bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mediators of burn‐induced neuromuscular changes in mice
Authors: Tomera John F. , Martyn Jeevendra 
Published: July 2012

Muscle paresis and aberrant pharmacological responses are two important pathophysiological changes that have been observed at the neuromuscular junction following thermal injury. By use of the mouse model of 20%, 30% and 50% total body surface area (BSA) burn, we examined the significance of intracellular mediators, adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and prostaglandin E2 (PGE2) in perturbing the physiological function of tension development and the pharmacological response to (+)‐tubocurarine (+)‐Tc at day 21 post‐burn.
Cyclic AMP levels increased with the size of burn. The relationship between mean cyclic AMP levels and burn size was significant (R2 = 0.96, r = 0.98). Significant (P < 0.05) reductions in tension development (g) were observed for the 30% and 50% BSA burn group compared to controls (30.3 ± 8.3 and 34.1 ± 5.9 vs 59.1 ± 1.0, respectively). Tension alterations were associated with increased cyclic AMP levels; the relationship between increased cyclic AMP levels and tension decrease was significant (R2 = 0.82, r = 0.91). The dose of (+)‐Tc required to inhibit twitch tension increased in proportion to burn size and was statistically significant in the 50% BSA burn group compared to controls (0.3320 ± 0.09 vs 0.1093 ± 0.11 mg kg−1, P < 0.05). The alterations in the effective dose of (+)‐Tc were significantly correlated to increases in cyclic AMP levels (R2 = 0.70, r = 0.83). Although PGE2 levels were elevated in the 30% and 50% burn groups, no relation was seen to either tension or (+)‐Tc doses.
These studies, therefore, support the hypothesis that cyclic AMP plays a significant role in physiological and pharmacological responses in skeletal muscle following thermal injury.
Effects of changes in extra‐ and intracellular K+ on the endothelial production of prostacyclin
Authors: Boeynaems J.M. , Ramboer I. 
Published: July 2012

Changes in the KCl concentration of the incubation medium, from 0 to 80 mm, had no effect on the basal or ATP‐stimulated release of prostacyclin (PGI2) from bovine aortic endothelial cells.
The monovalent cation ionophores, valinomycin and nigericin (5 μm), enhanced the release of PGI2 from endothelial cells stimulated by ATP or bradykinin.
The action of nigericin, unlike that of valinomycin, was time‐dependent, abolished in a high‐KCl medium and associated with an increased efflux of 86Rb and a time‐dependent depletion of intracellular K+.
Ouabain (1–100 μm) also enhanced the release of PGI2 in response to ATP and induced a significant depletion of intracellular K+ in bovine aortic endothelial cells.
In conclusion, modifications of the endothelial cell membrane potential, resulting from changes in the extracellular K+ concentration, do not modulate the basal or ATP‐stimulated production of PGI2. An acute depletion of intracellular K+ by nigericin or ouabain enhances the production of PGI2 in aortic endothelial cells stimulated by ATP or bradykinin.
Effects of amiloride analogues on the production of prostacyclin by aortic endothelial cells
Authors: Boeynaems J.M. , Demolle D. , Lagneau C. , Cragoe E.J. 
Published: July 2012

The release of prostacyclin (PGI2) from bovine aortic endothelial cells stimulated by adenosine 5′‐triphosphate (ATP) was decreased by amiloride analogues bearing alkyl groups on the 5‐amino nitrogen atom, like 5‐(N‐ethyl‐N‐isopropyl)amiloride (EIPA), which are inhibitors of the Na+/H+ exchanger. Analogues substituted on a terminal guanidino nitrogen atom were not inhibitory.
The release of PGI2 induced by ATP was not significantly depressed in a Na+‐poor medium or in a medium acidified to pH 6.9, two conditions known to inhibit the Na+/H+ exchanger.
Cytoplasmic alkalinization by ammonium chloride did not suppress the inhibitory action of EIPA. By itself, ammonium chloride decreased the response of endothelial cells to ionophore A23187 and ATP, whereas sodium acetate had no effect.
EIPA did not decrease the mobilization of free arachidonic acid induced by ATP. It inhibited the conversion of exogenous arachidonate into PGI2 and prostaglandin E2 (PGE2).
Although the intracellular pH was not measured in this study, it seems unlikely that cytoplasmic alkalinization via the activation of the Na+/H+ exchanger plays a significant role in the stimulatory action of ATP on the release of PGI2 from endothelial cells. The inhibition of that release by EIPA and other amiloride analogues might involve a direct effect on cyclo‐oxygenase, although an action on the reacylation of free arachidonic acid cannot be excluded.
δ‐Opioid mediated inhibitions of acute and prolonged noxious‐evoked responses in rat dorsal horn neurones
Authors: Sullivan A.F. , Dickenson A.H. , Roques B.P. 
Published: July 2012

