Published online before print October 28, 2002, doi: 10.1161/01.HYP.0000041221.13644.B9
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Hypertension. 2002;40:947.)
© 2002 American Heart Association, Inc.
Scientific Contributions |
Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure
From the Departments of Pharmacology (K.H., F.D.), Physiology (A.K.), and Anesthesiology (M.B.), University of Regensburg, Regensburg, Germany.
Correspondence to Michael Bucher, MD, Department of Anesthesiology, University of Regensburg, 93042 Regensburg, Germany. E-mail michael.bucher{at}klinik.uni-regensburg.de
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
The present study aimed to determine the relevance of cyclooxygenase-2 (COX-2)–derived prostanoids for the adverse effects of lipopolysaccharides (LPSs) on cardiovascular function. For this goal, male Sprague-Dawley rats received a single intravenous dose of LPS (10 mg/kg) and were treated with different cyclooxygenase inhibitors. Injection of LPS caused a marked decrease of systolic arterial pressure, from 128 to 79 mm Hg, and a concomitant increase of heart rate, from 380 to 530 minutes-1. Both the decrease of systemic arterial pressure and the increase of heart rate induced by LPS were almost absent if the animals also received the COX-2 blocker rofecoxib (20 mg/kg), regardless whether the drug was given 1 hour before or 1 hour after LPS. Although plasma and organ levels of prostanoids were lowered by rofecoxib, the characteristic LPS-induced increases of NO synthase II and COX-2 gene expression, as well as of plasma and tissue nitrate/nitrite concentrations, were not affected by rofecoxib. Although rofecoxib treatment did also not change LPS-induced tissue cytokine concentrations, it markedly improved LPS-induced liver damage, as indicated by the decrease of transaminases. Moreover, the overall well-being of the LPS-injected animals improved on concomitant treatment with the COX-2 inhibitor. Taken together, our data suggest that COX-2–derived prostanoids are major mediators for the detrimental effects of LPS on cardiovascular and organ function.
Key Words: shock • cyclooxygenase • hemodynamics • prostaglandins • nitric oxide
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
It is well known that the release of lipopolysaccharides (LPS) from Gram-negative bacteria into the blood stream (eg, in the course of an infection) causes a number of serious adverse effects, such as an increase of body temperature, decrease of blood pressure, and multiorgan failure.1–3 There is consensus that the first mediators in the cascade of LPS-induced events are cytokines.1,2 These, in turn, induce the expression of a number of enzymes, generating a second class of mediators, which are meant to support the body’s defense against bacterial invaders but also mediate adverse effects. Characteristic cytokine-induced enzymes in this context are the inducible isoforms of NO synthase (NOS-II) and cyclooxygenase-2 (COX-2).2,4,5 Thus, it is clear that the increase of body temperature and local inflammatory reactions are triggered by COX-2–derived prostanoids.5–7
LPS septicemia leads to cardiovascular failure, as reflected by a strong decrease of arterial blood pressure that is resistant to vasoconstrictor hormones.8–12 The mechanisms leading to LPS-induced hypotension have not yet been clearly identified. In view of the ubiquitous and strong stimulation of NO formation through NOS-II, it has been assumed that this particular vasodilator plays the major role for the decrease of arterial resistance.1,2,4 Moreover, it has been observed that inhibitors of NOS-II such as L-canavanine, S-methylisothiourea, or aminoguanidine attenuate LPS-induced decrease of blood pressure or vascular hyporeactivity.13–16 We have found that NO in concert with cytokines downregulates the expression of vasoconstrictor receptors during septicemia,8,17,18 and thus inhibits an endogenous counter-regulation of LPS-induced hypotension. NO in concert with cytokines, on the other hand, stimulates the expression of COX-2, leading to the enhanced formation of prostanoids.7,19 Because prostanoids such as prostaglandin E2 (PGE2) and prostacyclin are potent vasodilators,7,20,21 the question arises as to whether the stimulated COX-2 expression during LPS-septicemia and, in consequence, the enhanced formation of vasoactive prostaglandins contribute to the development of hypotension. No effect of selective COX-2 inhibition with NS398 on LPS-induced decrease in mean arterial blood pressure (MAP) has been reported.22 However, plasma- or tissue-levels of prostaglandins have not been determined in the present study.
