European Journal of Pharmacology (v.517, #3)

Cross-talk between adenosine and the oxatriazole derivative GEA 3175 in platelets by Anna Asplund Persson; Stefan Zalavary; Eva Lindström; Per A. Whiss; Torbjörn Bengtsson; Magnus Grenegård (149-157).
We examined the interplay between adenosine and the nitric oxide (NO)-containing oxatriazole derivative GEA 3175 in human platelets. The importance of cyclic guanosine 3′5′-monophosphate (cGMP)-inhibited phosphodiesterases (PDEs) was elucidated by treating the platelets with adenosine combined with either GEA 3175 or the PDE3-inhibitor milrinone. The drug combinations provoked similar cyclic adenosine 3′5′-monophosphate (cAMP) responses. On the contrary, cGMP levels were increased only in GEA 3175-treated platelets. Both drug combinations reduced P-selectin exposure, platelet adhesion and fibrinogen-binding. However, adenosine together with GEA 3175 was more effective in inhibiting platelet aggregation and ATP release. Thrombin-induced rises in cytosolic Ca2+ were suppressed by the two drug combinations. Adenosine administered with GEA 3175 was, however, more effective in reducing Ca2+ influx.In conclusion, the interaction between adenosine and GEA 3175 involves cGMP-mediated inhibition of PDE3. The results also imply that inhibition of Ca2+ influx represent another cGMP-specific mechanism that enhances the effect of adenosine.
Keywords: Adenosine; Calcium; cAMP; cGMP; GEA 3175; Milrinone; Nitric oxide; Phosphodiesterases; Platelets;

Aspirin inhibits NF-κB activation in a glycolysis-depleted lung epithelial cell line by Eduardo Cuesta; Jordi Boada; Jose C. Perales; Teresa Roig; Jordi Bermudez (158-164).
Inhibition of glycolysis at the phosphofructo-1-kinase step slows cell growth. For this reason, overexpression of fructose-2,6-bisphosphatase is a potential target for antineoplasic treatments. However, therapeutic objectives may be compromised by side effects of glycolysis restriction, including enhanced resistance to oxidants and tumor necrosis factor-alpha (TNF-α), as well as increased activity of the nuclear factor kappa B (NF-κB). In this study we evaluated aspirin as an adjuvant drug for glycolysis restriction by overexpression of fructose-2,6-bisphosphatase. The effect of aspirin on antioxidant defences and NF-κB activity were evaluated both in control cells and in fructose-2,6-bisphosphatase-overexpressing cells. Interestingly, aspirin-induced inhibition of NF-κB activity was greater in transfectants with restricted glycolysis than in control cells. Our results indicate that aspirin is a suitable complement to therapy based on glycolysis restriction to overcome resistance associated with increased NF-κB activity and oxidative stress.
Keywords: Glycolysis; 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; Fructose 2,6-bisphosphate; Pentose phosphate pathway; Aspirin; Apoptosis; Glutathione peroxidase; Glutathione; Nuclear factor kappa B;

In vitro profile of the antidepressant candidate OPC-14523 at rat and human 5-HT1A receptors by Shaun Jordan; Ruoyan Chen; Vuk Koprivica; Ronald Hamilton; Richard E. Whitehead; Katsura Tottori; Tetsuro Kikuchi (165-173).
This study determined the in vitro functional profile of 1-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-5-methoxy-3,4-dihydro-2-quinolinone monomethanesulfonate (OPC-14523) at rat and human serotonin (5-HT) 5-HT1A receptors and binding affinity of OPC-14523 at human frontocortical 5-HT1A receptors. OPC-14523 (1 μM) increased guanosine-5′-O-(3-[35S]thio)-triphosphate ([35S]GTPγS) binding to 5-HT1A receptor-containing regions of rat brain tissue sections (∼53% of the effect of 1 μM (+)8-hydroxy-2-(di-n-propylamino)tetralin ((+)8-OH-DPAT) that were blocked by the selective 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635). OPC-14523 also behaved as a partial agonist in its stimulation of [35S]GTPγS binding to membranes from rat hippocampus (pEC50  = 7.60 ± 0.23, E max  = 41.1% of the effect of 10 μM (+)8-OH-DPAT), human frontal cortex (pEC50  = 7.89 ± 0.08; E max  = 64% of the effect of 10 μM (+)8-OH-DPAT), and Chinese Hamster Ovary cells expressing cloned human 5-HT1A receptors (pEC50  = 8.0 ± 0.11; E max  = 85.5% of the effect of 10 μM 5-HT), and all of these effects of OPC-14523 were blocked by WAY-100635. Taken together, these data support the development of OPC-14523 as an antidepressant whose mechanism of action involves potent partial agonist activity at 5-HT1A receptors.
Keywords: OPC-14523; Depression; Serotonin;

