bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible role of nitric oxide in the development of L‐2‐chloropropionic acid‐induced cerebellar granule cell necrosis
Authors: Widdowson P.S. , Gyte A. , Simpson M.G. , Farnworth M. , Dunn D. , Moore R.B. , Wyatt I. , Lock E.A. 
Published: July 2012

L‐2‐Chloropropionic acid (L‐CPA) produces selective neuronal cell necrosis in rat cerebellum when administered orally at 750 mg kg−1 that is mediated in part through activation of N‐methyl‐D‐aspartate (NMDA) receptors. Cerebellar granule cell death occurs between 30 and 36 h following L‐CPA administration exhibiting a number of features in common with excitatory amino acid‐induced cell death. We have used this in vivo model to examine the neurochemical processes following L‐CPA‐induced activation of NMDA receptors leading to neuronal cell death in the rat cerebellum.
The effects of a number of compounds which potently block nitric oxide synthase in vitro were examined on L‐CPA‐induced neurotoxicity 48 h following L‐CPA dosing, to discover whether the neuronal cell death is mediated in part by excessive nitric oxide generation. Four inhibitors were studied, NG‐nitro‐L‐arginine (L‐NOARG), NG‐nitro‐L‐arginine methyl ester (L‐NAME), NG‐iminoethyl‐L‐ornithine (L‐NIO) and 3‐bromo‐7‐nitroindazole (BrNI).
L‐NAME (50 mg kg−1, i.p. twice daily) and BrIN (50 mg kg−1, i.p. twice daily) administration prevented the L‐CPA‐induced loss of granule cells which can reach up to 80–90% of the total cell number in rats treated with L‐CPA alone. L‐NOARG (50 mg kg−1, i.p. twice daily) and L‐NIO administered at either 25 or 100 mg kg−1, twice daily did not produce any significant protection against L‐CPA‐induced neurotoxicity.
Both L‐NAME and BrIN also prevented the L‐CPA‐induced increase in cerebellar water content and sodium concentrations. L‐NIO when administered at the highest doses prevented the increase in cerebellar sodium concentration but not water content. L‐NIO and L‐NOARG were ineffective in preventing the L‐CPA‐induced increases in cerebellar water and sodium concentrations.
L‐CPA‐induced reductions in cerebellar aspartate and glutamate concentrations and increases in glutamine and GABA concentrations were prevented by L‐NAME and BrIN, but not by L‐NIO or L‐NOARG. Also reductions in L‐[3H]‐glutamate binding to glutamate ionotrophic and metabotrophic receptors in the granule cell layer of rat cerebellum was prevented by L‐NAME and BrIN, but not L‐NIO or L‐NOARG.
In conclusion, the neuroprotection offered by L‐NAME and BrIN suggests that L‐CPA‐induced cerebellar granule cell necrosis is possibly mediated by or associated with excessive generation of nitric oxide. The inability of nitric oxide synthase inhibitors, L‐NOARG and L‐NIO to afford protection may result from their limited penetration into the brain (L‐NIO) or rapid dissociation from the enzyme.
Synthesis and characterization of a selective peptide antagonist of neuropeptide Y vascular postsynaptic receptors
Authors: Lew Michael J. , Murphy Roger , Angus James A. 
Published: July 2012

A cyclic dimeric nonapeptide neuropeptide Y (NPY) receptor antagonist, 1229U91, was synthesized by Fmoc chemistry and dimerised in solution. Its effects were assayed in mesenteric arteries from rats and mice, and in rat vas deferens.
Mesenteric arteries were cannulated and pressurised to 55 mmHg and the external diameters continuously measured. NPY, PYY, Leu31Pro34NPY and NPY(13–36) each caused concentration‐related contractions with the order of potency PYY≥Leu31Pro34NPY = NPY>NPY (13–36), consistent with the Y1 receptor subtype.
1229U91 had no agonist activity in the arteries but caused a concentration‐related rightward shift of NPY (mouse arteries) or Leu31Pro34NPY (rat) concentration‐response curves. The antagonism was competitive with pATBs of 7.69±0.15 and 7.47±0.13 in the mouse and rat arteries, respectively.
Sympathetic nerves in the vas deferens were stimulated with a single electrical field pulse every 20 s and the twitch responses recorded. NPY, PYY, Leu31Pro34NPY and NPY(13–36) inhibited the twitches with the order of potency PYY>NPY>NPY(13–36)> > Leu31Pro34NPY, consistent with the Y2 receptor subtype.
1229U91 inhibited the vas deferens twitch with a shallow concentration‐response curve and a time‐course of inhibition distinct from that of NPY. 1229U91 (30 μm) did not cause a rightward shift of the NPY concentration‐response curve. 1229U91 is at least 5 orders of magnitude less potent in the vas deferens than in rat brain Y2 binding assays reported by others, suggesting that the brain and vas deferens Y2 receptors are different.
It is concluded that 1229U91 is a competitive antagonist of NPY Y1 vascular receptors and has additional properties that inhibit the electrically evoked twitch of the rat vas deferens.
Effect of cyclo‐oxygenase inhibitors and modulators of cyclic AMP formation on lipopolysaccharide‐induced neutrophil infiltration in mouse lung
Authors: de Moraes Vera Lucia Gonçalves , Vargaftig B. Boris , Lefort Jean , Meager Anthony , Chignard Michel 
Published: July 2012