Because the role of COX-2–derived prostaglandins is still unknown in this context, we aimed to determine the impact of COX-2 activity for LPS-induced cardiovascular failure. Although COX-1 and COX-2 exhibit similar biochemical activities in converting arachidonate to prostaglandin H2,21,23 the precursor of the bioactive prostaglandins, the ultimate prostanoids produced by COX-1 and COX-2 may be different.24–26 As functionally antagonistic effects of COX-1 and COX-2 inhibition have been determined,27 we characterized the effects of selective inhibition of both COX isoforms on LPS-induced reactions such as generation of cytokines, induction of NOS-II and COX-2 with consecutive formation of NO and prostaglandins, and arterial hypotension and tachycardia.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animal Experiments
All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 93-23, revised 1985) and German laws relating to the protection of animals, and were approved by the local ethics committee. Male Sprague-Dawley rats (200 to 250 g) received Ringer’s solution intravenously (control) or LPS (Escherichia coli, Sigma) 10 mg/kg IV and were killed by decapitation 0, 5, or 10 hours (n=8 per group) after injection. Animals (n=8 per group) also received LPS (10 mg/kg IV) 1 hour after oral administration of ketorolac (2 mg/kg, Cayman) or rofecoxib (2 mg/kg or 20 mg/kg MSD) and were killed 5 hours after injection. One group (n=8) received LPS (10 mg/kg) 1 hour before rofecoxib administration (20 mg/kg).
Systolic arterial blood pressure and heart rate were measured by the tail-cuff method 0, 5, and 10 hours after injection of LPS or vehicle. MAP was recorded for 5 hours after injection of LPS without or with administration of rofecoxib (20 mg/kg) or vehicle (n=5 per group) in anesthetized rats as described.8
The dose of LPS was chosen from the literature to produce severe experimental endotoxemia leading to cardiovascular failure.28–30 Ketorolac (2 mg/kg) preferentially inhibits COX-1,31 whereas rofecoxib (2 or 20 mg/kg) selectively blocks COX-2.32
Determination of NOS-II, COX-1, COX-2, and ß-Actin mRNA
Total RNA (50 µg) from the heart, lung, and liver was extracted, and the abundance of NOS II mRNA, COX-1 mRNA, and COX-2 mRNA was semi-quantitated and related to ß-actin mRNA (1 µg) by specific RNase protection assay as described.8,33
Determination of Nitrate/Nitrite, PGE2, and 6-Keto PGF1
Nitrate/nitrite concentrations and concentrations of PGE2 and 6-keto prostaglandinF1 in plasma and liver were determined using commercially available assay kits (Cayman Chemical).
Immunoblotting for NOS-II, COX-1, and COX-2 Protein
Immunoblotting was performed with modifications as described.33 Total protein (100 µg) from liver and lung was determined by using a mouse monoclonal antibody against NOS II (BD Transduction Laboratories), rabbit polyclonal antibodies against COX-1 or COX-2 (Cayman), and a horseradish peroxidase–conjugated secondary antibody (BD Transduction Laboratories for NOS II and Santa Cruz for COX).
Cytokine Assays
Tissue concentrations of tumor necrosis factor-, interleukin-1ß, and interferon-
were determined by using enzyme-linked immunosorbent assay kits (R&D Systems).
Determination of Glutamate-Oxaloacetate-Transaminase and Glutamate-Pyruvate-Transaminase
Plasma-concentrations of glutamate-oxaloacetate-transaminase and of glutamate-pyruvate-transaminase were determined by using commercially available colorimetric assay kits (Reflotron, Roche).
Statistics
Data were analyzed by ANOVA with multiple comparisons followed by the t test with Bonferroni‘s adjustment. P<0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Animals became lethargic and showed piloerection starting 2 hours after LPS injection. This condition persisted for the whole observation period and was not affected by ketorolac (2 mg/kg). Pretreatment of LPS-injected rats with rofecoxib (2 mg/kg) attenuated these symptoms. The behavior of animals treated with rofecoxib (20 mg/kg) did not differ from control rats.
Whether rofecoxib (20 mg/kg) was administered 1 hour before or 1 hour after LPS injection did not affect any of the results obtained in the study (data not shown).
