bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cholecystokinin as a factor in the enhanced potency of spinal morphine following carrageenin inflammation
Authors: Stanfa Louise C. , Dickenson Anthony H. 
Published: July 2012

Cholecystokinin (CCK) has been shown to diminish opioid analgesia. Here we investigate whether changes in the physiological levels of spinal CCK are responsible for the enhanced potency of spinal morphine in animals following carrageenin inflammation, as compared with normal animals.
Single dorsal horn nociceptive neurones were recorded in intact halothane‐anaesthetized rats in the presence and absence of carrageenin‐induced inflammation and comparisons were made between the two groups of animals. Inflammation was induced by the injection of 100 μl of 2% λ‐carrageenin into the hind paw.
The inhibitory effect of intrathecal morphine on the C‐fibre‐evoked responses of the neurones was enhanced in the carrageenin‐treated animals such that the effects of 0.25 μg and 10 μg of morphine in normal animals were comparable to those of 0.01 μg and 2.5 μg in the carrageenin animals. The effect of 0.2 mg kg−1 of the CCKB antagonist, L‐365,260, on the antinociceptive potency of intrathecal morphine was examined in both groups of animals. In normal animals, L‐365,260 produced a significant enhancement in the effect of morphine indicating a tonic CCK modulation in these animals, but it had no effect on the inhibitions produced by either dose of morphine in the carrageenin animals.
The inhibition of the C‐fibre‐evoked response produced by intrathecal morphine in the presence of 1 μg of CCK was examined in both groups of animals. CCK attenuated the effects of morphine only in animals with carrageenin inflammation, having no effect on the action of morphine in normal animals.
The effects of both CCK and L‐365,260 were therefore dependent on the inflammatory state of the animal, with each drug being active in opposite situations.
We propose that in normal animals, morphine may produce a maximal stimulation of the release of CCK such that exogenous CCK is unable to reduce further the analgesic effects under these conditions. However, the differential effects of the agonist and antagonist in the normal and inflamed rats points to a role of CCK in the enhanced opiate actions. This enhancement of the potency of spinal morphine in inflammation is best explained by a reduction in spinal CCK release by morphine in this state.
Virus‐induced airway hyperresponsiveness in the guinea‐pig: possible involvement of histamine and inflammatory cells
Authors: Folkerts Gert , De Clerck Fred , Reijnart Ivonne , Span Paul , Nijkamp Frans P. 
Published: July 2012

Guinea‐pig tracheal contractions by histamine and by the cholinoceptor agonist, arecoline, are significantly enhanced (30% and 20%, respectively), 96 h after intra‐tracheal inoculation with Parainfluenza‐3 (PI‐3) virus.
The airway hyperresponsiveness in animals inoculated with virus coincides with a significant increase in the number of broncho‐alveolar cells (82%), and in the albumin concentration (121%) in lung lavage fluid, relative to values obtained in guinea‐pigs challenged with control solution.
The chemiluminescence production by isolated broncho‐alveolar cells, obtained from virus‐infected guinea‐pigs 96 h after inoculation stimulated with PI‐3 virus in vitro, is significantly reduced by 42% relative to broncho‐alveolar cells obtained from animals inoculated with control solution. This diminution was not specific for stimulation by PI‐3 virus since the chemiluminescence production was also significantly reduced by 30% in response to zymosan.
Pretreatment of the guinea‐pigs with the anti‐allergic drugs, oxatomide (2.5 mg kg−1) or nedocromil (2.5 mg kg−1), or the specific H1‐histamine receptor antagonist, levocabastine (0.25 mg kg−1), administered intra‐peritoneally twice a day for five successive days, inhibits the virus‐induced airway hyperresponsiveness, suppresses the influx of broncho‐alveolar cells and increase in albumin content, and corrects the reduced chemiluminescence production by broncho‐alveolar cells in response to zymosan.
In contrast, the cyclo‐oxygenase inhibitor, suprofen (5.0 mg kg−1), the 5‐HT2 receptor antagonist, ketanserin (0.63 mg kg−1), or the Ca2+ overload blocker, flunarizine (2.5 mg kg−1) do not modify the above mentioned processes.
The platelet‐activating factor receptor antagonist, WEB 2170 (10 mg kg−1), reduces virus‐induced airway hyperresponsiveness and influx of broncho‐alveolar cells into the lungs but does not attenuate the increase of albumin in the bronchial lavage fluid.
Guinea‐pigs nebulized with histamine, twice a day (30 min) during 4 successive days, do not demonstrate an increased airway responsiveness, but instead show tachyphylaxis in response to histamine in vitro. In addition, no influx of inflammatory cells is found in these animals.
These results suggest that histamine does not directly increase the responsiveness of the guinea‐pig trachea; however, histamine may be involved in a cascade of events leading to airway hyperresponsiveness after a viral infection, a process that could be related to an influx and/or an activation of broncho‐alveolar cells after PI‐3 virus stimulation.
Porcine ventricular endocardial cells in culture express the inducible form of nitric oxide synthase
Authors: Smith Jerry A. , Radomski Marek W. , Schulz Richard , Moncada Salvador , Lewis Malcolm J. 
Published: July 2012