The effects of a selective δ‐opioid agonist Tyr‐D‐Ser(Otbu)‐Gly‐Phe‐Leu‐Thr (DSTBULET) were examined on the C‐ and Aβ‐evoked responses of convergent dorsal horn neurones in the halothane anaesthetized, intact rat.
Intrathecal DSTBULET produced selective dose‐dependent inhibitions of electrically‐evoked C fibre responses of both superficial and deep neurones. A near‐complete inhibition of 83 ± 5% followed 100 μg of DSTBULET and the ED50 was 9 μg (13.5 nmol). Inhibitions were antagonised by intrathecal naloxone and ICI 174,864 but were not antagonised by pretreatment with intrathecal β‐funaltrexamine at a dose that blocked μ‐opioid effects. By contrast, DSTBULET produced excitations of electrically‐evoked responses of cells recorded in a zone intermediate between the superficial and deep neurones.
DSTBULET (50 μg) was also tested on the more prolonged noxious neuronal response produced by subcutaneous formalin (5%, 50 μl) into the receptive field. DSTBULET profoundly inhibited the response to formalin. Pretreatment with ICI 174, 864 before DSTBULET antagonised the effects of the δ‐agonist on the formalin response.
The full peptidase inhibitor kelatorphan, known to protect endogenous enkephalins, was also tested on the formalin response. The intrathecal administration of 50 μg kelatorphan has previously been shown to inhibit electrically‐evoked C fibre resonses of dorsal horn neurones and to be antagonised by ICI 174,864. The same dose of kelatorphan inhibited the formalin response in the present study.
From this study it appears that the δ‐opioid agonist DSTBULET can produce profound inhibitions of the responses of convergent neurones to nociceptive afferent inputs. Furthermore, activation of δ‐opioid receptors either by DSTBULET, or by protection of endogenous enkephalins with kelatorphan, can inhibit a more prolonged chemically‐evoked nociceptive input onto these dorsal horn neurones.
Antagonism of swim‐stress‐induced antinociception by the δ‐opioid receptor antagonist naltrindole in adult and young rats
Authors: Kitchen Ian , Pinker Sally R. 
Published: July 2012

The availability of the non‐peptide δ‐opioid receptor antagonist naltrindole has provided the possibility for in vivo studies on the function of δ‐opioid receptors. We have studied the effects of naltrindole on swim‐stress‐induced antinociception in adult and neonatal rats.
Adult, 25 and 20 day old rats were stressed by warm water (20°C) swimming for 3 min periods and antinociception was assessed by the tail immersion test (50°C).
Naltrindole (0.5 and 1 mg kg−1) antagonized swim‐stress‐induced antinociception in adult and 25 day old rats but in 20 day old rats naltrindole (1 mg kg−l) was without effect.
Antinociception induced by the highly μ‐opioid receptor selective agonist alfentanil was completely antagonized by naloxone (1 mg kg−l) but virtually unaffected by naltrindole (1 mg kg−1).
Neither naloxone nor naltrindole (1 mg kg−1) antagonized swim‐stress‐induced rises in plasma corticosterone in adult rats at the time of peak antinociception.
In conclusion, naltrindole shows in vivo antagonism of opioid‐mediated responses. Swim‐stress‐induced antinociception is mediated through the δ‐opioid receptor in 25 day old and adult rats and through the μ‐opioid site in 20 day old animals.
Nicergoline inhibits T‐type Ca2+ channels in rat isolated hippocampal CA1 pyramidal neurones
Authors: Takahashi Kazuyoshi , Akaike Norio 
Published: July 2012

The effects of nicergoline on the T‐ and L‐type Ca2+ currents in pyramidal cells freshly isolated from rat hippocampal CA1 region were investigated by use of a ‘concentration‐clamp’ technique. The technique combines a suction‐pipette technique, which allows intracellular perfusion under a single‐electrode voltage‐clamp, and rapid exchange of extracellular solution within 2 ms.
T‐type Ca2+ currents were evoked by step depolarizations from a holding potential of −100 mV to potentials more positive than −70 to −60 mV, and reached a peak at about −30 mV in the current‐voltage relationship. Activation and inactivation of T‐type Ca2+ currents were highly potential‐dependent.
Nicergoline and other Ca2+ antagonists dose‐dependently blocked the T‐type Ca2+ channel with an order of potency nicardipine > nicergoline > diltiazem.
The L‐type Ca2+ channel was also blocked in the order nicardipine > nicergoline > diltiazem, although the T‐type Ca2+ channel was more sensitive to nicergoline.
The inhibitory effects of nicergoline and nicardipine on the T‐type Ca2+ current were voltage‐, time‐, and use‐dependent, and the inhibition increased with a decrease in the external Ca2+ concentration. Diltiazem showed only a use‐dependent block.
The influence of the initial stretch and the agonist‐induced tone on the effect of basal and stimulated release of EDRF
Authors: Dainty I.A. , McGrath J.C. , Spedding M. , Templeton A.G.B. 
Published: July 2012