Characteristic Effects of LPS
Hemodynamic changes in the macrocirculation are shown in Figure 1. Blood pressure and heart rate remained stable in the control group. LPS challenge resulted in a decrease in blood pressure and increase in heart rate 5 and 10 hours after administration.
|
P<0.05 vs control.
Gene expression of inducible isoforms of NOS and COX was strongly elevated 5 and 10 hours after LPS injection, whereas COX-1 gene expression was downregulated (Figure 2). Plasma and tissue nitrate/nitrite concentrations were increased after LPS administration, indicating an increased formation of NO owing to induced NOS-II protein. Concentrations of the prostanoids 6-keto PGF1 and PGE2 in plasma and liver tissue were also increased owing to LPS treatment (Figure 3).
|
P<0.05 vs 5 hours.
|
Effect of COX-2 Inhibition on Hemodynamic Changes After LPS Injection
MAP in anesthetized rats was 
90 mm Hg and was not affected by treatment with rofecoxib (20 mg/kg) (Figure 4). In control rats, MAP did not change during the investigation period of 5 hours. LPS injection caused an initial transient decrease in MAP to <50 mm Hg, which was not prevented by pretreatment with rofecoxib (20 mg/kg). After 20 minutes, MAP reached control level in both groups again. From 2 hours after LPS injection, there was a progressive decrease in MAP to <40 mm Hg, which was clearly attenuated by rofecoxib (20 mg/kg).
|
As shown in Figure 5, even a lower dose of rofecoxib (2 mg/kg) attenuated LPS-induced arterial hypotension and tachycardia, whereas ketorolac did not improve LPS-induced hemodynamic changes.
|
Effect of COX Inhibition on LPS-Induced Formation of NO, Prostaglandins, and Cytokines
Treatment of LPS-injected rats with rofecoxib (20 mg/kg) did not influence induction of NOS-II and COX-2 gene expression (Figure 6). Also downregulation of COX-1 gene expression was unchanged after rofecoxib (20 mg/kg).
|
The highly elevated plasma and tissue nitrate/nitrite levels after LPS injection were not significantly reduced by COX inhibition (Figure 7, left panel). The increased concentrations of 6-keto PGF1 and PGE2 in plasma and liver, respectively, tended to be lower after pretreatment with ketorolac but did not reach significance. However, rofecoxib dose-dependently diminished formation of both prostaglandin isoforms, which even reached control levels after 20 mg/kg in the plasma and in both doses in hepatic tissue after 5 hours (Figure 7, right panel).
|
P<0.05 vs LPS+rofecoxib (2 mg/kg).Injection of LPS resulted in a time-dependent strong increase of plasma and tissue cytokine concentrations (Figure 8). Rofecoxib treatment (20 mg/kg) did not affect the LPS-induced cytokine formation in plasma and tissue after 5 hours.
|
Effect of COX Inhibition on Liver Parameters
LPS-treatment resulted in an elevation of transaminases, which was not affected by pretreatment with ketorolac or rofecoxib (2 mg/kg) (Figure 9). In contrast, rofecoxib (20 mg/kg) significantly diminished LPS-induced increase in transaminases.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Sepsis and endotoxin shock in patients are still associated with a high mortality rate of 30% to 50%.34 LPS injection in our experiments caused cardiovascular failure with pronounced arterial hypotension and tachycardia, which was associated with an overall mortality rate of
44% (n=75). LPS injection stimulated plasma and tissue cytokine formation, leading to a markedly enhanced expression of NOS-II with consecutive generation of great amounts of NO, as indicated by the elevated plasma and tissue levels of nitrate/nitrite concentrations. This constitution is well established and underlines the validity of our animal model.1–5 We observed a differential regulation of COX-isoforms in the way that COX-2 expression was strongly induced by the LPS treatment, and COX-1 expression was downregulated. This is in accordance with previous studies,35,36 in which this differential regulation has been assumed to promote organ damage during endotoxemia owing to loss of microvascular control because of possibly diminished production of COX-1–derived prostanoids.36
Plasma and tissue concentrations of vasodilatory prostanoids such as PGE2 and 6-keto PGF1 are known to be elevated during endotoxemia, as was the case in the present experiments. Therefore, there has been some effort in the past decade to define the therapeutic effect of inhibitors of prostaglandin synthesis in septic individuals. In both human and animal studies, nonspecific inhibitors of COX, such as indomethacin or ibuprofen, showed improvement in either the morbidity or mortality associated with sepsis or endotoxin shock.37–41 However, a recent randomized, double-blind, placebo-controlled trial42 including 455 septic patients revealed no improved survival in the ibuprofen group. The fact that adverse effects of nonselective COX inhibitors (eg, on renal function) are reportedly pronounced in states of sepsis may be of relevance for the outcome in this context.43 In addition, opposite effects of COX-1 and COX-2 activity on the pressor response to angiotensin II, one of the most potent endogenous vasoconstrictors, have been reported.27 The pressor effect of angiotensin II was blunted by COX-1 inhibition, whereas it was enhanced by COX-2 inhibition. These results indicate a possible disadvantage of nonselective COX inhibition during septic shock.
