Published online before print July 7, 2008, doi: 10.1161/HYPERTENSIONAHA.108.112029
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(Hypertension. 2008;52:330.)
© 2008 American Heart Association, Inc.
Original Articles |
Activation of the PGI2/IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock
From the Institutes of Physiology (K.H.) and Anesthesiology (C.S., B.K., M.B.), University of Regensburg, Regensburg, Germany.
Correspondence to Klaus Höcherl, Universität Regensburg, Institut für Physiologie, Universitätsstr 31, D-93040 Regensburg, Germany. E-mail klaus.hoecherl{at}chemie.uni-regensburg.de
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Abstract |
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Prostacyclin levels are increased in septic patients and several animal models of septic shock, and selective inhibition of cyclooxygenase-2 improved cardiovascular dysfunction in rats treated with lipopolysaccharide (LPS). Here, we examine the specific role of prostacyclin and of the receptor for prostacyclin (IP) in the development of LPS-induced circulatory failure. Intravenous injection of LPS (10 mg/kg) into male Sprague-Dawley rats caused a strong increase in plasma prostacyclin levels, which was paralleled by a decrease in blood pressure and an increase in heart rate. Moreover, LPS injection increased the mRNA expression of the IP receptor in the heart, aorta, lung, liver, adrenal glands, and kidneys. Cotreatment with the IP antagonist CAY-10441 (1, 10, 30, and 100 mg/kg) dose-dependently moderated the LPS-induced changes in mean arterial blood pressure, heart rate, cardiac output, and systemic vascular resistance. The development of cardiovascular failure was ameliorated by CAY-10441 in spite of the typical LPS-induced increases in plasma levels of cytokines and NO. In vitro, cytokines dose- and time-dependently induced IP expression in rat vascular smooth muscle cells. Incubation of cells with the stable IP agonist iloprost in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-mehylxanthine resulted in higher cAMP levels in cytokine-treated cells compared with untreated cells. Taken together, our data demonstrate a prominent role of the prostacyclin/IP system in the development of LPS-induced cardiovascular failure.
Key Words: prostacyclin • LPS • CAY-10441 • blood pressure • sepsis
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Introduction |
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Prostacyclin (PGI2) is a major product of the arachidonic acid metabolism formed in the vascular endothelium by the action of the enzymes cyclooxygenase (COX) and prostacyclin synthase (PGIS). PGI2 mediates its effects through a Gs protein–coupled receptor (IP), which is located on vascular smooth muscle cells (VSMCs).1 Stimulation of IP by PGI2 leads to an increase in cAMP, which likely mediates relaxation of VSMCs.2
Vasodilation is a major symptom of infection and inflammation, occurring systematically during sepsis. In the past years, it became obvious that an increased expression of the inducible isoform of NO synthase contributes fundamentally to septic shock. However, in contrast to the effect of the inducible isoform of NO synthase inhibitory drugs on hypotension in shock,3,4 administration of lipopolysaccharide (LPS) still causes hypotension in the inducible isoform of NO synthase–deficient mice,5,6 suggesting that NO is not the only mediator of LPS-induced hypotension.
Increased levels of PGI2 have been reported in patients under septic shock and in animals treated with LPS or proinflammatory cytokines.7–9 Because PGI2 is a potent vasodilator, one may assume that PGI2 could be involved in the development of septic shock. Recent evidence suggests that the inducible isoform of COX, COX-2, is the main responsible enzyme for the increased production of PGI2 in VSMCs.10,11 In line with this, it has been shown that inhibition of COX-2 attenuates the fall in blood pressure or improves vascular endothelial dysfunction in endotoxemic animals.12,13 Therefore, we hypothesized that the PGI2/IP system could especially contribute to the development of LPS-induced septic shock.
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Materials and Methods |
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Animal Experiments
All of the animal experiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and with the local ethics committee. Male Sprague-Dawley rats (200 to 250 g; n=8 per group) received 1 mL of Ringer’s solution (i.v., control), Escherichia coli–derived LPS (10 mg/kg i.v.), vehicle (10% polyethylene glycol–200 in isotonic NaCl, i.p.) or the IP antagonist CAY-10441 (i.p., Cayman Chemical, also known as RO113845214).