We have investigated whether porcine endocardial cells in culture express the inducible, Ca2+‐independent form of nitric oxide (NO) synthase.
NO synthase activity in cytosolic extracts of endocardial cells was measured by estimation of the rate of formation of l‐[14C]‐citrulline from l‐[14C]‐arginine.
Treatment of the cells in culture with lipopolysaccharide or cytokines induced a Ca2+‐independent NO synthase activity in the cell cytosol. The combination of tumour necrosis factor (TNFα, 10 ng ml−1) and interleukin‐1β (IL‐1β, 10 ng ml−1) induced the greatest enzyme activity.
The increased Ca2+‐independent NO synthase activity following exposure to cytokines was parallelled by an increase in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels in the endocardial cell cytosol.
Simultaneous addition of dexamethasone (0.01–1 μm) or cycloheximide (0.03–3 μm) inhibited in a concentration‐dependent manner TNFα‐ and IL‐1β‐induced expression of Ca2+‐independent NO synthase activity. Neither dexamethasone (1 μm) nor cycloheximide (3 μm) had any effect on the activity of the constitutive NO synthase.
The possible pathophysiological consequences of endocardial expression of the inducible NO synthase are discussed.
Nitric oxide synthase in pig lower urinary tract: immunohistochemistry, NADPH diaphorase histochemistry and functional effects
Authors: Persson Katarina , Alm Per , Johansson Kjell , Larsson Bengt , Andersson Karl‐Erik 
Published: July 2012