One could imagine that selective inhibition of COX-2 might give some advantage in the treatment of sepsis. Our study demonstrates that treatment of rats with rofecoxib clearly attenuates LPS-induced arterial hypotension and tachycardia, whereby the time point of rofecoxib administration—1 hour before or 1 hour after LPS injection—had no influence. Ketorolac, at a dose preferentially inhibiting COX-1,31 did not improve LPS-caused cardiovascular failure. Rofecoxib treatment had no effect on cytokine formation, induction of NOS-II and COX-2 expression, downregulation of COX-1 expression, and increased NO production. These parameters were also not affected by ketorolac. In contrast, LPS-induced enhanced production of PGE2 and 6-keto PGF1, the stable metabolite of prostacyclin, was clearly and dose-dependently diminished by rofecoxib and even reached control values after administration of 20 mg/kg rofecoxib, whereas ketorolac had no significant effect on the formation of these prostanoids. This is in accordance with a recent study44 reporting control values of PGE2 concentrations in plasma and lung after selective COX-2 inhibition in a murine model of endotoxemia. Our data provide convincing evidence that the hemodynamic improvement in the macrocirculation by rofecoxib treatment is mediated by the reduced generation of vasodilatory COX-2–derived prostanoids.
It is well established that PGE2 in the central nervous system triggers a response, generally called ‘acute phase reaction,‘ including fever and hyperalgesia.45 The diminished LPS-induced piloerection after treatment with rofecoxib (2 mg/kg), which was almost absent after administration of 20 mg/kg rofecoxib, and the improved overall well-being of the animals after treatment with rofecoxib may be owing to the reduced PGE2 production. In addition, PGE2-induced hyperpyrexia requires increased fluid uptake and could result in relative hypovolemia, which in turn provokes cardiovascular failure.
There is some evidence for an organ-protective effect of COX-2 inhibition during endotoxemia. LPS injection was associated with substantial rises in the plasma levels of glutamate-oxaloacetate-transaminase and glutamate-pyruvate-transaminase, indicating the development of acute liver injury, which is consistent with previous studies.46,47 Treatment of rats with rofecoxib dose-dependently attenuated the acute liver injury associated with endotoxin shock. This effect is possibly related to the dose-dependent diminished hepatic PGE2 levels after rofecoxib administration.
Regarding the enormous and widespread induction of NOS-II with consecutive formation of high amounts of NO in nearly all organs, this vasodilatory molecule has been made responsible for the cardiovascular failure in septic and endotoxic shock states. This hypothesis was strengthened by findings that selective NOS-II inhibition13–16,48–51 and also nonselective NOS inhibition15,52,53 prevents cardiovascular collapse. However, nonselective NOS inhibition was associated with marked side effects—such as provoked renal dysfunction,15 increased number of bacteria in plasma and tissue with higher cytokine levels,54 and accelerated and enhanced fall in blood pressure52—and overall did not improve49,55 or even reduce54 survival in experimental sepsis, possibly owing to detrimental effects of the inhibition of NO generation in the microcirculation. In addition, a multicenter trial using a nonselective NOS inhibitor in septic patients was stopped by the safety committee because of adverse effects. Studies with selective NOS-II inhibitors revealed that arterial hypotension and vascular hyporeactivity were only slightly alleviated, indicating that there may be other or additional pathways involved in the pathogenesis of septic cardiovascular failure.29,56–58 Also our findings do not support a central role of NO mediating the LPS-induced arterial hypotension, as 10 hours after injection of LPS, systolic arterial pressure tended to improve compared with the 5-hour value; plasma nitrate/nitrite levels 10 hours after injection, however, were as double as high as the 5-hour value. The possible role of prostanoids is pointed out by our results in this context because plasma and tissue levels of 6-keto PGF1 and PGE2 were clearly diminished 10 hours after LPS injection compared with the 5-hour value.