Measurement of Hemodynamic Parameters
Five hours after injection of LPS, mean arterial blood pressure (MAP) was measured as described.12 Heart rate (HR), cardiac output (CO), systemic vascular resistance (SVR), and pressure were measured by a 2.0-Fr Millar tip catheter (Model SPR-838, Millar Instruments). A recovery period of 30 minutes was allowed to establish steady-state conditions.
Cell Culture
Rat VSMCs (Dominion Pharmakine; passage 4 to 10) were incubated for 24 hours with medium (control) or increasing concentrations of a combination of cytokines (the 100% mix consisted of tumor necrosis factor [TNF]-
[100 ng/mL], interleukin [IL]-1β [50 ng/mL], and interferon-
[100 ng/mL]; Tebu-Bio). cAMP accumulation was determined 20 hours after incubation of VSMCs with cytokines and with 10 µmol/L of indomethacin or in cells incubated only with indomethacin. Cells were then incubated with 3-isobutyl-1-mehylxanthine (500 µmol/L) for 15 minutes. Thereafter, cells were stimulated with iloprost (100 nmol/L) or iloprost in combination with CAY-10441 (1 µmol/L) for 30 minutes. The supernatant was removed, cells were lysed, and cAMP concentration was directly measured in the samples using an ELISA (direct cAMP kit, Assay Designs).
Determination of IP and β-Actin mRNA Expression
Total RNA from tissues and cells was extracted, reverse transcribed, and real-time PCR or RNase protection assay for IP and β-actin was carried out as described previously.15,16
Western Blot Analysis for IP and β-Actin
Membrane fractions of total protein were prepared as described previously.17 Western blot analysis was performed using a primary rabbit polyclonal antibody against IP (Cayman Chemical; 1:1000) and a horseradish peroxidase–conjugated secondary donkey antirabbit antibody (Santa Cruz Biotechnology; 1:5000). For β-actin, a monoclonal antibody (1:5000; Sigma) and goat antimouse secondary antibody (1:5000; Santa Cruz Biotechnology) were used. Quantitative assessment of band densities was performed densitometrically.
Determination of Plasma Levels of Cytokines, Nitrate/Nitrite, and 6-Keto Prostaglandin F1
Plasma concentrations of cytokines, nitrate/nitrite, and 6-keto prostaglandin (PG) F1 were determined by using ELISA kits (R&D Systems and Cayman Chemical).
Statistics
Data were analyzed by ANOVA with multiple comparisons followed by the t test with Bonferroni’s adjustment. P<0.05 was considered significant.
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Results |
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Effect of LPS on Mean Arterial Pressure, HR, and Plasma Levels of 6-keto-PGF1
MAP and HR remained stable in the control group. LPS injection resulted in a decrease in MAP and in an increase in HR 3, 6, and 12 hours after administration. Plasma levels of 6-keto-PGF1
, the stable metabolite of PGI2, were not altered in the control animals but clearly increased 3, 6, and 12 hours after LPS treatment (Table).
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Effect of LPS on IP Expression
We further investigated the influence of LPS on the expression of IPs in cardiovascular tissues. We found that IP mRNA expression was increased 1.7-, 2.9-, and 3.2-fold in thoracic aortas 3, 6, and 12 hours after LPS injection, respectively. Similarly, LPS increased IP mRNA expression in lungs, hearts, livers, adrenal glands, and kidneys (Figure 1A). In addition, LPS injection for 6 hours increased IP mRNA expression 2.6-, 2.0-, 1.6-, and 2.7-fold in the right atria, left atria, right ventricle, and left ventricle, respectively (Figure 1B). We further examined the protein expression of IP receptors in lungs and found that the expression was increased 1.7-, 2.1-, and 2.0-fold 3, 6, or 12 hours after LPS injection, respectively (Figure 1C).
