Abstract. On the basis of recent evidence that the cyclooxygenase-2 (COX-2) gene promoter contains functional binding sites for the nuclear factor of activated T cells (NFAT) and that COX-2 is expressed in a regulated fashion in the kidney, this study aimed to assess the effect of immunosuppressants on COX-2 expression in the kidney. Therefore, Wistar-Kyoto rats were treated with cyclosporine A (CsA; 15 mg/kg per day) or tacrolimus (5 mg/kg per day) for 7 d each. Both drugs markedly lowered COX-2 expression while COX-1 expression remained unaltered. Furthermore, CsA blunted the increase of renocortical COX-2 expression in response to low salt intake or a combination of low-salt diet with the ACE inhibitor ramipril (10 mg/kg per day), which strongly stimulates renocortical COX-2 expression. At the same time, calcineurin inhibitors moderately enhanced basal as well as stimulated renin secretion and renin gene expression. These findings suggest that inhibition of calcineurin could be a crucial determinant for the regulated expression of COX-2 in the kidney. Inhibition of COX-2 expression may therefore at least in part account for the well-known adverse effects of immunosuppressants in the kidney. Moreover, our data suggest that the stimulation of the renin system by low salt and by ACE inhibitors is not essentially mediated by COX-2 activity.The family of cyclooxygenases (COX)

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 ...