The effects of initial stretch and degree of agonist‐induced tone on acetylcholine‐induced relaxations were examined in rings of rat isolated aorta. The relaxation to acetylcholine was antagonized by atropine and almost completely abolished by haemoglobin. Relaxation to sodium nitroprusside was similar in rings with an intact or disrupted endothelium but that to isoprenaline was greater in intact preparations.
In preparations with either an intact or disrupted endothelium there was a similar length‐dependent increase in the resting tension of the aortic rings. The size of the contractile response to phenylephrine (1 μm) was dependent on the initial length (and hence degree of stretch) of the preparation in both rubbed and unrubbed tissues. The absolute difference in contractile response between rubbed and unrubbed was greatest at 1.8 mm and less at the other lengths tested, including the optimum degree of stretch for contraction i.e. 2.4 mm.
The absolute acetylcholine‐induced relaxation (only seen in rings with an intact endothelium) was dependent on the initial length (and hence degree of stretch) of the preparation and was maximum at 2.4 mm. The proportionate relaxation (i.e. expressed as a percentage of induced tone) was also length‐dependent, being optimal at 1.5 mm.
The sensitivity of the vessels to acetylcholine varied depending on the level of agonist‐induced tone. When tone was low, acetylcholine sensitivity was high (at [NA] 0.03 μm: pIC50 = 7.36 ± 0.07), when the concentration of noradrenaline was increased the tone increased and the acetylcholine sensitivity was low (at [NA] 0.3 μm: pIC50 = 6.57 ± 0.07).
The absolute sensitivities and maximum relaxations induced by acetylcholine are discussed in relation to the initial degree of stretch (and hence length of the preparation) or the degree of agonist‐induced tone.
Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats
Authors: Invernizzi Roberto , Moralix Federica , Pozzi Laura , Samanin Rosario 
Published: July 2012

The effect of single and repeated (once daily for 23 days) oral doses of 20 and 60 mg kg−1 clozapine on dopamine release and metabolism were studied by intracerebral dialysis in the striatum and nucelus accumbens of conscious rats.
The basal output of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and nucleus accumbens of rats given clozapine 20 or 60 mg kg−1 chronically, measured one day after the last drug dose, was not significantly different from that of vehicle‐treated animals.
Challenge doses of 20 or 60 mg kg−1 clozapine produced similar increases in dopamine levels in the striatum and nucleus accumbens of animals which had received vehicle or clozapine 20 or 60 mg kg−1 once daily for 23 days, except that 1 h after administration 60 mg kg−1 clozapine had a greater effect in the nucleus accumbens.
In animals treated chronically with clozapine 20 and 60 mg kg−1 or vehicle, DOPAC levels in the striatum and nucleus accumbens were increased to the same extent by challenge doses of clozapine (20 or 60 mg kg−1). In animals treated chronically with clozapine, a challenge dose of 60 mg kg−1 had significantly greater effect on HVA only in the nucleus accumbens.
When DOPAC and HVA were measured post mortem in the striatum and nucleus accumbens 2h after various oral doses of clozapine, it was found that 10 mg kg−1 significantly increased dopamine metabolites only in the nucleus accumbens whereas 100 mg kg−1 had this effect in both regions. Clozapine, 30 mg kg−1 significantly raised DOPAC levels in both regions but HVA was elevated only in the nucleus accumbens.
There appeared to be no appreciable changes in dopamine release and metabolism nor any reduction in the effect of clozapine in the nucleus accumbens after chronic drug treatment. In fact the effect was greater in chronically treated rats, particularly in the nucleus accumbens of animals given 60 mg kg−1 clozapine.
It was confirmed that measurement of dopamine metabolites in post mortem tissue provides no valuable information on changes in the availability of synaptic dopamine.
The effect of putative protein kinase C inhibitors, K252a and staurosporine, on the human neutrophil respiratory burst activated by both receptor stimulation and post‐receptor mechanisms
Authors: Twomey B. , Muid R.E. , Dale M.M. 
Published: July 2012

