bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of trans‐resveratrol, a natural polyphenolic compound, on human polymorphonuclear leukocyte function
Authors: Rotondo Serenella , Rajtar Grazyna , Manarini Stefano , Celardo Antonio , Rotilio Domenico , De Gaetano Giovanni , Evangelista Virgilio , Cerletti Chiara 
Published: January 2005

Polymorphonuclear leukocytes (PMN) may contribute to the pathogenesis of acute coronary heart disease (CHD).
Epidemiological and laboratory evidence suggests that red wine, by virtue of its polyphenolic constituents, may be more effective than other alcoholic beverages in reducing the risk of CHD mortality.
The aim of the present study was to investigate the effects of trans‐resveratrol (3,4′,5‐trihydroxy‐trans‐stilbene), a polyphenol present in most red wines, on functional and biochemical responses of PMN, upon in vitro activation.
trans‐Resveratrol exerted a strong inhibitory effect on reactive oxygen species produced by PMN stimulated with 1 μM formyl methionyl leucyl phenylalamine (fMLP) (IC50 1.3±0.13 μM, mean±s.e.mean), as evaluated by luminol‐amplified chemiluminescence.
trans‐Resveratrol prevented the release of elastase and β‐glucuronidase by PMN stimulated with the receptor agonists fMLP (1 μM, IC50 18.4±1.8 and 31±1.8 μM), and C5a (0.1 μM, IC50 41.6±3.5 and 42±8.3 μM), and also inhibited elastase and β‐glucuronidase secretion (IC50 37.7±7 and 25.4±2.2 μM) and production of 5‐lipoxygenase metabolites leukotriene B4 (LTB4), 6‐trans‐LTB4 and 12‐trans‐epi‐LTB4 (IC50 48±7 μM) by PMN stimulated with the calcium ionophore A23187 (5 μM).
trans‐Resveratrol significantly reduced the expression and activation of the β2 integrin MAC‐1 on PMN surface following stimulation, as revealed by FACS analysis of the binding of an anti‐MAC‐1 monoclonal antibody (MoAb) and of the CBRM1/5 MoAb, recognizing an activation‐dependent epitope on MAC‐1. Consistently, PMN homotypic aggregation and formation of mixed cell‐conjugates between PMN and thrombin‐stimulated fixed platelets in a dynamic system were also prevented by trans‐resveratrol.
These results, indicating that trans‐resveratrol interferes with the release of inflammatory mediators by activated PMN and down‐regulates adhesion‐dependent thrombogenic PMN functions, may provide some biological plausibility to the protective effect of red wine consumption against CHD.

British Journal of Pharmacology (1998) 123, 1691–1699; doi:10.1038/sj.bjp.0701784
Neuroregulation of mucus secretion by opioid receptors and KATP and BKCa channels in ferret trachea in vitro
Authors: Ramnarine Sean I. , Liu Yu‐Chih , Rogers Duncan F. 
Published: January 2005