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denotes significance to all of the data points associated with the particular
Effect of CAY-10441 on Cardiovascular Parameters
Because we found an activation of PGI2/IP system by LPS treatment, we further investigated the impact of this activation on the development of hypotension in LPS-treated rats. We, therefore, used the IP receptor antagonist CAY-10441 and investigated the effect 6 hour after LPS injection. MAP in control animals was 78±4 mm Hg. Sole treatment with CAY-10441 did not alter MAP. LPS treatment decreased MAP to 51±4 mm Hg, and cotreatment with CAY-10441 dose-dependently attenuated the fall in blood pressure to 66±4 mm Hg at the highest dose level (Figure 2A). HR in control animals was 363±7 bpm. CAY-10441 did not alter HR. HR increased in animals treated with LPS to 518±14 bpm, and cotreatment with CAY-10441 dose-dependently attenuated the rise in HR to 425±13 mm Hg at the highest dose level (Figure 2B). CO in control animals was 63.2±4.2 mL/min and was not altered by sole treatment with CAY-10441. LPS injection increased CO to 92.8±7.4 mL/min, and cotreatment with CAY-10441 dose-dependently attenuated the rise in CO to 73.7±6.4 mL/min at the highest dose level (Figure 2C). SVR in control animals was 1.10±0.07 mm Hg · mL–1 · min and was not affected by treatment with CAY-10441. SVR decreased to 0.47±0.03 mm Hg · mL–1 · min in animals treated with LPS, and cotreatment with CAY-10441 dose-dependently attenuated the fall in SVR to 0.77±0.07 mm Hg · mL–1 · min at the highest dose level (Figure 2D).
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Effect of CAY-10441 on Plasma Levels of Cytokines and NO
Plasma values for TNF-, IL-1β, and interferon- and the sum of nitrite and nitrate were strongly increased by LPS challenge. Treatment with CAY-10441 did not alter basal or LPS-induced plasma values (Figure 3).
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Effect of Cytokines on IP mRNA Expression and cAMP Formation in VSMCs
To gain insight into the regulation and functional importance of our in vivo findings, we finally investigated the effect of cytokines in VSMCs. Incubation of VSMCs with a mixture of TNF-, IL-1β, and interferon- time- and dose-dependently increased the expression of IP receptors (Figure 4A and 4B). We further measured the formation of cAMP induced by the stable PGI2 agonist iloprost. To prevent a possible influence of endogenous and/or cytokine-induced prostanoid formation, we pretreated the cells with the COX inhibitor indomethacin. We found that iloprost increased cAMP levels 
17-fold. This increase was inhibited by CAY-10441. In cytokine-treated cells, iloprost increased cAMP levels 38-fold. This increase was also inhibited by CAY-10441 (Figure 4C).
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P<0.05 vs iloprost. |
Discussion |
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In line with previous studies, we observed a strong increase in plasma levels of 6-keto-PGF1
, which was accompanied by a time-dependent fall in systolic blood pressure and an increase in HR after injection of LPS.7,8 Under physiological conditions, it has been suggested that the endothelium regulates vascular tone by a constitutive formation of endothelial- isoform of NO synthase–derived NO and COX-1–derived PGI2.18,19 However, during inflammation, endothelial cells are capable of producing PGI2 in a COX-2–dependent manner.20 Notably, during severe sepsis, it has been suggested that high levels of endotoxin result in a complete loss of the endothelium and of course also of its function.21 In this context, it has been shown that VSMCs are also able to produce PGI2 in a COX-2–dependent manner in response to LPS.10 Thus, it seems likely that the strong rise in 6-keto-PGF1 plasma levels observed in our in vivo study may be the result of an induction of COX-2 leading to increased levels of PGI2. In line with this, it has been found that inhibition of COX-2 improves vascular endothelial dysfunction induced by LPS.13 In addition, renal-specific PGIS transgenic mice, which have an increased renal PGI2 formation, respond to LPS injection already with a low-dose of LPS, which did not alter renal function in wild-type mice.22
It is well known that PGI2 exerts its effects on VSMCs via activation of IP receptors.23 Recently, we have shown that the expression of several G-protein–coupled receptors is decreased on LPS challenge.24,25 Thus, a decrease in the expression of IPs may counteract the effect of an increase in plasma PGI2 levels. We now found that the expression of the IP is increased in vivo after an LPS challenge. This new in vivo finding fits very well with in vitro findings, demonstrating that LPS, IL-1β, and TNF- can increase the expression of IP mRNA.26–28 Moreover, these data may provide an explanation for the effectiveness of PGI2 or PGI2 agonists to increase splanchnic blood flow, especially in septic animals,29 and for the important role of PGI2 as an inflammatory mediator.30 The functional relevance of our observation is highlighted by the enhanced iloprost-induced cAMP synthesis after treatment of VSMCs with cytokines.
