bluuebunny/crossref_metadata_2025_split huggingface dataset:
A MODEL TO FACILITATE OUTCOME ASSESSMENT OF OBSTRUCTIVE SLEEP APNEA
Authors: Sonnad Seema S. , Moyer Cheryl A. , Patel Shushma , Helman Joseph I. , Garetz Susan L. , Chervin Ronald D. 
Published: February 2003

Objectives: Obstructive sleep apnea is a common disorder with significant morbidity and effects on quality of life. Management can include a range of mechanical, behavioral, and surgical approaches. This paper aims to devise a model of management options to assist in initial cost-effectiveness investigations.Methods: In the absence of practice pattern data and widely accepted guidelines, we reviewed published literature and devised a model of treatment options to facilitate initial studies of outcomes, costs, and cost-effectiveness.Results: Obstructive sleep apnea is rarely addressed by conservative behavioral-based strategies because these options, while inexpensive, have only limited effectiveness. Effective treatment most often relies on nasal continuous positive airway pressure, but poor tolerance or compliance sometimes leads to treatment with oral appliances or surgery. Patients treated by one modality may try another if the initial strategy is ineffective. Laboratory evidence that sleep apnea is effectively treated, and long-term follow-up, are necessary regardless of the treatment modality chosen.Conclusions: Each patient's treatment plan must be individually tailored, but the management model proposed here reflects available evidence-based literature and the authors' impression of current practice patterns. This model should be useful for initial cost-effectiveness investigations.
Implication of nigral tachykinin NK3 receptors in the maintenance of hypertension in spontaneously hypertensive rats: a pharmacologic and autoradiographic study
Authors: Lessard Andrée , Campos Maria M , Neugebauer Witold , Couture Réjean 
Published: February 2003

The role of nigral tachykinin NK1, NK2 and NK3 receptors in central cardiovascular regulation was studied by measuring the effects of selective agonists and antagonists on mean arterial pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra of spontaneously hypertensive rats (SHR). Quantitative in vitro autoradiography was also performed in the midbrain of SHR and Wistar‐Kyoto (WKY) with the NK3 receptor ligand [125I]‐HPP‐Senktide.
Tachycardia was elicited by the NK1 ([Sar9,Met(O2)11]SP) and NK2 ([βAla8]NKA(4‐10)) agonists at 25 and 100 pmol while the NK3 agonist (senktide, 50 and 100 pmol) had no significant effect. The three agonists had no effect on behaviour, and increases in MAP were elicited by the NK1 agonist only.
Whereas antagonists at NK1 (RP 67580, 500 pmol) and NK2 (SR 48968, 500 pmol) receptors had no significant effect on MAP and HR, the NK3 antagonist (R‐820, 500 pmol) reduced MAP for over 3 h in SHR. That anti‐hypertensive effect did not occur after intracerebroventricular or intravenous injection of R‐820. Also, R‐820 had no cardiovascular effect in WKY.
The affinity (KD: 0.7 nM) and densities of specific NK3 receptor binding sites measured in the substantia nigra, ventral tegmental area, hippocampus and amygdala were not significantly different in SHR and WKY.
It is concluded that endogenous tachykinins exert a tonic activity on NK3 receptors in the substantia nigra of SHR to maintain high blood pressure. Hence, nigral tachykinin NK3 receptors may represent a promising therapeutic target in the treatment of arterial hypertension.

British Journal of Pharmacology (2003) 138, 554–563. doi:10.1038/sj.bjp.0705042
Inhibition of intestinal dipeptide transport by the neuropeptide VIP is an anti‐absorptive effect via the VPAC1 receptor in a human enterocyte‐like cell line (Caco‐2)
Authors: Anderson Catriona M H , Mendoza Maria E , Kennedy David J , Raldua Demetrio , Thwaites David T 
Published: February 2003