Opioid agonists inhibit neurogenic mucus secretion in the airways. The mechanism of the inhibition is unknown but may be via opening of potassium (K+) channels. We studied the effect on neurogenic secretion in ferret trachea in vitro of the OP1 receptor (formerly known as δ opioid receptor) agonist [D‐Pen2,5]enkephalin (DPDPE), the OP2 receptor (formely κ) agonist U‐50,488H, the OP3 receptor (formerly μ) agonist [D‐Ala2, N‐Me‐Phe, Gly‐ol5]enkephalin (DAMGO), the ATP‐sensitive K+ (KATP) channel inhibitor glibenclamide, the large conductance calcium activated K+ (BKCa) channel blocker iberiotoxin, the small conductance KCa (SKCa) channel blocker apamin, the KATP channel opener levcromakalim, a putative KATP channel opener RS 91309, and the BKCa channel opener NS 1619. Secretion was quantified by use of 35SO4 as a mucus marker.
Electrical stimulation increased tracheal secretion by up to 40 fold above sham‐stimulated levels. DAMGO or DPDPE (10 μM each) significantly inhibited neurogenic secretion by 85% and 77%, respectively, effects which were reversed by naloxone. U‐50,488H had no significant inhibitory effect on neurogenic secretion, and none of the opioids had any effect on ACh‐induced or [Sar9]substance P‐induced secretion.
Inhibition of neurogenic secretion by DAMGO or DPDPE was reversed by iberiotoxin (3 μM) but not by either glibenclamide or apamin (0.1 μM each). Iberiotoxin alone did not affect the neurogenic secretory response.
Levcromakalim, RS 91309 or NS 1619 (3 nM–3 μM) inhibited neurogenic secretion with maximal inhibitions at 3 μM of 68%, 72% and 96%, respectively. Neither levcromakalim nor RS 91309 at any concentration tested significantly inhibited acetylcholine (ACh)‐induced secretion, whereas inhibition (60%) was achieved at the highest concentration of NS 1619, a response which was blocked by iberiotoxin.
Inhibition of neurogenic secretion by levcromakalim (3 μM) or RS 91309 (30 nM) was inhibited by glibenclamide but not by iberiotoxin. In contrast, inhibition by NS 1619 (30 nM and 3 μM) was blocked by iberiotoxin but not by glibenclamide.
We conclude that, in ferret trachea in vitro, OP1 or OP3 opioid receptors inhibit neurogenic mucus secretion at a prejunctional site and that the mechanism of the inhibition is via opening of BKCa channels. Direct opening of BKCa channels or KATP channels also inhibits neurogenic mucus secretion. In addition, opening of BKCa channels inhibits ACh‐evoked secretion of mucus. Drugs which open BKCa channels may have therapeutic anti‐secretory activity in bronchial diseases in which neurogenic mechanisms and mucus hypersecretion are implicated in pathophysiology, for example asthma and chronic bronchitis.

British Journal of Pharmacology (1998) 123, 1631–1638; doi:10.1038/sj.bjp.0701786
Endogenous orphanin FQ: evidence for a role in the modulation of electroacupuncture analgesia and the development of tolerance to analgesia produced by morphine and electroacupuncture
Authors: Tian Jin‐Hua , Zhang Wei , Fang Yuan , Xu Wei , Grandy David K , Han Ji‐Sheng 
Published: January 2005

Our previous work has demonstrated that exogenously administered orphanin FQ (OFQ) antagonizes morphine analgesia and electroacupuncture analgesia (EAA) in the brain and potentiates morphine analgesia and EAA in the spinal cord of the rat. In the present study we evaluated the role of endogenously released OFQ in the development of tolerance to morphine and electroacupuncture (EA) and the analgesia produced by electroacupuncture, by use of the IgG fraction of an anti‐OFQ antibody (OFQ‐Ab) microinjected into the rat central nervous system (CNS).
EAA was produced by stimulating rats at a frequency of 100 Hz. Rats were classified as either high responders (HR) or low responders (LR) based on the analgesic effects of EA. LRs could be converted into HRs by the intracerebroventricular (i.c.v.) microinjection of OFQ‐Ab at both 1 : 1 and 1 : 10 dilutions but not 1 : 100. HRs could be changed into LRs by the intrathecal (i.t.) injection of OFQ‐Ab at both 1 : 1 and 1 : 10 dilutions, but not 1 : 100.
Acute morphine tolerance was induced in rats by repeated subcutaneous (s.c.) injections of morphine (5 mg kg, every 2 h) for 16 h. When injected i.c.v. the OFQ‐Ab (1 : 1 dilution) had no effect on the development of acute morphine tolerance.
Chronic morphine tolerance was produced in rats by repeated injection of morphine (5–60 mg kg, s.c., 3× a day) for 6 days. I.c.v. injection of OFQ‐Ab (1 : 1 dilution) reversed this type of morphine tolerance in rats by 50% (P<0.01).
Acute tolerance to the analgesia produced by EA developed after 6 h of continuous (100 Hz, 3mA) stimulation. This tolerance was almost completely reversed by the i.c.v. injection of OFQ‐Ab (1 : 1 dilution) (P<0.05).
Chronic tolerance to the analgesic effect of EA was produced by repeatedly administering increasing current (1, 2 and 3 mA, each lasting for 10 min, for a total of 30 min) at a frequency of 100 Hz once a day for 6 days. I.c.v. injection of OFQ‐Ab (1 : 1 dilution) reversed this kind of tolerance by 50% (P<0.01).
Together these results suggest that 100 Hz EA may enhance the release of endogenous OFQ in the CNS of the rat, which in turn may act to antagonize EA‐produced analgesia in the brain but potentiate EA produced analgesia in the spinal cord. Therefore, OFQ appears to play an important role in the development of tolerance to the analgesic effects produced by EA.
The mechanisms underlying the development of acute morphine tolerance and chronic morphine tolerance appear to be different. Central OFQ may play an important role in the development of tolerance after chronic morphine administration.
The receptor subtype mediating the action of angiotensin II on intracellular sodium in rat proximal tubules
Authors: Wong Patrick S K , Johns Edward J 
Published: January 2005