The distribution and colocalization of nitric oxide synthase (NOS)‐like immunoreactivity and NADPH diaphorase activity in the pig lower urinary tract were investigated by immunohistochemical and histochemical staining techniques. Functional in vitro studies were performed to correlate the presence of NOS‐immunoreactivity/NADPH diaphorase staining with smooth muscle responses involving the l‐arginine/nitric oxide (NO) pathway.
NOS‐immunoreactivity and NADPH diaphorase activity were expressed in nerve trunks and fine nerve fibres in and/or around muscular bundles in the detrusor, trigone and urethra. Thin nerve fibres that dispersed within the muscle bundles were mainly found in the urethral/trigonal area, whereas such fibres were less common in the detrusor.
Almost all neuronal structures that were NOS‐immunolabelled were also stained for NADPH diaphorase. In contrast, the urothelium, which was intensively stained by the NADPH diaphorase technique, remained unstained by immunohistochemistry.
Electrical field stimulation of pig isolated trigonal and urethral preparations induced relaxations, which were inhibited by tetrodotoxin (1 μm) and NG‐nitro‐l‐arginine (l‐NOARG, 10 μm).
l‐Arginine (1 mm), but not d‐arginine, inhibited (25–30%) electrically evoked detrusor contractions. This inhibition was reversed by l‐NOARG (0.1 mm). l‐Arginine did not inhibit detrusor contractions in the presence of scopolamine (1 μm) and had no direct smooth muscle effects per se.
Acetylcholine (1 nm − 10 μm) caused concentration‐dependent relaxations of noradrenaline‐induced contractions in pig vesical arteries. Removal of the endothelium practically abolished the acetylcholine‐induced relaxation. Pretreatment with l‐NOARG (0.1 mm and 0.3 mm) caused a rightward shift of the concentration‐response curves to acetylcholine, but the maximal relaxation obtained was significantly reduced (to 65 ± 12%; n = 6; P < 0.05) only at 0.3 mml‐NOARG.
In vessel segments contracted with K+ (60 mm), acetylcholine induced concentration‐dependent relaxations. When the vessels were incubated with 0.3 mml‐NOARG and then contracted with K+ (60 mm) all relaxant responses to acetylcholine were abolished.
The presence of NO synthesizing enzyme in nerve fibres and the pharmacological evidence for NO‐mediated relaxation of the trigone and urethra suggest that NO or a NO‐related substance may have a role in inhibitory neurotransmission in these regions. In the detrusor, the presence of NO‐synthesizing enzyme in nerves can be demonstrated, but its functional importance is unclear. NO, as well as other endothelium‐derived factors seem to be involved in the endothelium‐dependent acetylcholine‐induced relaxation of pig vesical arteries.
Differential Class III and glibenclamide effects on action potential duration in guinea‐pig papillary muscle during normoxia and hypoxia/ischaemia
Authors: MacKenzie I. , Saville V.L. , Waterfall J.F. 
Published: July 2012

Microelectrode recording techniques were used to study the effects of several potassium channel blockers which are considered to be Class III antiarrhythmic compounds. The effects of (+)‐sotalol, UK‐66,914, UK‐68,798 and E‐4031 on action potential duration (APD) were determined in guinea‐pig isolated papillary muscles. The compounds were evaluated under normoxic or hypoxic/ischaemic conditions at 36.5°C and compared to glibenclamide, which is considered to be a blocker of ATP‐dependent potassium channels. Prolongation of action potential duration at 90% repolarization (APD90) was taken as an indirect measure of potassium channel blockade.
Under normoxic conditions, the Class III compounds prolonged APD in a concentration‐dependent manner. According to EC15 values, the order of potency of the Class III compounds was found to be UK‐68,798 > E‐4031 > UK‐66,914 > (+)‐sotalol. Glibenclamide did not significantly prolong APD90 under normoxic conditions.
Perfusion with an experimental hypoxic or ischaemic bathing solution produced qualitatively similar effects on action potentials. Over a period of 20–25 min in either of the experimental solutions, there was a small decrease in action potential amplitude (APA) and a prominent shortening of APD. The ischaemic solution also depolarized the resting membrane potential by about 15 mV.
(+)‐Sotalol and UK‐66,914 did not reverse the shortening of APD induced by perfusion with hypoxic Krebs solution. High concentrations of glibenclamide (10 μm) and UK‐68,798 (30 and 60 μm) partially reversed the hypoxia‐shortened APD. Glibenclamide was more potent and exhibited a greater time‐dependent action than UK‐68,798.
During experimental ischaemia, the Class III compound E‐4031 (10 μm, n = 7) produced small, but significant, increases in the APD90 (11 ± 3 ms after 20 min) which were not clearly time‐dependent (14 ± 4 ms after 30 min). UK‐68,798 (10 μm) also produced a small, but insignificant, increase in APD90 (12 ± 6 ms at 20 min, n = 4). Higher concentrations of UK‐68,798 (30 and 60 μm, n = 4) did not produce a consistently significant increase in APD90 during ischaemia: significance was only attained after 20 min in the presence of 60 μm UK‐68,798 (24 ± 12 ms). However, in marked contrast to the effects of the Class III compounds, glibenclamide (10 μm) produced large time‐dependent increases in ischaemic APD90 (34 ± 11 ms at 7 min, n = 9) which were significant 15 min or more after drug addition (52 ± 12 ms at 20 min, n = 7; 74 ± 5 ms at 30 min, n = 6).
The present microelectrode data suggest that blockers of ATP‐dependent potassium channels, such as glibenclamide, might prove to be more effective than Class III compounds against ischaemia‐induced shortening of cardiac action potentials.
Reduction in the number of thromboxane receptors on human platelets after exposure to GR32191
Authors: Armstrong Roma A. , Humphrey P.P.A. , Lumley P. 
Published: July 2012

