , Morimoto Shiro 
Published: July 2012

To search for a possible role for endothelin‐1 (ET‐1) in deoxycorticosterone acetate (DOCA)‐salt‐induced hypertension, we examined changes in concentration of ET‐1 in vascular and renal tissue in DOCA‐salt hypertensive rats and evaluated the antihypertensive effect of the ETA receptor antagonist, FR139317.
There was an increase in aortic immunoreactive‐ET (IR‐ET) concentrations in association with hypertension‐induced treatment. There were no significant changes in ET‐1 levels in the kidney with DOCA‐salt treatment.
In DOCA‐salt hypertensive rats, a significant correlation (r = 0.83, P <0.01) was found between aortic IR‐ET concentrations and systolic blood pressure.
High‐performance liquid chromatography analysis of the aortic extract from DOCA‐salt rats revealed one major component corresponding to the elution position of synthetic ET‐1.
The intravenous bolus injection of FR139317 (10 mg kg−1) produced a slight decrease in blood pressure in the control rats and in the DOCA‐salt hypertensive rat, FR139317 had a more pronounced hypotensive effect.
We propose that ET‐1 production in vascular tissues is increased in DOCA‐salt hypertensive rats. In addition, our study indicates the pathophysiological importance of increased endogenous ET‐1 in the maintenance of DOCA‐salt‐induced hypertension, through interaction of the peptide with ETA receptors.
Blockade of motion‐ and cisplatin‐induced emesis by a 5‐HT2 receptor agonist in Suncus murinus
Authors: Okada Fumihiko , Saito Hiroshi , Matsuki Norio 
Published: July 2012

The effects of (±)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane (DOl), a 5‐hydroxytryptamine 5‐HT2A/5‐HT2C receptor agonist, on motion‐ and cisplatin‐induced emesis were studied in Suncus murinus. Subcutaneous injection of DOl, 30 min prior to the emetic stimuli, dose‐dependently blocked the emesis induced by motion sickness and cisplatin (20 mg kg−1, i.p.) with estimated ID50 values of 640 and 780 μg kg−1, respectively.
α‐Methyl‐5‐hydroxytryptamine (α‐Me‐5‐HT), a peripheral 5‐HT2A/5‐HT2C receptor agonist, had no effect on motion‐ and cisplatin‐induced emesis.
The antiemetic effects of DOl on motion‐ and cisplatin‐induced emesis were attenuated by pre‐administration of ketanserin, a selective 5‐HT2A receptor antagonist.
The present results suggest an inhibitory role for central 5‐HT2 receptors in the emetic reflex mechanism and that a 5‐HT2 receptor agonist may be a useful tool to investigate the involvement of 5‐HT receptors in the emetic reflex.