Two compounds, reported to be potent inhibitors of protein kinase C (PKC), K252a and staurosporine, have been examined in order to gain further information as to the possible role played by PKC in the signal transduction sequence of the neutrophil respiratory burst as determined by superoxide (O−2) production.
A number of stimuli were used in the study, some acting at receptors i.e. fMet‐Leu‐Phe (fMLP), opsonized zymosan and heat‐aggregated IgG (HAGG), one acting on a G‐protein, fluoride, and two direct PKC activators, dioctanoylglycerol (diC8) and phorbol myristate acetate (PMA).
K252a and staurosporine inhibited the respiratory burst with all the stimuli but the order of agonist sensitivity was very different with the two inhibitors.
For K252a‐induced inhibition of O−2 release, the order of potency was fluoride > fMLP, HAGG > opsonized zymosan > PMA, DiC8. For staurosporine‐induced inhibition of O−2 release, the order of potency changed to fluoride > DiC8, PMA > HAGG, fMLP > opsonized zymosan. The significance of this unexpected difference in relative rank order of potency is discussed with reference to the reported mechanism of action of the two inhibitors and the events involved in the oxidative burst.
Staurosporine at low concentrations increased the fMLP‐stimulated O−2 response by 100%, the maximum effect occurring at 35 nm.
To the extent that the compounds used are specific inhibitors of PKC, these findings support a role for the enzyme PKC in stimulus‐activation coupling in O−2 generation with all the stimuli used in this study.
The ‘calcium sensitising’ effects of ORG30029 in saponin‐ or Triton‐skinned rat cardiac muscle
Authors: Miller David J. , Steele Derek S. 
Published: July 2012

The effects of a range of concentrations of ORG30029 (1 μm to 1 mm) were investigated on fully (Triton‐treated) or selectively (saponin‐treated) ‘skinned’ ventricle trabeculae from rat. The Ca‐sensitivity was increased by 100 μm and amounted to a mean reduction in the Ca2+ necessary for half‐maximal activation (1/Kapp) of 0.174 ± 0.053 (mean ± s.e.mean) pCa units. ORG30029 (50 μm) gave a smaller mean shift of 0.05 ± 0.016 pCa units. A slight shallowing of the relationship between ‐log[Ca2+] (pCa) and steady‐state tension was also generally found (mean Hill exponent reduction 0.37 ± 0.28 at 100 μm).
The Ca‐sensitizing action altered in a dose‐dependent fashion. Judged by the ability to enhance force from an initial level of activation of 10–20% of maximum Ca‐activated force (Cmax), the first significant effects occurred near 10 μm and continued to increase at 1 mm.
A small (3.7 ± 1.1%) but consistent increase in Cmax was produced by ORG30029 at 100 μm. Much larger increases were produced by the drug at higher concentrations (up to 20–50% at 1 mm).
The consequence of these changes is that at levels of activation likely to occur in the heart, the absolute increase in force by 100 μm ORG30029 was considerable: it amounted to a 150–200% increase at a [Ca2+] producing 20% at Cmax. At this drug concentration virtually all the effect was due to Ca‐sensitizing rather than increasing CMax.
In the saponin‐treated preparations, at concentrations up to 1 mm, ORG30029 did not release Ca from the sarcoplasmic reticulum, as indicated by the failure to evoke contracture under conditions where caffeine induced large responses.
At 100 μm, ORG30029 potentiated the transient, caffeine‐induced contracture (saponin‐treated preparation) to an extent consistent with the Ca‐sensitizing effect seen under conditions of steady‐state tension development.
Antiarrhythmic efficacy of labetalol as assessed by programmed electrical stimulation
Authors: Krumpl G. , Todt H. , Krejcy K. , Raberger G. 
Published: July 2012

The purpose of the present study was to investigate the haemodynamic, electrophysiological and antiarrhythmic effects of labetalol in the late reperfusion phase after myocardial infarction in conscious dogs.
Labetalol was administered in cumulative doses (0.5, 1 and 3 mg kg−1 90 min−1, i.v.). Compared to control the systolic blood pressure was significantly decreased 20 min after 0.5, 1 and 3mg kg−1 and up to 30 min after 3 mg kg−1 labetalol. The diastolic blood pressure was significantly decreased 20 and 30 min after 0.5 and 3 mg kg−1 but was not significantly altered after 1 mg kg−1 labetalol.
Labetalol significantly increased the PQ, QRS, QT and QTc intervals, the 2:1 AV‐conduction point, the ventricular effective refractory periods and the intraventricular conduction time from the apex of the right ventricle to the infarcted LAD‐area. With the exception of the alterations in the PQ interval and 2:1 AV‐conduction point the effects described above were dose‐dependent.
Labetalol was active against arrhythmias induced by programmed electrical stimulation. This effect was already present after the lowest dose (0.5 mg kg−1).
The good antiarrhythmic activity of labetalol in this study can be explained by the adrenoceptor blocking properties and both the class I and III activity of this drug. Labetalol may be of potential benefit in controlling arrhythmias arising following myocardial infarction.
Role of nitric oxide in maintaining vascular integrity in endotoxin‐induced acute intestinal damage in the rat
Authors: Hutcheson Iain R. , Whittle Brendan J.R. , Boughton‐Smith Nigel K. 
Published: July 2012