Optimal dipeptide and peptidomimetic drug transport across the intestinal mucosal surface is dependent upon the co‐operative functional activity of the di/tripeptide transporter hPepT1 and the Na+/H+ exchanger NHE3. The ability of the anti‐absorptive enteric neuropeptide VIP (vasoactive intestinal peptide) to modulate dipeptide uptake was determined using human intestinal (Caco‐2) epithelial cell monolayers.
Uptake of glycylsarcosine (Gly‐Sar) across the apical membrane of Caco‐2 cell monolayers is inhibited by basolateral exposure to either VIP, pituitary adenylate cyclase‐activating polypeptide (PACAP), or the VPAC1 receptor agonist [11,22,28Ala]‐VIP. Inhibition of Gly‐Sar uptake is observed only in the presence of extracellular Na+. Reverse‐transcription polymerase chain reaction (RT–PCR) demonstrates that VPAC1 mRNA is expressed in Caco‐2 cells whereas VPAC2 mRNA is not detected.
The VIP‐induced inhibition of Gly‐Sar uptake is abolished in the presence of the protein kinase A (PKA) inhibitor H‐89 (N‐[2‐(p‐bromocinnamylamino)ethyl]‐5‐isoquinolinesulfonamide.2HCl).
22Na+ uptake across the apical membrane is inhibited by the selective NHE3 inhibitor S1611. Experiments with BCECF [2′,7′‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein]‐loaded Caco‐2 cells demonstrate that VIP reduces the NHE3‐dependent recovery of intracellular pH (pHi) after dipeptide‐induced acidification. Western blot of Caco‐2 cell protein demonstrates expression of the NHE regulatory factor NHERF1 (expression of which is thought to be required for PKA‐mediated inhibition of NHE3).
VIP has no effect on Gly‐Sar uptake in the presence of S1611 suggesting that VIP and S1611 both modulate dipeptide uptake via the same mechanism.
These observations demonstrate that VIP (and PACAP) modulate activity of the H+/dipeptide transporter hPepT1 in a Na+‐dependent manner consistent with the modulation being indirect through inhibition of NHE3.

British Journal of Pharmacology (2003) 138, 564–573. doi:10.1038/sj.bjp.0705049
Selective blockade of endothelial Ca2+‐activated small‐ and intermediate‐conductance K+‐channels suppresses EDHF‐mediated vasodilation
Authors: Eichler Ines , Wibawa Judith , Grgic Ivica , Knorr Andrea , Brakemeier Susanne , Pries Axel R , Hoyer Joachim , Köhler Ralf 
Published: February 2003

Activation of Ca2+‐activated K+‐channels (KCa) has been suggested to play a key role in endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation. However, due to the low selectivity of commonly used KCa‐channel blockers it is still elusive which endothelial KCa‐subtypes mediate hyperpolarization and thus initiate EDHF‐mediated vasodilation.
Using the non‐cytochrome P450 blocking clotrimazole‐derivatives, 1‐[(2‐chlorophenyl) diphenylmethyl]‐1H‐pyrazole (TRAM‐34) and 2‐(2‐chlorophenyl)‐2,2‐diphenylacetonitrile (TRAM‐39) as highly selective IK1‐inhibitors, we investigated the role of the intermediate‐conductance KCa (rIK1) in endothelial hyperpolarization and EDHF‐mediated vasodilation.
Expression and function of rIK1 and small‐conductance KCa (rSK3) were demonstrated in situ in single endothelial cells of rat carotid arteries (CA). rIK1‐currents were blocked by TRAM‐34 or TRAM‐39, while rSK3 was blocked by apamin. In current‐clamp experiments, endothelial hyperpolarization in response to acetylcholine was abolished by the combination of apamin and TRAM‐34.
In phenylephrine‐preconstricted CA, acetylcholine‐induced NO and prostacyclin‐independent vasodilation was almost completely blocked by ChTX, CLT, TRAM‐34, or TRAM‐39 in combination with the SK3‐blocker apamin. Apamin, TRAM‐34, and CLT alone or sulphaphenzole, a blocker of the cytochrome P450 isoform 2C9, were ineffective in blocking the EDHF‐response.
In experiments without blocking NO and prostacyclin synthesis, the combined blockade of SK3 and IK1 reduced endothelium‐dependent vasodilation.
In conclusion, the use of selective IK1‐inhibitors together with the SK3‐blocker apamin revealed that activation of both KCa, rIK1 and rSK3 is crucial in mediating endothelial hyperpolarization and generation of the EDHF‐signal while the cytochrome P450 pathway seems to play a minor or no role in rat CA.