Exposure of human resuspended platelets in vitro for 30 min to the potent thromboxane A2 (TP)‐receptor blocking drug GR32191, followed by its removal by dilution‐dissociation, reduced the degree of subsequent binding to 2 nm [3H]‐GR32191 by almost 50%. Exposure for longer periods (60 min) led to a further reduction. However, no change in the Kd of the radioligand was observed.
This effect of GR32191 could not be explained by persistent binding of drug to platelets since a dilution‐dissociation stage, designed to remove all drug, was included prior to measurement of binding.
Using an alternative TP‐receptor radioligand, [3H]‐SQ29,548, to monitor receptor number, a reduction in Bmax was observed after GR32191 pre‐treatment; the Kd value of the radioligand remained unchanged.
The effect was not a common property of TP‐receptor blocking drugs since pre‐exposure of platelets in vitro for 30 min to BM13.177 or SQ29,548 did not produce a fall in subsequent Bmax to [3H]‐SQ29,548.
While the mechanism behind this apparent down‐regulation of platelet TP‐receptor is unknown, it may explain the long duration of action of GR32191 upon platelets in man which persists in the absence of detectable drug in the plasma.
The effect of nitric oxide on the efficacy of synaptic transmission through the chick ciliary ganglion
Authors: Scott T.R.D. , Bennett M.R. 
Published: July 2012

The effect of nitric oxide on the efficacy of synaptic transmission in the chick ciliary ganglion of post‐hatched birds has been determined by use of the size of the postganglionic compound action potential resulting from chemical transmission through the ganglion as a measure of synaptic efficacy.
Sodium nitroprusside (100 μm) increased the synaptic efficacy by an average 26%. This is likely to be due to its ability to release nitric oxide, as potassium ferricyanide (100 μm) did not cause a potentiation. Sodium azide (100 μm), shown in sympathetic ganglia to stimulate production of cyclic GMP, did not modulate synaptic efficacy significantly.
8‐Br‐cyclic‐GMP (100 μm) increased synaptic efficacy by an average 61%. The addition of 8‐Br‐cyclic‐AMP (100 μm) had less effect, increasing transmission by on average 46%.
The nitric oxide synthase blocker, NG‐nitro‐l‐arginine methyl ester (l‐NAME, 100 μm) was added prior to the tetanic stimulation of the preganglionic nerves at 30 Hz for 20 s, a procedure known to produce both post‐tetanic potentiation and long‐term potentiation of synaptic transmission through the ganglion. l‐NAME reduced the long‐term potentiation by an average of 47% but did not significantly change the post‐tetanic potentiation.
Following the brief application of 8‐Br‐cyclic AMP, 8‐Br‐cyclic GMP and sodium nitroprusside there was an enhancement of the efficacy of synaptic transmission that persisted after the withdrawal of the drugs. The maximum increase in synaptic efficacy following the brief addition of 8‐Br‐cyclic GMP was 116%, sodium nitroprusside was 110% and 8‐Br‐cyclic AMP was 126%.
These results suggest that nitric oxide modulates synaptic transmission through the ganglion by acting on an endogenous guanylate cyclase that produces cyclic GMP.
Pharmacological characterization of the dopamine receptor coupled to cyclic AMP formation expressed by rat mesenteric artery vascular smooth muscle cells in culture
Authors: Hall Alistair S. , Bryson Susan E. , Vaughan Peter F.T. , Ball Stephen G. , Balmforth Anthony J. 
Published: July 2012