The role of endogenous nitric oxide (NO) in maintaining intestinal vascular integrity following acute endotoxin (E. coli. lipopolysaccharide) challenge was investigated in the anaesthetized rat by use of NG‐monomethyl‐l‐arginine (l‐NMMA), a selective inhibitor of NO synthesis.
l‐NMMA (10–50 mg kg−1, i.v.) pretreatment enhanced both the macroscopic and histological intestinal damage and the increases in vascular permeability, measured as the leakage of [125I]‐labelled human serum albumen, induced after 15 min by endotoxin (50 mg kg−1, i.v.).
The effects of l‐NMMA (50 mg kg−1, i.v.) were enantiomer specific, as d‐NMMA had no effect. Furthermore, these effects were reversed by l‐arginine (300 mg kg−1, i.v.), the precursor of NO synthesis but not by d‐arginine (300 mg kg−1, i.v.).
l‐NMMA (10–50 mg kg−1, i.v.) increased mean systemic arterial blood pressure but this does not appear to be the mechanism by which endotoxin‐induced intestinal damage was enhanced, since similar systemic pressor responses induced by phenylephrine (10 μg kg−1 min−1, i.v.), had no such effect.
The results suggest that synthesis of NO from l‐arginine has a role in maintaining the microvascular integrity of the intestinal mucosa following acute endotoxin challenge.
Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA‐receptor function
Authors: Galpern Wendy R. , Miller Lawrence G. , Greenblatt David J. , Shader Richard I. 
Published: July 2012

Chronic benzodiazepine administration has been associated with tolerance and with downregulation of γ‐aminobutyric acidA (GABAA)‐receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied.
To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg−1 day−1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg−1 i.p., and GABA‐dependent chloride uptake in 3 brain regions at these time points.
Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872‐resistant (Type 2) sites in both regions. Maximal GABA‐dependent chloride uptake was also decreased in the cortex and hippocampus at day 7.
Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA‐dependent chloride uptake was also decreased only in the cortex.
These data suggest that the effects of chronic benzodiazepine administration on the GABAA‐receptor may be both region‐specific and receptor subtype‐specific.
Endotoxin‐induced impairment of vasopressor and vasodepressor responses in the pithed rat
Authors: Guc M. Oguz , Furman Brian L. , Parratt James R. 
Published: July 2012

Effects of E. coli endotoxin on vascular responsiveness to a variety of agents were compared with those of the calcium channel blocking drug nicardipine in pithed rats.
Infusion of endotoxin (250 μg kg−1 h−1) produced a fall in mean arterial blood pressure (8 mmHg). A similar fall (11 mmHg) was seen in rats receiving nicardipine (1.0 mg kg−1).
Endotoxin impaired responsiveness to vasopressin, phenylephrine and cirazoline, producing a shift to the right in the dose‐response curves without any change in the maximum response. Responsiveness to 5‐hydroxytryptamine (5‐HT) and to the α2‐adrenoceptor agonists clonidine and BHT 933, was also impaired with a marked reduction in their maximum responses. The dose‐response curve to the pressor effects of endothelin was not significantly modified.
Nicardipine produced a similar pattern of impairment of responsiveness to these agents to that produced by endotoxin. However, nicardipine also shifted the pressor dose‐response curve to endothelin to the right with no significant alteration in its maximum response.
The pressor responses to endothelin and to 5‐HT were, respectively, preceded and followed by dose‐dependent depressor responses, which were markedly reduced by endotoxin and nicardipine.
The concomitant infusion of arginine vasopressin (0.64 iu kg−1 h−1) prevented endotoxin‐induced hypotension and also prevented the impairment in responsiveness to cirazoline and to BHT 933.
The similarity of the pattern of impaired pressor responsiveness (except in relation to endothelin) and depressor responsiveness produced by endotoxin and nicardipine may be consistent with a common mechanism of action.