Perspectives
We found that COX-2 inhibitors prevented the fall of blood pressure and the rise of heart rate and in general improved the well-being of LPS-treated rats. We infer from our findings that COX-2–derived prostanoids are of particular relevance for the changes of cardiovascular function during endotoxemia. Further animal and human studies are necessary to clarify whether inhibition of the generation of COX-2–derived prostanoids is beneficial in the treatment of septic circulatory failure. Possible effects of COX-2 inhibitors on, eg, renal and pulmonary function and on hemostasis would be areas of interest in this context, as well as the question whether therapeutic strategies taken from experimental sepsis are useful under clinical conditions of sepsis.
|
Acknowledgments |
|---|
The expert technical assistance provided by Gertraud Wilberg and Regina Menrath is gratefully acknowledged. The study was financially supported by a grant from the Deutsche Forschungsgemeinschaft (BU 1360/1-1).
Received August 8, 2002; first decision September 12, 2002; accepted September 30, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001; 345: 588–595.
2. Parrillo JE. Pathogenetic mechanisms of septic shock. N Engl J Med. 1993; 328: 1471–1477.
3. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med. 1989; 321: 280–287.[Abstract]
4. Moncada S, Higgs A. The L-arginine–nitric oxide pathway. N Engl J Med. 1993; 329: 2002–2012.
5. Vane JR, Mitchell JA, Appleton I, Tomlinson A, Bishop-Bailey D, Croxtall J, Willoughby DA. Inducible isoforms of cyclooxygenase and nitric-oxide synthase in inflammation. Proc Natl Acad Sci U S A. 1994; 91: 2046–2050.
6. Tilley SL, Coffman TM, Koller BH. Mixed messages: modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001; 108: 15–23.[CrossRef][Medline] [Order article via Infotrieve]
7. Smith WL, DeWitt DL, Garavito RM. Cyclooxygenases: structural, cellular, and molecular biology. Annu Rev Biochem. 2000; 69: 145–182.[CrossRef][Medline] [Order article via Infotrieve]
8. Bucher M, Ittner KP, Hobbhahn J, Taeger K, Kurtz A. Downregulation of angiotensin II type 1 receptors during sepsis. Hypertension. 2001; 38: 177–182.
9. Chernow B, Rainey TG, Lake CR. Endogenous and exogenous catecholamines in critical care medicine. Crit Care Med. 1982; 10: 409–416.[Medline] [Order article via Infotrieve]
10. Hollenberg SM, Tangora JJ, Piotrowski MJ, Easington C, Parrillo JE. Impaired microvascular vasoconstrictive responses to vasopressin in septic rats. Crit Care Med. 1997; 25: 869–873.[CrossRef][Medline] [Order article via Infotrieve]
11. Ishimaru S, Shichiri M, Mineshita S, Hirata Y. Role of endothelin-1/endothelin receptor system in endotoxic shock rats. Hypertens Res. 2001; 24: 119–126.[CrossRef][Medline] [Order article via Infotrieve]
12. Wray GM, Coakley JH. Severe septic shock unresponsive to noradrenaline. Lancet. 1995; 346: 1604.[CrossRef][Medline] [Order article via Infotrieve]
13. Booke M, Hinder F, McGuire R, Traber LD, Traber DL. Selective inhibition of inducible nitric oxide synthase: effects on hemodynamics and regional blood flow in healthy and septic sheep. Crit Care Med. 1999; 27: 162–167.[Medline] [Order article via Infotrieve]
14. Liaudet L, Feihl F, Rosselet A, Markert M, Hurni JM, Perret C. Beneficial effects of L-canavanine, a selective inhibitor of inducible nitric oxide synthase, during rodent endotoxaemia. Clin Sci (Lond). 1996; 90: 369–377.[Medline] [Order article via Infotrieve]
15. Schwartz D, Mendonca M, Schwartz I, Xia Y, Satriano J, Wilson CB, Blantz RC. Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats. J Clin Invest. 1997; 100: 439–448.[Medline] [Order article via Infotrieve]
16. Szabo C, Southan GJ, Thiemermann C. Beneficial effects and improved survival in rodent models of septic shock with S-methylisothiourea sulfate, a potent and selective inhibitor of inducible nitric oxide synthase. Proc Natl Acad Sci U S A. 1994; 91: 12472–12476.