The adult respiratory distress syndrome (ARDS) is an acute lung inflammation developed after direct or indirect contact with pathogenic agents. In the present study, a mouse model was developed to mimic this condition using aerosolized bacterial lipopolysaccharide (LPS) and to investigate the mechanisms involved in the lung inflammatory response.
Inhalation of LPS led to a time and dose‐dependent increase in tumour necrosis factor‐α (TNF‐α) production and neutrophil recruitment into the bronchoalveolar lavage fluid (BALF) of Balb/c mice. Under the same conditions, neutrophil infiltration was also found in the BALF of the LPS‐sensitive mouse strain C3H/HeN, but was absent in the LPS‐resistant strain C3H/HeJ. Intranasal administration of murine recombinant TNF‐α also triggered neutrophil recruitment.
One hour after inhalation of LPS, half of the maximal level of TNF‐α was measured in the BALF, but only a few neutrophils were detected at this time. The peak TNF‐α concentration was reached at 3 h, when the neutrophil amount started to increase. At 24 h, maximal neutrophil number was found in the BALF and TNF‐α was no longer present.
Pretreatment of mice under different experimental conditions demonstrated that: (a) cycloheximide almost completely blocks both neutrophil recruitment and TNF‐α production; (b) anti TNF‐α antibodies block neutrophil recruitment; (c) indomethacin or aspirin enhance by two fold neutrophil recruitment; (d) indomethacin significantly increases TNF‐α production 1 h after inhalation of LPS; (e) dibutyryl cyclic AMP and prostaglandin E2 (PGE2) block both neutrophil recruitment and TNF‐α production.
It is concluded that aerosolized LPS in mice triggers an acute lung inflammation which can be used as a potential model of inhalational ARDS and that, strategies leading to the elevation of cyclic AMP levels in vivo can be effective in modulating LPS‐induced TNF‐α synthesis and neutrophil recruitment.
Relative contribution of P2U‐ and P2Y‐purinoceptors to endothelium‐dependent vasodilatation in the golden hamster isolated mesenteric arterial bed
Authors: Ralevic Vera , Burnstock Geoffrey 
Published: July 2012