British Journal of Pharmacology (2003) 138, 594–601. doi:10.1038/sj.bjp.0705075
The cyclopentenone prostaglandin 15‐deoxy‐Δ12,14‐ PGJ2 attenuates the development of colon injury caused by dinitrobenzene sulphonic acid in the rat
Authors: Cuzzocrea Salvatore , Ianaro Angela , Wayman Nicole S , Mazzon Emanuela , Pisano Barbara , Dugo Laura , Serraino Ivana , Di Paola Rosanna , Chatterjee Prabal K , Di Rosa Massimo , Caputi Achille P , Thiemermann Christoph 
Published: February 2003

Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and increased expression of the adhesion molecules intercellular adhesion molecule 1 (ICAM‐1) in the colon. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15‐deoxy‐Δ12,14‐PGJ2 (15d‐ PGJ2) functions as an early anti‐inflammatory signal.
The aim of the present paper is to investigate the effects of 15d‐PGJ2 in rats subjected to experimental colitis.
Colitis was induced in rats by intra‐colonic instillation of dinitrobenzene sulphonic acid (DNBS). 15d‐PGJ2 was administered daily as intraperitoneal injection (20 or 40 μg kg−1). On day 4, animals were sacrificed and tissues were taken for histological and biochemical analysis.
15d‐PGJ2 significantly reduced the degree of haemorrhagic diarrhoea and weight loss caused by administration of DNBS. 15d‐PGJ2 also caused a substantial reduction of (i) the degree of colonic injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in the tissue levels of malondialdehyde (MDA) and (iv) of the pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐α) and interleukin‐1β (IL‐1β).
Furthermore, 15d‐PGJ2 reduced the increase in immunohistochemical staining for (i) inducible nitric oxide synthase (iNOS), (ii) nitrotyrosine and (iii) poly (ADP‐ribose) polymerase (PARP), as well as (iv) the increased expression of ICAM‐1 caused by DNBS in the colon.
Electrophoresis mobility shift assay (EMSA) of inflamed colon revealed that 15d‐ PGJ2 also caused a substantial reduction of the activation of nuclear factor‐kappaB (NF‐κB). Furthermore, 15d‐PGJ2 stimulates the activation of heat shock protein 72 (hsp72) in the inflamed colon, as assessed by Western blot analysis.
In conclusion, 15d‐PGJ2 reduces the development of experimental colitis.

British Journal of Pharmacology (2003) 138, 678–688. doi:10.1038/sj.bjp.0705077
Effects of acetaminophen on constitutive and inducible prostanoid biosynthesis in human blood cells
Authors: Sciulli Maria G , Seta Francesca , Tacconelli Stefania , Capone Marta L , Ricciotti Emanuela , Pistritto Giuseppa , Patrignani Paola 
Published: February 2003