Mesenteric artery vascular smooth muscle cells derived from male Wistar rats and grown in culture were prelabelled with [3H]‐adenine and exposed to a range of dopamine receptor agonists and antagonists. Resultant [3H]‐cyclic AMP formation was determined and concentration‐effect curves constructed, in the presence of propranolol (10−6 m) and the phosphodiesterase inhibitor IBMX (5× 10−4 m).
Ka apparent values for D1/DA1 dopamine receptor agonists SKF 38393, fenoldopam, 6,7‐ADTN, and dopamine were 0.06, 0.59, 4.06 and 5.77 × 10−6 m respectively. Although fenoldopam and SKF 38393 were more potent than dopamine, they were partial agonists with efficacies, relative to dopamine of approximately 48% and 24% respectively. 6,7‐ADTN, in contrast, behaved as a full agonist.
Dopamine‐stimulated cyclic AMP formation was inhibited in a concentration‐dependent manner by the D1/DA1 dopamine receptor selective antagonists, SCH 23390 and cis‐flupenthixol (Ki values 0.53 and 36.1 × 10−1 m respectively). In contrast, the D2/DA2 dopamine receptor selective antagonists, domperidone and (−)‐sulpiride, were less potent (Ki values 2.06 and 5.82 × 10−6 m respectively). Furthermore, the stereoisomers of SCH 23390 and cis‐flupenthixol, SCH 23388 and trans‐flupenthixol, were at least two orders of magnitude less potent (Ki values 0.14 and 13.2 × 10−6 m respectively) indicating the stereoselective nature of this receptor.
Our results indicate that rat mesenteric artery vascular smooth muscle cells in culture express a dopamine receptor coupled to cyclic AMP formation, which has the pharmacological profile, characteristic of the D1 dopamine receptor subfamily.
Identification of both NK1 and NK2 receptors in guinea‐pig airways
Authors: McKee Katherine T. , Millar Lorna , Rodger Ian W. , Metters Kathleen M. 
Published: July 2012

NK1 and NK2 receptors have been characterized in guinea‐pig lung membrane preparations by use of [125I‐Tyr8]‐substance P and [125I]‐neurokinin A binding assays in conjunction with tachykinin‐receptor selective agonists ([Sar9Met(O2)11]substance P for NK1 and [βAla8]neurokinin A (4–10) for NK2) and antagonists (CP‐99,994 for NK1 and SR48968 for NK2).
The presence of high affinity, G‐protein‐coupled NK1 receptors in guinea‐pig lung parenchymal membranes has been confirmed. The rank order of affinity for competing tachykinins was as predicted for an NK1 receptor: substance P = [Sar9Met(O2)11]substance P > substance P‐methyl ester = physalaemin > neurokinin A = neurokinin B >> [βAla8]neurokinin A (4–10). The novel NK1 antagonist CP‐99,994 has a Ki of 0.4 nm at this NK1 site.
In order to characterize [125I]‐neurokinin A binding to guinea‐pig lung, the number of [125I]‐neurokinin A specific binding sites was increased 3–4 fold by purification of the parenchymal membranes over discontinuous sucrose gradients. The rank order of affinity determined for NK1‐ and NK2‐receptor agonists and antagonists in competition for these sites showed that the majority (80%) of [125I]‐neurokinin A specific binding was also to the NK1 receptor.
Under conditions where the guinea‐pig lung parenchymal NK1 receptor was fully occupied by a saturating concentration of either [Sar9Met(O2)11]substance P (1 μm) or CP‐99,994 (2.7 μm), residual [125I]‐neurokinin A specific binding was inhibited in a concentration‐dependent manner by both [βAla8]neurokinin A and SR48968. This result shows that the NK2 receptor is also present in these preparations.
Similar studies using guinea‐pig tracheal membranes demonstrated that [125I]‐neurokinin A specific binding was composed of a NK1‐receptor component (60%), inhibited by both [Sar9Met(O2)11]substance P and CP‐99,994, and a significant NK2‐receptor component, inhibited by both [βAla8]neurokinin A and SR48968.
In summary, these data demonstrate that guinea‐pig lung parenchyma and guinea‐pig trachea express both NK1 and NK2 receptors.
Enhancement of D2 receptor agonist‐induced inhibition by D1 receptor agonist in the ventral tegmental area
Authors: Momiyama Toshihiko , Sasa Masashi , Takaori Shuji 
Published: July 2012