P2‐purinoceptors were characterized pharmacologically in the constantly perfused isolated mesenteric arterial vascular bed of the golden hamster. Vasoconstrictor and vasodilator responses to the nucleotides ATP, ADP, 2 methylthio ATP (2MeSATP), α,β‐methylene ATP (αβ‐meATP) and uridine 5′‐triphosphate (UTP) and a role for ATP in sympathetic constriction were examined.
At basal tone nucleotides elicited dose‐dependent vasoconstriction with an observed rank order of potency of αβ‐meATP»2MeSATP>ATP=ADP>UTP (based on the doses required to elicit constrictor responses of 25 mmHg). Adenosine had no vasoconstrictor action at doses up to 5 μumol. After application of a single dose (0.5 μmol) of αβ‐meATP preparations were desensitized to constriction by subsequent application of nucleotides.
Electrical field stimulation (4–64 Hz, 90 V, 1 ms, 30 s) elicited frequency‐dependent constrictions which were abolished by guanethidine (5 μm) and by prazosin (1 μm).
The non‐selective P2‐purinoceptor antagonist suramin (100 μm) did not significantly affect vasoconstrictor responses to ATP. The P2X‐selective purinoceptor antagonist pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS, 3 μm), virtually abolished responses to ATP. When the endothelium was removed vasoconstrictor responses to ATP and noradrenaline were augmented.
In preparations with tone raised with methoxamine (10–80 μm) nucleotides elicited vasodilatation with an observed potency order of ATP=UTP>ADP>>adenosine. 2MeSATP had relatively minor vasodilator effects and at the highest dose tested (50 nmol) elicited only vasoconstriction. α,β‐meATP did not elicit vasodilatation but produced further constriction of the raised tone preparation. At the highest doses of ATP and ADP (0.5 μm) responses were biphasic with vasoconstriction preceding vasodilatation. After removal of the endothelium, with the exception of adenosine, vasodilator responses to purines and to UTP were abolished; vasoconstriction to ATP, ADP, UTP and 2MeSATP was evident at the highest doses.
Suramin (100 μm) inhibited vasodilatation to both ATP and UTP and abolished responses to 2MeSATP. PPADS (3 μm) inhibited relaxation to 2MeSATP but did not affect relaxation to ATP, UTP, adenosine and acetylcholine and ADP.
Reactive blue 2 (30 μm) blocked vasodilator responses to ATP, UTP, 2MeSATP and acetylcholine; it was without effect when used at 3 μm.
The results of this study show that ATP elicits vasoconstriction of mesenteric arteries of the golden hamster via P2X‐purinoceptors located on the smooth muscle, and vasodilatation via P2U‐receptors which are located on the endothelium. 2MeSATP has marginal vasodilator activity, suggesting that P2Y‐purinoceptors contribute minimally to relaxation to ATP in hamster mesenteric arteries.
Cerebrovascular responsiveness to NG‐nitro‐L‐arginine methyl ester in spontaneously diabetic rats
Authors: Fouyas Ioannis P. , Kelly Paul A.T. , Ritchie Isobel M. , Whittle Ian R. 
Published: July 2012

There is evidence that endothelial dysfunction is associated with diabetes mellitus. The purpose of the present study was to assess local cerebral blood flow (LCBF) and cerebrovascular responsiveness to the NOS inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME) in spontaneously diabetic insulin‐dependent BioBred (BB) rats.
Diabetic rats, and non‐diabetic controls, were treated with L‐NAME (30 mg kg−1, i.v.) or saline, 20 min prior to the measurement of LCBF by the fully quantitative [14C]‐iodoantipyrine autoradiographic technique.
There were no significant differences in physiological parameters (blood pH, pH, PCO2, and PO2, rectal temperature, arterial blood pressure, or plasma glucose) between any of the groups of rats, and no difference in either the extent or the temporal characteristics of the hypertensive response to L‐NAME between diabetic and non‐diabetic rats.
In diabetic rats, a global reduction in basal LCBF was observed, although significant reductions (between −20 and −30%) were found in only 5 (mainly subcortical) out of the 13 brain regions measured. Following L‐NAME injection, significant reductions in LCBF (between −20 and −40%) were found in the non‐diabetic animals. In diabetic animals treated with L‐NAME, a significant reduction in LCBF was measured only in the hypothalamus (−33%).
The cerebrovascular response to acute L‐NAME is attenuated in spontaneously diabetic insulin‐dependent BB rats. This would be consistent with the endothelial dysfunction in cerebral vessels, known to be associated with diabetes mellitus and it is possible that a loss of NO‐induced dilator tone, amongst other factors, may underlie the observed reductions of basal LCBF in these animals.
The effect of a tachykinin NK1 receptor antagonist, SR140333, on oedema formation induced in rat skin by venom from the Phoneutria nigriventer spider
Authors: Palframan R.T. , Costa S.K.P. , Wilsoncroft P. , Antunes E. , de Nucci G. , Brain S.D. 
Published: July 2012