17. Bucher M, Hobbhahn J, Taeger K, Kurtz A. Cytokine-mediated downregulation of vasopressin V1A receptors during acute endotoxemia in rats. Am J Physiol Regul Integr Comp Physiol. 2002; 282: R979–R984.
18. Bucher M, Taeger K. Endothelin-receptor gene-expression in rat endotoxemia. Intensive Care Med. 2002; 28: 642–647.[CrossRef][Medline] [Order article via Infotrieve]
19. Salvemini D, Seibert K, Masferrer JL, Misko TP, Currie MG, Needleman P. Endogenous nitric oxide enhances prostaglandin production in a model of renal inflammation. J Clin Invest. 1994; 93: 1940–1947.[Medline] [Order article via Infotrieve]
20. Davidge ST. Prostaglandin H synthase and vascular function. Circ Res. 2001; 89: 650–660.
21. Smith WL, Langenbach R. Why there are two cyclooxygenase isozymes. J Clin Invest. 2001; 107: 1491–1495.[Medline] [Order article via Infotrieve]
22. Vayssettes-Courchay C, Bouysset F, Verbeuren TJ. Involvement of COX and NOS induction in the sympatho-activation during sepsis. Auton Neurosci. 2002; 98: 33–36.[CrossRef][Medline] [Order article via Infotrieve]
23. Fitzpatrick FA, Soberman R. Regulated formation of eicosanoids. J Clin Invest. 2001; 107: 1347–1351.[Medline] [Order article via Infotrieve]
24. Brock TG, McNish RW, Peters-Golden M. Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2. J Biol Chem. 1999; 274: 11660–11666.
25. Harris RC, McKanna JA, Akai Y, Jacobson HR, Dubois RN, Breyer MD. Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest. 1994; 94: 2504–2510.[Medline] [Order article via Infotrieve]
26. McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci U S A. 1999; 96: 272–277.
27. Qi Z, Hao CM, Langenbach RI, Breyer RM, Redha R, Morrow JD, Breyer MD. Opposite effects of cyclooxygenase-1 and -2 activity on the pressor response to angiotensin II. J Clin Invest. 2002; 110: 61–69.[CrossRef][Medline] [Order article via Infotrieve]
28. Chu EK, Ribeiro SP, Slutsky AS. Heat stress increases survival rates in lipopolysaccharide-stimulated rats. Crit Care Med. 1997; 25: 1727–1732.[CrossRef][Medline] [Order article via Infotrieve]
29. Pedoto A, Tassiopoulos AK, Oler A, McGraw DJ, Hoffmann SP, Camporesi EM, Hakim TS. Treatment of septic shock in rats with nitric oxide synthase inhibitors and inhaled nitric oxide. Crit Care Med. 1998; 26: 2021–2028.[CrossRef][Medline] [Order article via Infotrieve]
30. Zingarelli B, Hasko G, Salzman AL, Szabo C. Effects of a novel guanylyl cyclase inhibitor on the vascular actions of nitric oxide and peroxynitrite in immunostimulated smooth muscle cells and in endotoxic shock. Crit Care Med. 1999; 27: 1701–1707.[CrossRef][Medline] [Order article via Infotrieve]
31. Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 2000; 119: 706–714.[CrossRef][Medline] [Order article via Infotrieve]
32. Gretzer B, Maricic N, Respondek M, Schuligoi R, Peskar BM. Effects of specific inhibition of cyclo-oxygenase-1 and cyclo-oxygenase-2 in the rat stomach with normal mucosa and after acid challenge. Br J Pharmacol. 2001; 132: 1565–1573.[CrossRef][Medline] [Order article via Infotrieve]
33. Hocherl K, Kammerl M, Kees F, Kramer BK, Grobecker HF, Kurtz A. Role of renal nerves in stimulation of renin, COX-2, and nNOS in rat renal cortex during salt deficiency. Am J Physiol Renal Physiol. 2002; 282: F478–F484.
34. Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. The natural history of the systemic inflammatory response syndrome (SIRS): a prospective study. JAMA. 1995; 273: 117–123.
35. Ichitani Y, Holmberg K, Maunsbach AB, Haeggstrom JZ, Samuelsson B, De Witt D, Hokfelt T. Cyclooxygenase-1 and cyclooxygenase-2 expression in rat kidney and adrenal gland after stimulation with systemic lipopolysaccharide: in situ hybridization and immunocytochemical studies. Cell Tissue Res. 2001; 303: 235–252.[CrossRef][Medline] [Order article via Infotrieve]
36. Liu SF, Newton R, Evans TW, Barnes PJ. Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin Sci (Lond). 1996; 90: 301–306.[Medline] [Order article via Infotrieve]
37. Almqvist PM, Ekstrom B, Kuenzig M, Haglund U, Schwartz SI. Increased survival of endotoxin-injected dogs treated with methylprednisolone, naloxone, and ibuprofen. Circ Shock. 1984; 14: 129–136.[Medline] [Order article via Infotrieve]
38. Fink MP, MacVittie TJ, Casey LC. Inhibition of prostaglandin synthesis restores normal hemodynamics in canine hyperdynamic sepsis. Ann Surg. 1984; 200: 619–626.[Medline] [Order article via Infotrieve]
39. Hanly PJ, Roberts D, Dobson K, Light RB. Effect of indomethacin on arterial oxygenation in critically ill patients with severe bacterial pneumonia. Lancet. 1987; 1: 351–354.[Medline] [Order article via Infotrieve]
40. Jacobs ER, Soulsby ME, Bone RC, WilsonFJ Jr, Hiller FC. Ibuprofen in canine endotoxin shock. J Clin Invest. 1982; 70: 536–541.[Medline] [Order article via Infotrieve]
41. Parratt JR, Sturgess RM. E. coli endotoxin shock in the cat: treatment with indomethacin. Br J Pharmacol. 1975; 53: 485–488.[Medline] [Order article via Infotrieve]
42. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med. 1997; 336: 912–918.
43. Fink MP, MacVittie TJ, Casey LC. Effects of nonsteroidal anti-inflammatory drugs on renal function in septic dogs. J Surg Res. 1984; 36: 516–525.[CrossRef][Medline] [Order article via Infotrieve]
44. Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ. Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol. 2001; 281: L537–L543.
45. Yamagata K, Matsumura K, Inoue W, Shiraki T, Suzuki K, Yasuda S, Sugiura H, Cao C, Watanabe Y, Kobayashi S. Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J Neurosci. 2001; 21: 2669–2677.