A microiontophoretic study was performed on chloral hydrate‐anaesthetized rats to examine the role of D1 receptors in the ventral tegmental area (VTA) neurones, which are inhibited by autoreceptor and D2 receptor agonists.
Inhibition by microiontophoretic application of quinpirole (a D2 agonist) of antidromic spikes elicited by stimulation of the nucleus accumbens in dopaminergic neurones of the VTA, was significantly enhanced by simultaneous application of SKF 38393 (D1 agonist), although SKF 38393 alone had little effect on the neurones.
In addition, quinpirole‐induced inhibition was antagonized by iontophoretic application of domperidone (D2 antagonist), but was not affected by SCH 23390 (D1 antagonist).
Furthermore, SKF 38393‐induced enhancement of inhibition by quinpirole was antagonized by simultaneous application of SCH 23390.
These results suggest that activation of D1 receptors located on the VTA dopaminergic neurones or on non‐dopaminergic nerve terminals is not essential for inducing inhibition of the dopaminergic neurones, but enhances D2 receptor‐mediated inhibition directly or indirectly via inhibitory neurones.
Differential inhibition by NG‐monomethyl‐l‐arginine of vasodilator effects of acetylcholine and methacholine in human forearm vasculature
Authors: Chowienczyk P.J. , Cockcroft J.R. , Ritter J.M. 
Published: July 2012

We compared the effects of NG‐monomethyl‐l‐arginine (l‐NMMA), an NO synthase inhibitor, on vasodilatation produced by acetylcholine and methacholine in human forearm vasculature.
Acetylcholine (83 nmol min−1) infused into the brachial artery of 8 healthy volunteers caused a submaximal increase in forearm blood flow, measured by venous occlusion plethysmography, from 3.3 ± 0.5 (mean ± s.e.mean) to 13.3 ± 1.7 ml min−1 100 ml−1.
Co‐infusion of l‐NMMA (4 μmol min−1) with acetylcholine (83 nmol min−1) over 6 min resulted in a 58% ± 12% fall in the response to acetylcholine whereas during co‐infusion of saline over the same time period in the same subjects (n = 8) on a different day the response to acetylcholine fell by only 9% ± 17% (P < 0.01).
Methacholine (1.5 and 15 nmol min−1) increased forearm blood flow from 2.5 ± 0.4 to 5.9 ± 0.9 and from 3.2 ± 0.4 to 17.0 ± 1.9 ml min−1 100 ml−1 respectively.
Co‐infusion of l‐NMMA (4 μmol min−1) had no significant effect on the response to methacholine (1.5 or 15 nmol min−1) when compared with saline control (n = 8). Co‐infusion of a higher dose of l‐NMMA (8 μmol min−1) with methacholine (1.5 nmol min−1) did not significantly inhibit the vasodilator response (n = 7).
These results suggest that, in human forearm vasculature, methacholine acts predominantly through mechanisms other than the l‐arginine/nitric oxide pathway.