Anandamide induced PPARγ transcriptional activation and 3T3-L1 preadipocyte differentiation by Monsif Bouaboula; Sandrine Hilairet; Jean Marchand; Lluis Fajas; Gerard Le Fur; Pierre Casellas (174-181).
We investigated the effects of anandamide on peroxisome proliferator-activated receptor γ (PPARγ) activity. In two different transactivation systems using either full-length or only the ligand binding domain of PPARγ, we showed that anandamide, but not palmitoylethanolamide induced transcriptional activation of PPARγ in a dose dependent manner with an EC50 of 8 μM. In addition, competition binding experiments showed that anandamide but not palmitoylethanolamide binds directly to PPAR-ligand binding domain. We also found that anandamide treatment induced 3T3-L1 fibroblast differentiation into adipocytes. Indeed, anandamide induced triglyceride droplet accumulation and the expression of PPARγ responsive genes such as CCAAT enhancer binding protein α (C-EBPα), aP2, PerilipinA and Acrp30. Furthermore, the PPARγ antagonist (GW9662) inhibited the anandamide-induced 3T3-L1 differentiation confirming that this is a PPARγ-mediated process. Altogether, these data indicate that anandamide binds PPARγ and induces cellular PPARγ signaling.
Keywords: Anandamide; PPARγ; 3T3-L1; Adipocyte;

To clarify the receptor subtype(s) contributing to the RhoA activation by endothelin-1 in bronchial smooth muscle, the effects of BQ-123 [cycro(D-Asp-Pro-D-Val-Leu-D-Trp)], an endothelin ETA receptor antagonist, and/or BQ-788 [2,6-dimethylpiperidinecarbonyl-g-methyl-Leu-Nin-(Methoxycarbonyl)-D-Trp-D-Nle], an endothelin ETB receptor antagonist, on the endothelin-1-induced translocation of RhoA to plasma membrane were examined. Incubation of rat bronchial smooth muscle with endothelin-1 induced a distinct translocation of RhoA to plasma membrane, indicating an activation of RhoA by endothelin-1. The endothelin-1-induced translocation of RhoA was completely blocked by treatment with BQ-123, whereas BQ-788 had no effect. Thus, endothelin ETA but not ETB receptors might be involved in the endothelin-1-induced translocation of RhoA in rat bronchial smooth muscle.
Keywords: Bronchial smooth muscle; RhoA translocation; Endothelin-1;