Acetaminophen, an analgesic and antipyretic drug with weak antiinflammatory properties, has been suggested to act as a tissue‐selective inhibitor of prostaglandin H synthases (PGHSs) (e.g. COX‐1 and COX‐2) through its reducing activity, that is influenced by the different cellular levels of peroxides.
We have studied the effects of acetaminophen on inducible and constitutive prostanoid biosynthesis in monocytes and platelets in vitro. To discriminate between the inhibitory effect of the drug on PGHS‐isozymes vs PGE‐synthases (PGESs), parallel measurements of PGE2 and thromboxane (TX) B2 were carried out. Since antioxidant enzymes and cofactors, present in plasma, may affect acetaminophen‐dependent inhibition of prostanoids, comparative experiments in whole blood vs isolated monocytes were performed.
Acetaminophen inhibited LPS‐induced whole blood PGE2 and TXB2 production, in a concentration‐dependent fashion [IC50 μM (95% confidence intervals): 44 (27–70) and 94 (79–112), respectively]. Therapeutic plasma concentrations (100 and 300 μM) of the drug more profoundly reduced PGE2 than TXB2 (71±3 vs 54±4 and 95±0.8 vs 78±2%, respectively, mean±s.e.mean, n=6, P<0.01).
Differently, in isolated monocytes stimulated with LPS, both PGE2 and TXB2 production was maximally reduced by only 60%.
At 100 and 300 μM, the drug caused a similar and incomplete inhibition of platelet PGE2 and TXB2 production during whole blood clotting (45±4 vs 54±4 and 75±2 vs 75±1%, respectively, mean±s.e.mean, n=4).
In conclusion, therapeutic concentrations of acetaminophen caused an incomplete inhibition of platelet COX‐1 and monocyte COX‐2 but in the presence of plasma, the drug almost completely suppressed inducible PGE2 biosynthesis through its inhibitory effects on both COX‐2 and inducible PGES.

British Journal of Pharmacology (2003) 138, 634–641. doi:10.1038/sj.bjp.0705078
Nitric oxide, superoxide, and peroxynitrite in myocardial ischaemia‐reperfusion injury and preconditioning
Authors: Ferdinandy Péter , Schulz Richard 
Published: February 2003

There appears to be a controversy in the study of myocardial ischaemia‐reperfusion injury and preconditioning whether nitric oxide (NO) plays a protective or detrimental role. A number of findings and the interpretation of the results to date do not support such a controversy. An understanding of the latest developments in NO, superoxide (O2−·) and peroxynitrite (ONOO−) biology, as well as the various ischaemic animal models utilized is necessary to resolve the apparent controversy. NO is an important cardioprotective molecule via its vasodilator, antioxidant, antiplatelet, and antineutrophil actions and it is essential for normal heart function. However, NO is detrimental if it combines with O2−· to form ONOO− which rapidly decomposes to highly reactive oxidant species. There is a critical balance between cellular concentrations of NO, O2−·, and superoxide dismutase which physiologically favour NO production but in pathological conditions such as ischaemia and reperfusion result in ONOO− formation. In contrast, exposure of the heart to brief episode(s) of ischaemia markedly enhances its ability to withstand a subsequent ischaemic injury. The triggering of this endogenous cardioprotective mechanism known as preconditioning requires both NO and O2−· synthesis. However, preconditioning in turn attenuates the overproduction of NO, O2−· and ONOO− during a subsequent episode of ischaemia and reperfusion, thereby protecting the heart. Here we review the roles of NO, O2−·, and ONOO− in both ischaemia‐reperfusion injury and preconditioning.British Journal of Pharmacology (2003) 138, 532–543. doi:10.1038/sj.bjp.0705080
Differential engagements of glutamate and GABA receptors in cardiovascular actions of endogenous nNOS or iNOS at rostral ventrolateral medulla of rats
Authors: Chan Samuel H H , Wang Ling‐Lin , Chan Julie Y H 
Published: February 2003