An investigation was undertaken to explore the subtype of receptor involved in mediating the actions of angiotensin II on intracellular sodium content in suspensions of isolated proximal tubules of the rat.
Intracellular sodium content of the proximal tubules was measured with 23Na n.m.r. spectroscopy and under these conditions basal sodium content of the tubular cells was 69.04±1.73 nmol mg−1 dry weight and the ATP levels, at 8.3±0.9 nmol ATP mg−1 protein, were consistent with active respiration by the tissue.
In the presence of 10−4M PD123319, a selective non‐peptide AT2 receptor antagonist, intracellular sodium levels rose from steady state by 30% (P<0.01; n=7) within 10 min of exposure to angiotensin II 10−11M. Over the subsequent 30 min steady state levels were re‐established. Administration of angiotensin II 10−11M, in the presence of the selective AT1 receptor antagonist, losartan at either 10−6M (n=5) or 10−4M (n=6), was without effect on intracellular sodium levels, which were significantly different (P<0.001) from those observed when PD 123319 was present.
Angiotensin II 10−5M, administered to the tubular suspension in the presence of 10−4M PD123319, decreased (P<0.01, n=6) intracellular sodium content by 16% in the first 5 min, but in the following 25 min returned to steady state levels. However, in the presence of losartan 10−4M, angiotensin II 10−5M had no effect on intracellular sodium content which was markedly different (P<0.001) from that obtained in the presence of PD123319.
These findings show that at both the high and low concentrations of angiotensin II, its modulation of intracellular sodium levels within the proximal tubule cells is mediated via the activation of AT1 receptors. The intracellular mechanism underlying this effect remain to be investigated.
Modulation of spasmogen‐stimulated Ins(1,4,5)P3 generation and functional responses by selective inhibitors of types 3 and 4 phosphodiesterase in airways smooth muscle
Authors: Challiss R A John , Adams David , Mistry Rajendra , Nicholson C David 
Published: January 2005