Intravenous butyrylcholinesterase administration and plasma and brain levels of cocaine and metabolites in rats by Gilberto N. Carmona; Charles W. Schindler; Nigel H. Greig; Harold W. Holloway; Rebecca A. Jufer; Edward J. Cone; David A. Gorelick (186-190).
Butyrylcholinesterase is a major cocaine-metabolizing enzyme in humans and other primates, catalyzing hydrolysis to ecgonine methylester. Increasing butyrylcholinesterase activity may be a treatment for cocaine addiction. We evaluated the effect of 30-min pretreatment with horse-derived butyrylcholinesterase (5–15,000 U i.v.) or with the selective butyrylcholinesterase inhibitor cymserine (10 mg/kg i.v.) on the metabolism of cocaine (17 mg/kg i.p.) in anesthetized rats. Venous blood samples were collected for two hours after cocaine administration and later assayed for cocaine and metabolites by gas chromatography/mass spectroscopy. Whole brains were collected after the last blood sample and similarly assayed. Butyrylcholinesterase significantly increased plasma and brain ecgonine methylester levels and decreased cocaine plasma half-life from 26.2 min (saline) to 16.4 min (15,000 U). Butyrylcholinesterase had no significant effect on plasma or brain cocaine or benzoylecgonine levels. Cymserine had no effect on any variable. These findings suggest that butyrylcholinesterase treatment may have benefits in enhancing cocaine metabolism and in increasing levels of ecgonine methylester, which may have a protective action against cocaine.
Keywords: Cocaine; Butyrylcholinesterase; Ecgonine methylester; Cymserine; Benzoylecgonine; (Rat);

Suppressive effects of isorhynchophylline on 5-HT2A receptor function in the brain: Behavioural and electrophysiological studies by Kinzo Matsumoto; Ryo Morishige; Yukihisa Murakami; Michihisa Tohda; Hiromitsu Takayama; Iwao Sakakibara; Hiroshi Watanabe (191-199).
Isorhynchophylline is a major oxindole alkaloid found in Uncaria species which have long been used in traditional Chinese medicine. Here, we investigated the effects of isorhynchophylline and isorhynchophylline-related alkaloids on 5-hydroxytryptamine (5-HT) receptor-mediated behavioural responses in mice and 5-HT-evoked current responses in Xenopus oocytes expressing 5-HT2A or 5-HT2C receptors. Isorhynchophylline dose-dependently inhibited 5-HT2A receptor-mediated head-twitch but not 5-HT1A receptor-mediated head-weaving responses evoked by 5-methoxy-N,N-dimethyltryptamine. Pretreatment with reserpine, a monoamine-depleting agent, enhanced the head-twitching, but did not influence the effect of isorhynchophylline on the behavioural response. Isocorynoxeine, an isorhynchophylline-related alkaloid in which the configuration of the oxindole moiety is the same as in isorhynchophylline, also reduced the head-twitch response in reserpinized mice over the same dose range as isorhynchophylline, while both rhynchophylline and corynoxeine, stereoisomers of isorhynchophylline and isocorynoxeine, did not. None of the alkaloids tested had an effect on meta-chlorophenylpiperazine-induced hypolocomotion, a 5-HT2C receptor-mediated behavioural response. In experiments in vitro, isorhynchophylline and isocorynoxeine dose-dependently and competitively inhibited 5-HT-evoked currents in Xenopus oocytes expressing 5-HT2A receptors, but had less of a suppressive effect on those in oocytes expressing 5-HT2C receptors. These results indicate that isorhynchophylline and isocorynoxeine preferentially suppress 5-HT2A receptor function in the brain probably via a competitive antagonism at 5-HT2A receptor sites and that the configuration of the oxindole moiety of isorhynchophylline is essential for their antagonistic activity at the 5-HT2A receptor.
Keywords: Isorhynchophylline; Isocorynoxeine; Uncaria alkaloid; 5-HT2A receptor-mediated head twitch response; 5-HT2A receptor-mediated current response; Xenopus oocyte;

