Cyclooxygenase-2 Inhibition Attenuates Lipopolysaccharide-Induced Cardiovascular Failure

Abstract

Abstract-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 Ϫ1 . 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 Ⅲ cyclooxygenase Ⅲ hemodynamics Ⅲ prostaglandins Ⅲ nitric oxide I t 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][2][3] There is consensus that the first mediators in the cascade of LPSinduced 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][6][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 LPSinduced 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 ...

Cyclooxygenase-2 Inhibition Improves Vascular Endothelial Dysfunction in a Rat Model of Endotoxic Shock: Role of Inducible Nitric-Oxide Synthase and Oxidative Stress

“…Concomitantly, we detected an enhanced expression of iNOS in mesenteric vascular walls, whereas eNOS was unaffected. These findings, although extending to the mesenteric vascular district the concept that endotoxemia is associated with up-regulated iNOS expression (Hocherl et al, 2002), indicate that LPS-induced endothelial dysfunction is characterized by a significant reduction in stimulated NO availability. The different behavior of NOS isoforms in response to LPS (up-regulation of iNOS and unmodified eNOS expression), together with the reduced NO availability, is in line with a previous report on rabbit carotid arteries exposed to inflammatory cytokines (Kessler et al, 1997), showing that iNOS up-regulation was associated with an unmodified eNOS expression and an impaired endothelial function.…”

Activation of the PGI 2 /IP System Contributes to the Development of Circulatory Failure in a Rat Model of Endotoxic Shock

“…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 PGI 2 synthesis via inactivation of PGIS. 32 Furthermore, it has been suggested that the induction of COX-2 in the heart is involved in myocardial dysfunction 33,34 and that increased PGI 2 synthesis via COX-2 could in part mediate LPS-induced cardiac failure.…”

“…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.…”

Lipopolysaccharide-binding protein modulates hepatic damage and the inflammatory response after hemorrhagic shock and resuscitation

“…Because endotoxemia affects blood pressure (19,35), we first determined whether the blood pressures of wild-type and knockout mice were comparable before, during, and after hemorrhage/resuscitation. Before the imposition of hemorrhagic shock, the blood pressures of wild-type mice and knockout mice were nearly identical (Table 1).…”