The possibility that tachykinin NK1 receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated.
Local oedema formation induced by the i.d. injection of test agents was measured by the extravascular accumulation of intravenously (i.v.) injected 125I‐labelled human serum albumin over a 30 min period.
The tachykinin NK1 agonist, GR73632 (30 pmol per site), induced local oedema formation which was potentiated by co‐injection with the neuropeptide vasodilator, calcitonin gene‐related peptide (CGRP, 10 pmol per site). The non‐peptide tachykinin NK1 receptor antagonist, SR140333 (0.03‐1 nmol per site co‐injected, i.d.) significantly inhibited (0.3 nmol per site, P<0.05; 1 nmol per site, P<0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histamine (10 nmol per site) with CGRP.
PNV (0.03‐0.3 μg per site) injected i.d. induced dose‐dependent local oedema formation. SR140333 (1 nmol per site, co‐injected i.d.) inhibited oedema formation; with complete inhibition observed at doses of 0.03 μg (P<0.05) and 0.1 μg (P<0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 μg (P<0.05).
Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B2 receptor antagonist, Hoe 140 (80 nmol kg−1, i.v.), which was used at a dose which significantly inhibited oedema formation by bradykinin (1 nmol per site).
Local oedema formation induced by PNV was significantly inhibited (P<0.01) by co‐injection of the histamine H1 receptor antagonist, mepyramine (2.5 nmol per site), together with the 5‐hydroxytryptamine (5‐HT) antagonist, methysergide (2.8 nmol per site).
In the presence of all three antagonists (mepyramine 2.5 nmol per site; methysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasma extravasation induced by PNV was further significantly inhibited (P<0.001, when compared with PNV injected i.d. alone; P<0.05 when compared with PNV co‐injected with mepyramine and methysergide and P<0.01, when compared with PNV co‐injected with SR140333).
These results suggest that oedema formation evoked by i.d. PNV in rat skin may be partially mediated via a mechanism involving tachykinin NK1 receptors and that this effect is independent of histamine and 5‐HT.
Effects of dexamethasone and cyclosporin A on the accumulation of eosinophils in acute cutaneous inflammation in the guinea‐pig
Authors: Teixeira M.M. , Williams T.J. , Hellewell P.G. 
Published: July 2012

Eosinophils are thought to play an important role in the pathophysiology of allergic diseases and pharmacological suppression of their recruitment is considered to be of therapeutic benefit. In the present study we have assessed and compared the effects of treatment with dexamethasone and cyclosporin A on the accumulation of 111In‐labelled eosinophils and local oedema formation in sites of acute inflammation in guinea‐pig skin.
When injected locally 150 min prior to i.d. administration of antigen in a passive cutaneous anaphylactic (PCA) reaction, dexamethasone (10−9 to 3 × 10−7 mol per site) dose‐dependently inhibited oedema formation by up to 50%. Similarly, oedema formation induced by PAF and lipopolysaccharide (LPS), but not by zymosan‐activated plasma (ZAP), was significantly inhibited by dexamethasone. In contrast, 111In‐eosinophil accumulation measured in response to i.d. injection of PAF, LPS and ZAP or in the PCA reaction was not altered.
Systemic treatment with dexamethasone (4 mg kg−1, i.v., 150 min pretreatment period) inhibited both oedema formation and 111In‐eosinophil accumulation induced by PAF, ZAP, LPS and in the PCA reaction.
The effects of i.d. injection of cyclohexamide (2 × 10−7 mol per site) on 111In‐eosinophil accumulation and oedema formation induced by PAF, ZAP or in a PCA reaction were evaluated in order to assess the dependency of these responses on protein synthesis. Cycloheximide had no effect on the responses measured. In contrast, 111In‐eosinophil accumulation, but oedema formation, induced by LPS was inhibited by 30%.
Acute (10 mg kg−1, i.v., 15 min pretreatment) or prolonged (10 mg kg−1, s.c. daily for 3 days) systemic treatment with cyclosporin A had no effect on 111In‐eosinophil accumulation or oedema formation induced by PAF, ZAP, LPS or in the PCA reaction.
In conclusion, we demonstrate preferential inhibitory effects of dexamethasone on 111In‐eosinophil accumulation according to its site of administration. In addition we show that dexamethasone inhibits protein synthesis‐independent acute inflammation in guinea‐pig skin. Finally, our results do not support the concept that eosinophils are an important cellular site of action for the inhibitory effects of cyclosporin A in a guinea‐pig model of allergic inflammation.
Pharmacokinetic‐haemodynamic relationships of 2‐chloroadenosine at adenosine A1 and A2a receptors in vivo
Authors: Mathôt R.A.A. , Soudijn W. , Breimer D.D. , IJzerman A.P. , Danhof M. 
Published: July 2012