Stimulation of α2-adrenoceptors increases the ultrasonic vocalization production of preweanling rats, however it is not known whether these critical α2-adrenoceptors are located peripherally or centrally. In a series of three experiments, ultrasonic vocalizations were measured after 11-day-old rats had been administered clonidine or 2-[2,6-diethylphenylamino]-2-imidazole (ST-91) either systemically (i.p.) or into the third ventricle (i.c.v.). These particular α2-adrenoceptor agonists were chosen because clonidine is lipophilic and enters the central nervous system, while ST-91 is hydrophilic and does not readily cross the blood–brain barrier. In the third experiment, clonidine- (1 μg, i.c.v.) and ST-91-induced (15 μg, i.c.v.) ultrasonic vocalizations were measured after systemic injection of the α2-adrenoceptor antagonist yohimbine (0.5 or 1 mg/kg, i.p.). Results showed that central administration of both clonidine and ST-91 increased the ultrasonic vocalization production of 11-day-old rats, whereas peripheral administration of only clonidine, and not ST-91, increased ultrasonic vocalizations. These results indicate that the α2-adrenoceptors mediating ultrasonic vocalization production are located in the central nervous system. Yohimbine fully attenuated clonidine-induced ultrasonic vocalizations but only partially attenuated ST-91-induced vocalizations. This pattern of results may have been due to the differential selectivity of clonidine and ST-91 for α2-adrenoceptor subtypes (α2A, α2B, and α2C) or imidazoline receptors. When combined with past research, the present results are consistent with the hypothesis that centrally located α2-adrenoceptors are a component of a neural system that mediates ultrasonic vocalization production.
Keywords: Ultrasonic vocalization; α2-adrenoceptor; Clonidine; ST-91 (2-[2,6-diethylphenylamino]-2-imidazole);

Effect of prostaglandin I2 analogues on left ventricular diastolic function in vivo by Hille Kisch-Wedel; Gregor Kemming; Franz Meisner; Michael Flondor; Sebastian Bruhn; Carolina Koehler; Konrad Messmer; Bernhard Zwissler (208-216).
The prostaglandin I2 analogues epoprostenol and iloprost increase left ventricular contractility. Therefore, we hypothesize that the prostaglandin I2 analogues epoprostenol and iloprost improve also left ventricular diastolic function. To test this hypothesis, the effects of epoprostenol and iloprost on left ventricular diastolic function were assessed in vivo and compared to two vasodilators sodium nitroprusside and adenosine, not formerly associated with changes of left ventricular contractility. Eleven pigs (25.9 ± 2.8 kg, balanced anaesthesia) were exposed to the short-acting intravenous vasodilators sodium nitroprusside, adenosine and epoprostenol in a randomized cross over design. The long-acting iloprost was administered at the end of the protocol. The drugs are titrated to achieve a 25% reduction of diastolic aortic pressure. Active isovolumic relaxation properties of the left ventricle were assessed by the maximum velocity of left ventricular pressure drop. Passive phase of relaxation and filling was assessed by the determination of end diastolic compliance during a preload reduction manoeuvre.The maximum velocity of left ventricular pressure drop worsened during the infusion of sodium nitroprusside (baseline: − 1950; sodium nitroprusside: − 1293 mm Hg/s, p  < 0.05, Wilcoxon signed rank test versus vs. baseline) and adenosine (baseline: − 2015; adenosine: − 1345 mm Hg/s, p  < 0.05), but remained stable during the infusion of the prostaglandins (baseline: − 1943; epoprostenol: − 1785 mm Hg/s; baseline: − 2042; iloprost: − 1923 mm Hg/s). End diastolic compliance was not altered significantly by any vasodilator. Interstitial myocardial cAMP increased during the infusion of epoprostenol (7.60 to 13.87 fmol/ml, p  < 0.05) and tended to increase during the infusion of iloprost (7.56 to 11.66 fmol/ml, p  = 0.21). The prostaglandin I2 analogues epoprostenol and iloprost preserved the early phase of active isovolumic relaxation, presumably mediated by myocardial cAMP, whereas sodium nitroprusside and adenosine impaired early active isovolumic relaxation. Passive relaxation and filling properties remained stable during the infusion of each applied vasodilator in the intact left ventricle in vivo.
Keywords: Diastole; Prostaglandin; Vasodilatation; Adenosine; Nitric oxide;