To define the functional relevance of an activation of the PGI2/IP system in the development of LPS-induced cardiovascular failure, we investigated the effect of the IP receptor antagonist CAY-10441.14 Confirming a previous report, sole treatment with CAY-10441 did not influence MAP and HR.31 We now found that CAY-10441 attenuated the fall in blood pressure induced by LPS. This finding fits very well with the attenuation of LPS-induced hypotension by COX-2 inhibition.12 In line with this, the positive effect of cPTIO on LPS-induced cardiovascular failure and mortality has been linked in part to an inhibition of PGI2 synthesis via inactivation of PGIS.32 Furthermore, it has been suggested that the induction of COX-2 in the heart is involved in myocardial dysfunction33,34 and that increased PGI2 synthesis via COX-2 could in part mediate LPS-induced cardiac failure.35,36 Therefore, our data provide further evidence for the involvement of COX-2–derived PGI2 in endotoxin-induced cardiovascular dysfunction.
Because our findings suggest that the attenuation of hypotension by CAY-10441 does not result from a decreased production of NO, our data are in agreement with the concept that NO is a major substance leading to hypotension in septic rodent models. However, in larger mammalians and humans, NO overproduction does not occur to the same extent.37 Therefore, attenuation of hypotension by IP receptor antagonism might be more pronounced in humans.
Perspectives
Taken together, our data demonstrate an LPS-induced activation of the PGI2/IP system, which is probably mediated by proinflammatory cytokines. We infer from our findings that PGI2 is of particular relevance for the development of LPS-induced cardiovascular failure. Additional animal and human studies are necessary to clarify whether inhibition of the IP receptor is beneficial in the treatment of septic circulatory failure. Possible effects of IP antagonism on renal, hepatic, and pulmonary function and on blood homeostasis would be areas of interest in this context, as well as the question of whether therapeutic strategies taken from experimental sepsis are useful under clinical conditions.
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Acknowledgments |
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We thank Maria Hirblinger (Institute of Anesthesiology, University of Regensburg) and Ramona Mogge (Institute of Physiology, University of Regensburg) for expert technical assistance.
Sources of Funding
This study was financially supported by the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 699, projects B4 and B5.
Disclosures
None.
Received February 14, 2008; first decision March 13, 2008; accepted June 11, 2008.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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1. Vane J, Corin RE. Prostacyclin: a vascular mediator. Eur J Vasc Endovasc Surg. 2003; 26: 571–578.[CrossRef][Medline] [Order article via Infotrieve]
2. Hata AN, Breyer RM. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol Ther. 2004; 103: 147–166.[CrossRef][Medline] [Order article via Infotrieve]
3. Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, Levi R, Lodato RF. NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci USA. 1990; 87: 3629–3632.
