Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS‐induced DIC model rats

Abstract

To cite this article: Asakura H, Asamura R, Ontachi Y, Hayashi T, Yamazaki M, Morishita E, Miyamoto K-I, Nakao S. Selective inducible nitric oxide synthase inhibition attenuates organ dysfunction and elevated endothelin levels in LPS-induced DIC model rats. J Thromb Haemost 2005; 3:Summary. We examined the role of nitric oxide (NO) produced by an inducible isoform of NO synthase (iNOS) using N[6]-(iminoethyl)-lysine (L-NIL), a selective iNOS inhibitor, in the rat model of lipopolysaccharide (LPS)-induced disseminated intravascular coagulation (DIC) and investigated changes in organ function, plasma levels of NOX (metabolites of NO) and endothelin. We induced experimental DIC by the sustained infusion of 30 mg kgLPS for 4 h via the tail vein. We then investigated the effect of L-NIL (6 mg kg, from ) 0.5 to 4 h) on LPS-induced DIC. Blood was withdrawn at 4 and 8 h, and all four groups (LPS with or without L-NIL at 4 and 8 h) consisted of eight rats. Three of the animals in the 8-h LPS group died, and we examined blood samples from five rats in this group. None of the other rats died. The LPS-induced elevation of creatinine, alanine aminotransferase, glomerular fibrin deposition and plasminogen activator inhibitor was significantly suppressed by L-NIL coadministration, although L-NIL did not affect the platelet count, fibrinogen concentration or the level of thrombin-antithrombin complex. Moreover, plasma levels of the D-dimer that reflect the lysis of cross-linked fibrin were significantly increased by L-NIL coadministration in the LPS-induced DIC model. Plasma levels of NOX and endothelin were obviously increased by LPS infusion. However, both levels were significantly suppressed in the LPS + L-NIL group, when compared with the LPS group. Although mean arterial pressure (MAP) was significantly decreased between 2 and 8 h compared with the control in the LPS group, this depression was significantly attenuated in the LPS + L-NIL group. Our results suggest that NO induced by iNOS contributes to hypotension (depressed MAP), the progression of hepatic and renal dysfunction, microthrombus deposition and elevated endothelin levels in the rat model of LPS-induced DIC.

Lack of iNOS Impairs Endothelial Function in Endothelin-1 Transgenic Mice

“…We furthermore showed in ET+/+ eNOS-/-crossbred mice that the absence of eNOS promotes hypertension in states of ET-1 upregulation [26] . On the other hand, inhibition of iNOS is known to attenuate impairment of organ function in states of elevated ET-1 levels [27] . Shimojo et al [28] recently described an upregulation of iNOS gene expression in cardiomyocytes exposed to elevated levels of ET-1.…”

Propofol attenuates cytokine-mediated upregulation of expression of inducible nitric oxide synthase and apoptosis during regeneration post-partial hepatectomy

“…As such, PHT or ischemia-reperfusion injury may result in increased expression of iNOS [24][25][26][27] . The twosided effects of NO must be understood.…”

Sepsis mediators

“…Enhanced iNOS activity in inflamed tissues and vessel walls of sepsis patients has been demonstrated [37]. NO production has been involved in many pathophysiologic processes during sepsis or endotoxemia models, and NO is rendered responsible for multiorgan failure [38]. On the other hand, NO was shown to reduce neutrophil migration to infected tissues by inhibiting leukocyte rolling.…”