Increased serum level of homocysteine is an independent risk factor for vascular disease. The effect of dl-homocysteine on the endothelial production of kynurenic acid, an antagonist of α7-nicotinic and N-methyl-d-aspartate (NMDA) glutamate receptors, has been evaluated in vitro and in vivo. In rat aortic rings, dl-homocysteine at 40–100 μM enhanced, whereas at ≥ 400 μM decreased the synthesis of kynurenic acid. S-adenosylhomocysteine mimicked the biphasic action of dl-homocysteine. On the contrary, thiol-containing compounds, l-cysteine and l-methionine, were only inhibiting kynurenic acid production. l-kynurenine uptake blockers, l-phenylalanine and l-leucine, reversed the stimulatory effect of S-adenosylhomocysteine. l-glycine, co-agonist of NMDA receptor, and cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), an antagonist of NMDA receptor, have not influenced kynurenic acid formation. In vivo, dl-homocysteine (1.3 mmol, i.p.) increased the level of kynurenic acid in rat serum from 23.7 ± 7.1 to 60.7 ± 14.2 (15 min, P  < 0.01) and 55.7 ± 13.6 (60 min, P  < 0.01) pmol/ml, respectively; the endothelial content of kynurenic acid was also increased (51.6 ± 5.8 vs. 73.2 ± 9.4 fmol/μg of protein; 15 min; P  < 0.01). dl-homocysteine seems to modulate the production of kynurenic acid both directly and indirectly, possibly following the conversion to S-adenosylhomocysteine. The obtained data suggest a potential contribution of altered formation of kynurenic acid to the endothelial changes induced by hyperhomocysteinemia.
Keywords: Endothelium; Homocysteine; Kynurenic acid; S-adenosylhomocysteine;

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra™), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (NCX 911), an NO donating derivative of sildenafil. The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether NCX 911 confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors. Both sildenafil citrate and NCX 911 significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, NCX 911 being more potent. NCX 911 also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ). These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.
Keywords: Erectile dysfunction; Cholesterol; Superoxide; NADPH oxidase;

Protective effect of nitric oxide on ischemia/reperfusion-induced renal injury and endothelin-1 overproduction by Hayato Kurata; Masanori Takaoka; Yasuhiro Kubo; Tomoaki Katayama; Hidenobu Tsutsui; Junji Takayama; Mamoru Ohkita; Yasuo Matsumura (232-239).
To elucidate the role of nitric oxide (NO) in the pathogenesis of ischemic acute renal failure, we examined the effects of (±)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (FK409) and N G-nitro-l-arginine methyl ester (l-NAME) as a NO donor and a non-selective NO synthase inhibitor on ischemia/reperfusion-induced renal injury and renal endothelin-1 content. Ischemic acute renal failure was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. At 24 h after reperfusion, renal function in untreated acute renal failure rats markedly decreased and histological examination revealed severe renal damage. In addition, increases in renal endothelin-1 contents were evident in the acute renal failure rats at 2, 6, and 24 h after reperfusion, respectively. Pretreatment with FK409 (1 or 3 mg/kg, i.v.) attenuated ischemia/reperfusion-induced renal dysfunction, histological damage, and endothelin-1 overproduction after reperfusion. In contrast, pretreatment with l-NAME (1 or 10 mg/kg, i.v.) aggravated renal injuries of acute renal failure rats at 24 h after reperfusion, and the effect is accompanied by further increases in the renal endothelin-1 content at 2 and 6 h, but not at 24 h, after reperfusion. These results suggest that suppressive effects of NO on the renal endothelin-1 overproduction induced by ischemia/reperfusion in an early phase are probably responsible for the protective effect of NO against ischemic acute renal failure.
Keywords: Nitric oxide; Acute renal failure; Ischemia/reperfusion; Endothelin-1;