4. Thiemermann C, Vane J. Inhibition of nitric oxide synthesis reduces the hypotension induced by bacterial lipopolysaccharides in the rat in vivo. Eur J Pharmacol. 1990; 182: 591–595.[CrossRef][Medline] [Order article via Infotrieve]
5. Hickey MJ, Sharkey KA, Sihota EG, Reinhardt PH, Macmicking JD, Nathan C, Kubes P. Inducible nitric oxide synthase-deficient mice have enhanced leukocyte-endothelium interactions in endotoxemia. FASEB J. 1997; 11: 955–964.[Abstract]
6. MacMicking JD, Nathan C, Hom G, Chartrain N, Fletcher DS, Trumbauer M, Stevens K, Xie QW, Sokol K, Hutchinson N, Chen H, Mudget J. Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell. 1995; 81: 641–650.[CrossRef][Medline] [Order article via Infotrieve]
7. Bernard GR, Reines HD, Halushka PV, Higgins SB, Metz CA, Swindell BB, Wright PE, Watts FL, Vrbanac JJ. Prostacyclin and thromboxane A2 formation is increased in human sepsis syndrome. Effects of cyclooxygenase inhibition. Am Rev Respir Dis. 1991; 144: 1095–1101.[Medline] [Order article via Infotrieve]
8. Klosterhalfen B, Horstmann-Jungemann K, Vogel P, Flohe S, Offner F, Kirkpatrick CJ, Heinrich PC. Time course of various inflammatory mediators during recurrent endotoxemia. Biochem Pharmacol. 1992; 43: 2103–2109.[CrossRef][Medline] [Order article via Infotrieve]
9. Wang P, Zhou M, Cioffi WG, Bland KI, Ba ZF, Chaudry IH. Is prostacyclin responsible for producing the hyperdynamic response during early sepsis? Crit Care Med. 2000; 28: 1534–1539.[CrossRef][Medline] [Order article via Infotrieve]
10. Schildknecht S, Bachschmid M, Baumann A, Ullrich V. COX-2 inhibitors selectively block prostacyclin synthesis in endotoxin-exposed vascular smooth muscle cells. FASEB J. 2004; 18: 757–759.
11. Schildknecht S, Bachschmid M, Ullrich V. Peroxynitrite provides the peroxide tone for PGHS-2-dependent prostacyclin synthesis in vascular smooth muscle cells. FASEB J. 2005; 19: 1169–1171.
12. Hocherl K, Dreher F, Kurtz A, Bucher M. Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure. Hypertension. 2002; 40: 947–953.
13. Virdis A, Colucci R, Fornai M, Blandizzi C, Duranti E, Pinto S, Bernardini N, Segnani C, Antonioli L, Taddei S, Salvetti A, Del Tacca M. Cyclooxygenase-2 inhibition improves vascular endothelial dysfunction in a rat model of endotoxic shock: role of inducible nitric-oxide synthase and oxidative stress. J Pharmacol Exp Ther. 2005; 312: 945–953.
14. Bley KR, Bhattacharya A, Daniels DV, Gever J, Jahangir A, O'Yang C, Smith S, Srinivasan D, Ford AP, Jett MF. RO1138452 and RO3244794: characterization of structurally distinct, potent and selective IP (prostacyclin) receptor antagonists. Br J Pharmacol. 2006; 147: 335–345.[CrossRef][Medline] [Order article via Infotrieve]
15. Jensen BL, Mann B, Skott O, Kurtz A. Differential regulation of renal prostaglandin receptor mRNAs by dietary salt intake in the rat. Kidney Int. 1999; 56: 528–537.[CrossRef][Medline] [Order article via Infotrieve]
16. Matzdorf C, Kurtz A, Hocherl K. COX-2 activity determines the level of renin expression but is dispensable for acute upregulation of renin expression in rat kidneys. Am J Physiol Renal Physiol. 2007; 292: F1782–F1790.
17. Schmidt C, Hocherl K, Schweda F, Kurtz A, Bucher M. Regulation of renal sodium transporters during severe inflammation. J Am Soc Nephrol. 2007; 18: 1072–1083.
18. Cines DB, Pollak ES, Buck CA, Loscalzo J, Zimmerman GA, McEver RP, Pober JS, Wick TM, Konkle BA, Schwartz BS, Barnathan ES, McCrae KR, Hug BA, Schmidt AM, Stern DM. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood. 1998; 91: 3527–3561.
19. Liou JY, Shyue SK, Tsai MJ, Chung CL, Chu KY, Wu KK. Colocalization of prostacyclin synthase with prostaglandin H synthase-1 (PGHS-1) but not phorbol ester-induced PGHS-2 in cultured endothelial cells. J Biol Chem. 2000; 275: 15314–15320.
20. Tan X, Essengue S, Talreja J, Reese J, Stechschulte DJ, Dileepan KN. Histamine directly and synergistically with lipopolysaccharide stimulates cyclooxygenase-2 expression and prostaglandin I(2) and E(2) production in human coronary artery endothelial cells. J Immunol. 2007; 179: 7899–7906.