46. Ruetten H, Thiemermann C. Effects of tyrphostins and genistein on the circulatory failure and organ dysfunction caused by endotoxin in the rat: a possible role for protein tyrosine kinase. Br J Pharmacol. 1997; 122: 59–70.[CrossRef][Medline] [Order article via Infotrieve]
47. Ruetten H, Thiemermann C. Effect of calpain inhibitor I, an inhibitor of the proteolysis of I kappa B, on the circulatory failure and multiple organ dysfunction caused by endotoxin in the rat. Br J Pharmacol. 1997; 121: 695–704.[Medline] [Order article via Infotrieve]
48. Teale DM, Atkinson AM. L-Canavanine restores blood pressure in a rat model of endotoxic shock. Eur J Pharmacol. 1994; 271: 87–92.[Medline] [Order article via Infotrieve]
49. Avontuur JA, Tutein Nolthenius RP, van Bodegom JW, Bruining HA. Prolonged inhibition of nitric oxide synthesis in severe septic shock: a clinical study. Crit Care Med. 1998; 26: 660–667.[CrossRef][Medline] [Order article via Infotrieve]
50. Grover R, Zaccardelli D, Colice G, Guntupalli K, Watson D, Vincent JL. An open-label dose escalation study of the nitric oxide synthase inhibitor, NG-methyl-L-arginine hydrochloride (546C88), in patients with septic shock: Glaxo Wellcome International Septic Shock Study Group. Crit Care Med. 1999; 27: 913–922.[CrossRef][Medline] [Order article via Infotrieve]
51. Kiehl MG, Ostermann H, Meyer J, Kienast J. Nitric oxide synthase inhibition by L-NAME in leukocytopenic patients with severe septic shock. Intensive Care Med. 1997; 23: 561–566.[CrossRef][Medline] [Order article via Infotrieve]
52. Nava E, Palmer RM, Moncada S. Inhibition of nitric oxide synthesis in septic shock: how much is beneficial? Lancet. 1991; 338: 1555–1557.[CrossRef][Medline] [Order article via Infotrieve]
53. Wang D, Wei J, Hsu K, Jau J, Lieu MW, Chao TJ, Chen HI. Effects of nitric oxide synthase inhibitors on systemic hypotension, cytokines and inducible nitric oxide synthase expression and lung injury following endotoxin administration in rats. J Biomed Sci. 1999; 6: 28–35.[Medline] [Order article via Infotrieve]
54. Fukatsu K, Saito H, Fukushima R, Inoue T, Lin MT, Inaba T, Muto T. Detrimental effects of a nitric oxide synthase inhibitor (Nw-nitro-L-arginine-methyl-ester) in a murine sepsis model. Arch Surg. 1995; 130: 410–414.
55. Evans T, Carpenter A, Silva A, Cohen J. Inhibition of nitric oxide synthase in experimental gram-negative sepsis. J Infect Dis. 1994; 169: 343–349.[Medline] [Order article via Infotrieve]
56. Fox GA, Paterson NA, McCormack DG. Effect of inhibition of NO synthase on vascular reactivity in a rat model of hyperdynamic sepsis. Am J Physiol. 1994; 267: H1377–H1382.[Medline] [Order article via Infotrieve]
57. Scott JA, McCormack DG. Selective in vivo inhibition of inducible nitric oxide synthase in a rat model of sepsis. J Appl Physiol. 1999; 86: 1739–1744.
58. Thiemermann C, Wu CC, Szabo C, Perretti M, Vane JR. Role of tumour necrosis factor in the induction of nitric oxide synthase in a rat model of endotoxin shock. Br J Pharmacol. 1993; 110: 177–182.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. A. Steiner, J. C. Hunter, S. M. Phipps, T. B. Nucci, D. L. Oliveira, J. L. Roberts, A. C. Scheck, D. L. Simmons, and A. A. Romanovsky Cyclooxygenase-1 or -2--which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2009; 297(2): R485 - R494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Foudi, L. Louedec, T. Cachina, C. Brink, and X. Norel Selective cyclooxygenase-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation Cardiovasc Res, February 1, 2009; 81(2): 269 - 277. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Hocherl, C. Schmidt, B. Kurt, and M. Bucher Activation of the PGI2/IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock Hypertension, August 1, 2008; 52(2): 330 - 335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-c. Huang, P.-C. Chen, C.-W. Huang, and J. Yu Aristolochic Acid Induces Heart Failure in Zebrafish Embryos That is Mediated by Inflammation Toxicol. Sci., December 1, 2007; 100(2): 486 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lotter, K. Hocherl, M. Bucher, and F. Kees In vivo efficacy of telithromycin on cytokine and nitric oxide formation in lipopolysaccharide-induced acute systemic inflammation in mice J. Antimicrob. Chemother., September 1, 2006; 58(3): 615 - 621. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lehnert, T. Uehara, B. U. Bradford, H. Lind, Z. Zhong, D. A. Brenner, I. Marzi, and J. J. Lemasters Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation Am J Physiol Gastrointest Liver Physiol, September 1, 2006; 291(3): G456 - G463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Virdis, R. Colucci, M. Fornai, C. Blandizzi, E. Duranti, S. Pinto, N. Bernardini, C. Segnani, L. Antonioli, S. Taddei, et al. 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., March 1, 2005; 312(3): 945 - 953. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. LaPointe, M. Mendez, A. Leung, Z. Tao, and X.-P. Yang Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1416 - H1424. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||