Comparative relaxant effects of YC-1 and DETA/NO on spontaneous contractions and the levels of cGMP of isolated pregnant rat myometrium by Nihal Demirkoprulu; Meral Cetin; Ihsan Bagcivan; Tijen Kaya; Ahmet Serdar Soydan; Baris Karadas; Ali Cetin (240-245).
This study was designed to compare the effects of YC-1 (3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole), a nitric oxide (NO)-independent soluble guanylate cyclase activator, and diethylenetriamine-NONOate (DETA/NO), a NO donor, on spontaneous contractions and the levels of cyclic GMP (cGMP) of myometrial strips isolated from timed-pregnant rats. Myometrial strips were obtained from timed-pregnant Wistar albino rats (n  = 10) and were mounted in organ baths and tested for changes in isometric tension in response to YC-1 and DETA/NO. We also evaluated the effect of YC-1 and DETA/NO on the levels of cGMP in myometrial strips obtained from timed-pregnant rat uterine horns (n  = 20). YC-1 (10− 9–3 × 10− 5 M) and DETA/NO (10− 7–10− 4 M) concentration-dependently decreased the amplitude and frequency of spontaneous contractions of myometrial strips isolated from term-pregnant rats. The inhibitions of the amplitude and frequency of spontaneous contractions by YC-1 and DETA/NO were antagonized with methylene-blue (10− 5 M). Antagonistic effect of methylene-blue (10− 5 M) was more on DETA/NO responses than that of YC-1 (P  < 0.05). In addition, YC-1-stimulated myometrial strips showed more elevation in myometrial cGMP than that of DETA/NO (P  < 0.05). We demonstrated that YC-1 and DETA/NO induce relaxations in the amplitude and frequency of spontaneous contractions of myometrial strips with different potencies. We also found that YC-1 and DETA/NO-induced relaxations are associated with significant increases in cGMP. These results might suggest that the relaxant effects of YC-1 and DETA/NO on the rat myometrium could be due to the stimulation of the soluble guanylate cyclase and cGMP may play a role for the maintenance of uterine quiescence during pregnancy.
Keywords: YC-1; DETA/NO; Soluble guanylate cyclase activator; Nitric oxide donor; Myometrium;

Nicotinic receptors regulate B lymphocyte activation and immune response by Marina Skok; Régis Grailhe; Jean-Pierre Changeux (246-251).
The presence of nicotinic acetylcholine receptors (nicotinic receptors) composed of either α7 or α4 and β2 subunits is revealed in B lymphocytes by means of radioligand binding assay and Cell ELISA. Mouse B lymphocytes contained 12,200 ± 3200 of epibatidine-binding sites and 3130 ± 750 of α-Bungarotoxin-binding sites per cell. Mice lacking nicotinic receptor subunits α4, β2 or α7 had less serum IgG and IgG-producing cells in the spleen, but showed stronger immune response to both protein antigen in vivo and CD40-specific antibody in vitro than wild-type mice. Anti-CD40-stimulated proliferation of B lymphocytes from β2 knockout, but not wild-type mice was inhibited with nicotine. Our results indicate that signalling through nicotinic receptors affects both the pre-immune state and activation of B lymphocytes in the immune response, possibly via CD40-dependent pathway. This could contribute to immune depression found in tobacco smokers.
Keywords: Nicotinic receptor; Lymphocyte; Immune response;

Prostaglandins E1 and E2 inhibit lipopolysaccharide-induced interleukin-18 production in monocytes by Hideo K. Takahashi; Hiromi Iwagaki; Shuji Mori; Tadashi Yoshino; Noriaki Tanaka; Masahiro Nishibori (252-256).
The purpose of this present study was to explore the therapeutic potential of prostaglandins E1 and E2 on the systemic inflammatory response evoked by endotoxin. Since interleukin-18, a monocyte-derived cytokine, is increased during sepsis, decreasing the production of interleukin-18 is important in treating this condition. Prostaglandin E1 and E2 inhibited interleukin-18 production in human monocytes treated with lipopolysaccharide and prostanoid IP-, EP2- and EP4-receptor agonists mimicked the effects of prostaglandins E1 and E2. Therefore, prostanoid IP, EP2- and EP4-receptors might be involved in the decrease in interleukin-18 production during sepsis.
Keywords: Prostaglandin; Monocyte; Adhesion molecule;

Author index (257-259).

Keyword index (260-264).