21. Vallet B. Bench-to-bedside review: endothelial cell dysfunction in severe sepsis: a role in organ dysfunction? Crit Care. 2003; 7: 130–138.[CrossRef][Medline] [Order article via Infotrieve]
22. Wang W, Zolty E, Falk S, Summer S, Stearman R, Geraci M, Schrier R. Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice. Am J Physiol Renal Physiol. 2007; 293: F1131–F1136.
23. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999; 79: 1193–1226.
24. Bucher M, Ittner KP, Hobbhahn J, Taeger K, Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension. 2001; 38: 177–182.
25. Bucher M, Kees F, Taeger K, Kurtz A. Cytokines down-regulate alpha1-adrenergic receptor expression during endotoxemia. Crit Care Med. 2003; 31: 566–571.[CrossRef][Medline] [Order article via Infotrieve]
26. Plum J, Huang C, Grabensee B, Schror K, Meyer-Kirchrath J. Prostacyclin enhances the expression of LPS/INF-gamma-induced nitric oxide synthase in human monocytes. Nephron. 2002; 91: 391–398.[CrossRef][Medline] [Order article via Infotrieve]
27. Sasaki Y, Takahashi T, Tanaka I, Nakamura K, Okuno Y, Nakagawa O, Narumiya S, Nakao K. Expression of prostacyclin receptor in human megakaryocytes. Blood. 1997; 90: 1039–1046.
28. Wang J, Yamamoto K, Sugimoto Y, Ichikawa A, Yamamoto S. Induction of prostaglandin I(2) receptor by tumor necrosis factor alpha in osteoblastic MC3T3-E1 cells. Biochim Biophys Acta. 1999; 1441: 69–76.[Medline] [Order article via Infotrieve]
29. Tadros T, Traber DL, Herndon DN. Opposite effects of prostacyclin on hepatic blood flow and oxygen consumption after burn and sepsis. Ann Surg. 2004; 239: 67–74.[CrossRef][Medline] [Order article via Infotrieve]
30. Murata T, Ushikubi F, Matsuoka T, Hirata M, Yamasaki A, Sugimoto Y, Ichikawa A, Aze Y, Tanaka T, Yoshida N, Ueno A, Oh-ishi S, Narumiya S. Altered pain perception and inflammatory response in mice lacking prostacyclin receptor. Nature. 1997; 388: 678–682.[CrossRef][Medline] [Order article via Infotrieve]
31. Yamada Y, Yamauchi D, Usui H, Zhao H, Yokoo M, Ohinata K, Iwai M, Horiuchi M, Yoshikawa M. Hypotensive activity of novokinin, a potent analogue of ovokinin(2-7), is mediated by angiotensin AT(2) receptor and prostaglandin IP receptor. Peptides. 2008; 29: 412–418.[CrossRef][Medline] [Order article via Infotrieve]
32. Soler M, Camacho M, Molins-Pujol AM, Vila L. Effect of an imidazolineoxyl nitric oxide on prostaglandin synthesis in experimental shock: possible role of nitrogen dioxide in prostacyclin synthase inactivation. J Infect Dis. 2001; 183: 105–112.[CrossRef][Medline] [Order article via Infotrieve]
33. Grandel U, Fink L, Blum A, Heep M, Buerke M, Kraemer HJ, Mayer K, Bohle RM, Seeger W, Grimminger F, Sibelius U. Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts: evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production. Circulation. 2000; 102: 2758–2764.
34. Peng T, Lu X, Feng Q. NADH oxidase signaling induces cyclooxygenase-2 expression during lipopolysaccharide stimulation in cardiomyocytes. FASEB J. 2005; 19: 293–295.
35. Mittra S, Hyvelin JM, Shan Q, Tang F, Bourreau JP. Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis? Am J Physiol Heart Circ Physiol. 2004; 286: H1034–H1042.
36. Zhang XH, Li GR, Bourreau JP. The effect of adrenomedullin on the L-type calcium current in myocytes from septic shock rats: signaling pathway. Am J Physiol Heart Circ Physiol. 2007; 293: H2888–H2893.
37. Feihl F, Waeber B, Liaudet L. Is nitric oxide overproduction the target of choice for the management of septic shock? Pharmacol Ther. 2001; 91: 179–213.[CrossRef][Medline] [Order article via Infotrieve]
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