We evaluated in Sprague–Dawley rats anaesthetized with propofol the engagement of soluble guanylyl cyclase (sGC)/cGMP cascade, glutamatergic and GABAergic neurotransmission in the cardiovascular actions of endogenous nitric oxide (NO) at the rostral ventrolateral medulla (RVLM).
Microinjection bilaterally into the RVLM of a selective iNOS inhibitor, S‐methylisothiourea (SMT, 250 pmoles), or a selective nNOS inhibitor, 7‐nitroindazole (7‐NI, 5 pmoles), induced respectively an enhancement or a reduction in systemic arterial pressure, heart rate and power density of the vasomotor components in the spectrum of arterial blood pressure signals, our experimental index for sympathetic neurogenic vasomotor tone.
The cardiovascular actions of SMT or 7‐NI in the RVLM were significantly antagonized by co‐administration into the RVLM of the sGC inhibitor, 1H‐[1,2,4]Oxadiazole[4,3‐α]quinoxalin‐1‐one (ODQ, 250 or 500 pmoles).
The cardiovascular excitatory effects after blockade of endogenous iNOS activity were significantly attenuated when N‐methyl‐D‐aspartate (NMDA) receptor antagonist, dizocilpine (20 or 50 pmoles), or non‐NMDA receptor antagonist, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (250 or 500 pmoles), was co‐microinjected bilaterally into the RVLM.
On the other hand, the cardiovascular depressive responses to blockade of endogenous nNOS activity were significantly antagonized on co‐administration of GABAA receptor antagonist, bicuculline methiodine (5 or 10 pmoles), but not GABAB receptor antagonist, 2‐hydroxy saclofen (50 or 100 pmoles).
We conclude that the cardiovascular actions of endogenous NO in the RVLM engage the sGC/cGMP pathway. In addition, whereas NO derived from nNOS induced sympathoexcitation via both NMDA and non‐NMDA receptors in the RVLM, NO generated by iNOS elicited sympathoinhibition via GABAA receptors.

British Journal of Pharmacology (2003) 138, 584–593. doi:10.1038/sj.bjp.0705081
The ACh‐induced contraction in rat aortas is mediated by the Cys Lt1 receptor via intracellular calcium mobilization in smooth muscle cells
Authors: Mazzetti Luca , Franchi‐Micheli Sergio , Nistri Silvia , Quattrone Silvia , Simone Ruggero , Ciuffi Mario , Zilletti Lucilla , Failli Paola 
Published: February 2003

Our previously published data indicate that an endogenously produced 5‐lipoxygenase metabolite can strongly contract isolated endothelium‐preserved rat aortic strips when cyclo‐oxygenase isoenzymes are inhibited. Therefore, we decided to investigate if cysteinyl‐containing leukotrienes (Cys Lts) are involved in this endothelium‐dependent contraction.
The isometric contraction of endothelium‐preserved rat aortic strips was recorded in preparations preincubated with 5 μM indomethacin and precontracted with phenylephrine, adjusting resting tension at 0.7 g. Acetylcholine (ACh) contracted control strips. Montelukast and MK‐571, selective type 1 Cys Lts receptor (Cys Lt1) antagonists and the Cys Lt1/Cys Lt2 (type 2 Cys Lts receptor) antagonist BAYu9773 dose‐dependently prevented ACh‐induced contraction, their IC50s being 2.2, 3.1 and 7.9 nM respectively. The leukotriene B4 receptor antagonist U75302 was far less potent (IC50 1.5 μM).
In rat aorta smooth muscle cells (RASMs), Western blot analysis showed the presence of Cys Lt1 and Cys Lt2 receptors, the Cys Lt1 receptor being predominantly expressed.
In fura‐2 loaded RASMs, LTD4 (0.01–100 nM) and LTC4 (200–800 nM) dose‐dependently increased intracellular calcium concentration ([Ca2+]i). Montelukast (1–100 nM) reduced LTD4‐induced [Ca2+]i increase, its IC50 being approximately 10 nM. BAY u9773 exhibited significantly low effectiveness.
LTD4 (10 nM) induced a redistribution of smooth muscle actin fibres throughout the cytoplasm as visualized by confocal microscopy.
In conclusion, Cys Lt1 activation by endogenously produced Cys Lts, can contract rat aortas, while Cys Lt2 only marginally influences aortic tone. Intracellularly, this effect is mediated by an increase in [Ca2+]i. Therefore, Cys Lts, by inducing vascular contraction, can contribute to systemic hypertension.