The purpose of the present study was to develop an experimental strategy for the quantification of the cardiovascular effects of non‐selective adenosine receptor ligands at the adenosine and A1 and A2a receptor in vivo. 2‐Chloroadenosine (CADO) was used as a model compound.
Three groups of normotensive conscious rats received an short intravenous infusion of 1.4 mg kg−1 CADO during constant infusions of the A1‐selective antagonist, 8‐cyclopentyltheophylline (CPT; 20 μm min−1 kg−1), the A2a‐selective antagonist, 8‐(3‐chlorostyryl)caffeine (CSC; 32 μm min−1 kg−1) or the vehicle. The heart rate (HR) and mean arterial blood pressure (MAP) were recorded continuously during the experiment and serial arterial blood samples were taken for analysis of drug concentrations. The ratio MAP/HR was also calculated, which may reflect changes in total peripheral resistance on the assumption that no changes in stroke volume occur.
During the infusion of CPT, CADO produced a reduction in both blood pressure and MAP/HR by activation of the A2a receptor. The concentration‐effect relationships were described according to the sigmoidal Emax model, yielding potencies based on free drug concentrations (EC50,u) of 61 and 68 ng ml−1 (202 and 225 nM) for the reduction of blood pressure and MAP/HR, respectively. During the infusion of CSC, an EC50,u value of 41 ng ml−1 (136 nM) was observed for the A1 receptor‐mediated reduction in heart rate. The in vivo potencies correlated with reported receptor affinities (Ki(A1)=300 nM and Ki(A2a)=80 nM). The maximal reductions in MAP/HR and heart rate were comparable to those of full agonists, with the values of −12 ± 1 × 1O−2 mmHg b.p.m.−1 and −205 b.p.m. respectively.
It is concluded that this integrated pharmacokinetic‐pharmacodynamic approach can be used to obtain quantitative information on the potency and intrinsic activity of new non‐selective adenosine receptor agonists at different receptor subtypes in vivo.
Vasoconstrictor responsiveness of the rat mesenteric arterial bed in cirrhosis
Authors: Ralevic Vera , Mathie Robert T. , Moore Kevin P. , Burnstock Geoffrey 
Published: July 2012

The effects of cirrhosis on mesenteric vascular reactivity were assessed in constantly perfused mesenteric arterial beds isolated from cirrhotic rats (carbon tetrachloride with phenobarbitone, n=6), and from phenobarbitone‐treated and untreated age‐matched controls (n=4,5).
At a constant flow rate of 5 ml min−1 there was no difference in basal perfusion pressure between the groups. Electrical field stimulation (EFS; 4–32 Hz, 90V, 1 ms, 30 s) of perivascular nerves caused frequency‐dependent increases in perfusion pressure which were not different between the groups. Dose‐dependent vasoconstrictor responses to exogenous noradrenaline (NA), methoxamine (an α1‐adrenoceptor agonist), adenosine 5′‐triphosphate (ATP) and vasopressin were also similar between the groups.
The nitric oxide (NO) synthesis inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME; 30 μm) augmented constrictor responses to NA, EFS, methoxamine and vasopressin in all groups, and as shown for EFS and NA, this was reversed by L‐arginine (300 μm). However, the maximum constrictor responses of cirrhotic preparations in the presence of L‐NAME were significantly lower than those of both groups of control animals at the highest frequency of EFS (32 Hz) and highest doses of NA (0.15 and 0.5 μmol) and, compared to phenobarbitone‐treated controls, methoxamine (5 μmol). Responses to ATP were significantly augmented by L‐NAME only in the cirrhotic group.
A step‐wise increase in perfusate flow to 10, 15 and 20 ml min−1 produced a broadly similar increase in perfusion pressure within each group. At increased flow rates, cirrhotic preparations were hyporesponsive to NA (15 nmol) compared to the phenobarbitone‐treated animals but not the untreated controls. Glibenclamide (5 μm) or L‐NAME (30 μm) had no significant effect on the relationship between flow and perfusion pressure or on responses to NA at the different flow rates.
We conclude that sympathetic neurotransmission is unchanged in cirrhosis. Endogenous NO is important in modulation of constriction in both normal and cirrhotic states. Changes in NO may occur in cirrhosis, although the role of this in hyporesponsiveness of cirrhotic preparations to NA at higher flow rates and to the greater potentiation of ATP‐mediated constriction in the presence of L‐NAME, together with the impact of factors such as changes in calcium and potassium channels, is not entirely clear.