The effects of isoenzyme‐selective inhibitors of phosphodiesterases PDE3 and PDE4 on cyclic AMP concentration, two indices of phosphoinositide hydrolysis, and contractile responses to spasmogens have been investigated in bovine tracheal smooth muscle (BTSM).
Neither the PDE3‐selective inhibitor ORG 9935, nor the PDE4‐selective inhibitor rolipram increased cyclic AMP levels in BTSM. However, rolipram addition in the presence of PDE3 inhibition (ORG 9935; 1 μM) concentration‐dependently (−log EC50 (M), 6.55±0.15; n=3) increased cyclic AMP levels to about 70% of the maximal response to the β‐adrenoceptor agonist isoprenaline.
Rolipram per se inhibited histamine‐stimulated [3H]‐inositol (poly)phosphate ([3H]‐InsPX) accumulation by >80% (−log EC50 (M), 6.92±0.11; n=3). Although ORG 9935 (1 μM) had little effect on histamine‐stimulated [3H]‐InsPX accumulation alone it greatly facilitated the inhibitory action of rolipram (−log EC50 (M), 8.82±0.39; n=3). The effects of PDE3 and/or PDE4 inhibition on [3H]‐InsPX accumulation stimulated by muscarinic acetylcholine (mACh) receptor activation were less marked. However, combined PDE3/4 inhibition significantly decreased this response at a submaximal concentration of mACh receptor agonist (carbachol; 1 μM).
The greater‐than‐additive effect of combined PDE3/4 inhibition was also observed at the level of contractile responses to histamine and carbachol. In experiments designed to investigate the effects of PDE3 and/or 4 inhibitors on the carbachol‐mediated phasic contraction, additions of rolipram (10 μM) or ORG 9935 (1 μM) were without effect, whereas added together the inhibitors caused a significant (P<0.01) 40% reduction in the peak phasic contractile response.
The effect on contraction correlated with a substantial inhibitory effect of PDE3/4 inhibition on the initial increase in inositol 1,4,5‐trisphosphate (InsP3) accumulation stimulated by spasmogen. Thus, in the presence of ORG 9935 (1 μM) rolipram concentration‐dependently inhibited carbachol‐stimulated InsP3 accumulation by 50% (−log EC50 (M), 6.77±0.21; n=4).
Carbachol (100 μM) addition caused a rapid decrease (by 67% at 10 s) in BTSM cyclic AMP level in the presence of PDE3/4 inhibition. However, omission of Ca2+ from the incubation medium prevented the carbachol‐evoked decrease in cyclic AMP and this coincided with a greater inhibition (80%) of the carbachol‐stimulated InsP3 response.
These data indicate that combined PDE3 and PDE4 inhibition has greater‐than‐additive effects on second messenger and functional responses to spasmogens in BTSM. Furthermore, the ability of PDE3/4 inhibition significantly to attenuate mACh receptor‐mediated contractile responses, may be, at least in part, attributed to an effect exerted at the level of InsP3 generation.
Electrophysiological and neurochemical evidence that pindolol has agonist properties at the 5‐HT1A autoreceptor in vivo
Authors: Clifford Elizabeth M , Gartside Sarah E , Umbers Valerie , Cowen Philip J , Hajós Mihály , Sharp Trevor 
Published: January 2005

It has been hypothesized that 5‐HT1A autoreceptor antagonists may enhance the therapeutic efficacy of SSRIs and other antidepressants. Although early clinical trials with the β‐adrenoceptor/5‐HT1 ligand, pindolol, were promising, the results of recent more extensive trials have been contradictory. Here we investigated the actions of pindolol at the 5‐HT1A autoreceptor by measuring its effect on 5‐HT neuronal activity and release in the anaesthetized rat.
Pindolol inhibited the electrical activity of 5‐HT neurones in the dorsal raphe nucleus (DRN). This effect was observed in the majority of neurones tested (10/16), was dose‐related (0.2–1.0 mg kg−1, i.v.), and was reversed by the 5‐HT1A receptor antagonist, WAY 100635 (0.1 mg kg−1, i.v.), in 6/7 cases tested.
Pindolol also inhibited 5‐HT neuronal activity when applied microiontophoretically into the DRN in 9/10 neurones tested. This effect of pindolol was current‐dependent and blocked by co‐application of WAY 100635 (3/3 neurones tested).
In microdialysis experiments, pindolol caused a dose‐related (0.8 and 4 mg kg−1, i.v.) fall in 5‐HT levels in dialysates from the frontal cortex (under conditions where the perfusion medium contained 1 μM citalopram). In rats pretreated with WAY 100635 (0.1 mg kg−1, i.v.), pindolol (4 mg kg−1, i.v.) did not decrease, but rather increased 5‐HT levels.
We conclude that, under the experimental conditions used in this study, pindolol displays agonist effects at the 5‐HT1A autoreceptor. These data are relevant to previous and ongoing clinical trials of pindolol in depression which are based on the rationale that the drug is an effective 5‐HT1A autoreceptor antagonist.
Effect of chronic bradykinin B2 receptor blockade on blood pressure of conscious Dahl salt‐resistant rats
Authors: Mukai Hiroya , Fitzgibbon Wayne R , Ploth David W , Margolius Harry S 
Published: January 2005