British Journal of Pharmacology (2003) 138, 707–715. doi:10.1038/sj.bjp.0705087
Comparison of human recombinant adenosine A2B receptor function assessed by Fluo‐3‐AM fluorometry and microphysiometry
Authors: Patel H , Porter R H P , Palmer A M , Croucher M J 
Published: February 2003

The aim of this study was to establish the utility of a fluorometric imaging plate reader (FLIPR) assay to assess human adenosine A2B receptor function by characterizing its receptor pharmacology and comparing this profile to that obtained using a microphysiometer.
FLIPR was used, in conjunction with a Ca2+‐sensitive dye (Fluo‐3‐AM), to measure rapid rises in intracellular calcium in a Chinese Hamster Ovary (CHO‐K1) cell line stably transfected with both the human A2B receptor and a promiscuous Gα16 protein. Microphysiometry was used to measure rapid changes in the rate of extracellular acidification in a Human Embryonic Kidney (HEK‐293) cell line also stably transfected with human A2B receptor.
Activation of A2B receptors by various ligands caused a concentration‐dependent increase in both the intracellular calcium concentration and the extracellular acidification rate in the cells tested, with a similar rank order of potency for agonists: NECA>N6‐Benzyl NECA>adenosineR‐PIA>CPA>S‐PIA>CHA>CGS 21680. No comparable effects were observed in the non‐transfected control cell lines.
The rank order of potency of the agonists examined was the same in all studies, whereas absolute potency and efficacy varied. Thus, all compounds exhibited greater potency in FLIPR than the microphysiometer and the efficacies obtained with CHO‐K1+Gα16+A2B cell line and FLIPR were greater than those obtained with HEK‐293+A2B cell line in the microphysiometer.
ZM‐241385 was the most potent of a range of adenosine antagonists tested with a pA2 of 8.0 in both the FLIPR and microphysiometer assays.
In conclusion, the profile of the responses to both A2B receptor agonists and antagonists in FLIPR were similar to those obtained by the microphysiometer, although both potency and efficacy values were higher in the FLIPR assay. With this caveat in mind, this study shows that FLIPR coupled with a cell line transfected with both the human A2B receptor and a promiscuous Gα16 protein provides a useful, high throughput method for the assessment of A2B receptor function.

British Journal of Pharmacology (2003) 138, 671–677. doi:10.1038/sj.bjp.0705091
Expression of prostanoid receptors in human ductus arteriosus
Authors: Leonhardt Andreas , Glaser Alexander , Wegmann Markus , Schranz Dietmar , Seyberth Hannsjörg , Nüsing Rolf 
Published: February 2003

Prostaglandins play a major role in maintaining ductal patency in utero. Ductal tone is regulated by both locally released and circulating vasodilatory prostaglandins. In infants with ductus arteriosus‐dependent congenital heart disease, ductal patency is maintained by intravenous administration of prostaglandin (PG) E1. Little information is available regarding the expression of prostaglandin receptors in man.
By means of RT–PCR and immunohistochemistry we studied the expression of the PGI2 receptor (IP), the four different PGE2 receptors (EP1, EP2, EP3 and EP4), and the receptors for thromboxane (Tx) A2 (TP), PGD2 (DP) and PGF2α (FP) in the ductus arteriosus of three newborn infants with ductus arteriosus‐dependent congenital heart disease and intravenous infusion of PGE1 and of one 8 month old child with a patent ductus arteriosus.
The EP3, EP4, FP, IP and TP receptor were markedly expressed at the mRNA and protein level, whereas the EP2 receptor was weakly expressed and the EP1 receptor was detected in two out of four tissue specimens only. The DP receptor was not detected in any of the samples. The most pronounced expression, which was located in the media of the ductus arteriosus, was observed for the EP4 and TP receptors followed by IP and FP receptor protein.
These data indicate that ductal patency during the infusion of PGE1 in infants with ductus arteriosus‐dependent congenital heart disease might be mediated by the EP4 and IP receptor. The data further suggest that a heterogeneous population of prostanoid receptors may contribute to the regulation of ductus arteriosus tone in humans.

British Journal of Pharmacology (2003) 138, 655–659. doi:10.1038/sj.bjp.0705092