In this study 3 protocols were utilized to determine the role of endogenous kinins in the resistance of the inbred Dahl (Rapp) salt‐resistant (SR/Jr) rats to high salt diet‐induced blood pressure elevation.
The bradykinin B2 receptor antagonist, Hoe 140 (D‐Arg[Hyp3, Thi5, D‐Tic7, Oic8]‐bradykinin) at doses of either 10–20 or 20–40 nmol day−1 (subcutaneously (s.c), via osmotic minipumps, for either 1 or 3 weeks during a high (8%) salt diet) effectively blocked or attenuated the hypotensive responses to 100–1000 ng of bradykinin.
In the first protocol, 5 week old SR/Jr rats treated with Hoe 140 (10–20 nmol day−1, n=9, s.c., via osmotic minipumps) for 3 weeks and concomitantly fed high (8%) NaCl diet had significantly higher conscious tail cuff blood pressures (BPc) at 1 and 3 weeks when compared with rats treated with vehicle (0.9% NaCl, n=6). The differences in BPc between the 2 groups were 13 mmHg (P<0.001) after 1 week and 8 mmHg (P<0.05) after 3 weeks of treatment.
In the second protocol, 5 week old SR/Jr rats were treated with Hoe 140 (20–40 nmol day−1, n=8, s.c., via osmotic minipumps) or vehicle (n=8) for 3 weeks. During the first week of treatment the rats were fed normal (0.8%) NaCl diet. The rats were then switched to 8% NaCl for 2 remaining weeks of the protocol. The mean BPc of Hoe 140‐treated rats was not significantly different from that of the vehicle‐treated rats when fed 0.8% NaCl diet. In contrast, rats treated with Hoe 140 and concomitantly fed high (8%) NaCl diet had significantly increased BPc (123±2 vs 111±1 mmHg, P<0.001 for the Hoe 140‐ and vehicle‐treated rats, respectively).
In the third protocol, treatment with Hoe 140 (20–40 nmol day−1, s.c., via osmotic minipumps) during high salt diet did not increase BPc in rats that were pre‐exposed to the high salt diet for 2 weeks.
At the end of 3 weeks of study, blood pressure was measured via an arterial catheter during pentobarbitone‐induced anaesthesia. Rats treated with Hoe 140 for 1 or 3 weeks had significantly lower mean arterial blood pressures than the vehicle‐treated rats.
Our findings suggest that in SR/Jr rats, kinin activation of bradykinin B2 receptors at least partially contributes to early regulatory mechanisms that resist an increase in blood pressure following exposure to a high salt diet. The mechanism underlying the decreased blood pressure during pentobarbitone anaesthesia of SR/Jr rats chronically treated with Hoe 140 has yet to be elucidated.
Responses to endothelium‐dependent agonists in subcutaneous arteries excised from hypercholesterolaemic men
Authors: Lewis Tamara V , Cooper Bridget A , Dart Anthony M , Chin‐Dusting Jaye P F 
Published: January 2005

Vasomotor function of the vascular endothelium was examined in human subcutaneous arteries excised from 8 hypercholesterolaemic and 7 normolipidaemic subjects.
Left gluteal skin biopsies were performed under local anaesthesia. Subcutaneous arteries were isolated and two vessels from each subject mounted in separate myographs. A 20 ml fasting blood sample was taken at the time of the biopsy.
Hypercholesterolaemic subjects had either never been treated with lipid lowering therapy or therapy had been stopped at least two weeks before the study (n=2). At the time of the study total plasma cholesterol levels (control: 4.6±0.3 vs hypercholesterolaemic: 8.3±0.6 mmol l−1: P<0.01) were significantly elevated in hypercholesterolaemic subjects when compared with controls.
Full concentration‐response curves to the vasoconstrictor noradrenaline and the vasodilators acetylcholine and substance P were constructed. A single point concentration‐response to sodium nitroprusside (10 μM) was also obtained. Dilator responses were obtained in vessels pre‐constricted with a submaximal concentration of noradrenaline. Vessels were then incubated for 30 min with either L‐ or D‐arginine (10 μM) and the concentration‐response curves to the three dilator agonists repeated in the presence of the amino acid.
Maximum relaxation responses to acetylcholine (control vs hypercholesterolaemic: 83.3±6.1% vs 47.4±13.5%; P<0.05), but not to substance P or sodium nitroprusside, were dampened in the hypercholesterolaemic group when compared with controls.
Neither incubation with L‐arginine nor D‐arginine had any effect on maximum relaxation responses to acetylcholine in either the control group (pre L‐arginine vs plus L‐arginine: 83.3±6.1 vs 82.3±5.5%, pre D‐arginine vs plus D‐arginine: 98.9±1.2 vs 98.2±1.1%) or the hypercholesterolaemic group (pre L‐arginine vs plus L‐arginine: 47.4±13.5 vs 55.3±14.3%, pre D‐arginine vs plus D‐argenine: 43.3±13.6 vs 65.4±12.3%).
When results from the two study groups were pooled, the strongest predictor of maximum relaxation obtained to acetylcholine was apolipoprotein A1 (r=0.67; P=0.001).
In conclusion, relaxation responses mediated by the endothelium‐dependent agonist acetylcholine, but not by substance P, are impaired in hypercholesterolaemic patients. L‐Arginine did not improve the impaired relaxation responses to acetylcholine. We suggest that impaired endothelium‐dependent relaxation is specific to acetylcholine and not to an abnormal L‐arginine‐nitric oxide pathway in subcutaneous arteries excised from this study group.
Irreversible binding of a carbostyril‐based agonist and antagonist to the β‐adrenoceptor in DDT1 MF‐2 cells and rat aorta
Authors: Deyrup Malgorzata D , Greco Phillip G , Otero Deborah H , Dennis Donn M , Gelband Craig H , Baker Stephen P 
Published: January 2005

The chemoreactive ligands 5(2‐(((1′‐(4′‐isothiocyanatophenylamino)thiocarbonyl)‐amino)‐2‐methyl‐propyl)amino‐2‐hydroxypropoxy)‐3,4‐dihydrocarbostyril (DCITC) and 8‐hydroxy‐5(2‐(((1′‐(4′‐isothiocya‐natophenylamino)thiocarbonyl)amino)‐2‐methylprop‐2‐yl)amino‐1‐hydroxyethyl)‐carbostyril (HCITC)were synthesized and shown to be potent irreversible antagonist and agonist ligands, respectively, for the β‐adrenoceptor in DDT1 MF‐2 (DDT) cells and the rat isolated aorta.
In DDT cell membranes DCITC and HCITC inhibited (−)[125I]‐iodocyanopindolol (CYP) binding to the β‐adrenoceptor with IC50 values of 1.1 and 18 nM, respectively. (−)‐Isoprenaline inhibited [125I]‐CYP binding with an IC50 of 355 nM. Pretreatment of membranes with either chemoreactive ligand produced a time‐ and concentration‐dependent decrease in the β‐adrenoceptor content, indicating irreversible receptor binding. DCITC at concentrations up to 10 μM did not stimulate cyclic AMP accumulation in DDT cells nor did it amplify forskolin‐stimulated cyclic AMP accumulation.
In the rat isolated aorta, DCITC (0.1 μM) did not affect either the phenylephrine‐mediated tissue contraction or the acetylcholine‐mediated relaxation. DCITC attenuated the maximal (−)‐isoprenaline‐mediated relaxation of a phenylephrine contracted aorta in a concentration‐dependent manner and shifted the dose‐response curves for (−)‐isoprenaline to the right. The DCITC‐induced decrease in maximal response was not reversed by extensive tissue washing. By use of the operational model of agonism, the calculated dissociation constant for (−)‐isoprenaline ws 286 nM and the estimated receptor reserve for this agonist was 23% at the maximal response.
HCITC and (−)‐isoprenaline stimulated cyclic AMP accumulation in DDT cells with pD2 values (negative logarithm to base 10 of EC50) of 7.95 and 7.97, respectively, and both mediated the same maximal stimulation. In the rat isolated aorta, HCITC produced a concentration‐dependent relaxation of the tissue with a pD2 value of 6.62, whereas the pD2 for (−)‐isoprenaline was 7.03. However, HCITC produced a greater maximal relaxation of the tissue than (−)‐isoprenaline. The HCITC‐mediated stimulation of cyclic AMP accumulation and relaxation of the isolated tissue were blocked when the β‐antagonist propranolol was added concurrently. In contrast, once the HCITC‐mediated responses were established, the addition of propranolol did not result in any attenuation indicating that HCITC is an irreversible β‐agonist.