Endogenously synthesized nitric oxide prevents endotoxin-induced glomerular thrombosis.

Abstract

Escherichia coli endotoxin (LPS) can induce the clinical syndrome of septic shock and renal cortical necrosis and can stimulate nitric oxide (NO) production from macrophages, vascular smooth muscle, and glomerular mesangial cells in vitro. NO is an endogenous vasodilator, which also inhibits platelet aggregation and adhesion. We therefore sought to determine whether LPS would stimulate NO production in vivo and, if so, whether this NO would modulate endotoxin-induced glomerular thrombosis. The stable NO endproducts, NO2 and NO3, were measured in serum and urine collections from rats during baseline and after injection of LPS, with or without substances that modulate NO synthesis. The urinary excretion of NO2/NO3 was 1,964±311 nm/8 h during the baseline and increased to 6,833±776 nm/8 h after a single intraperitoneal injection of0.1 mg/kg LPS (P < 0.05). The serum concentration of NO2/ NO3 also significantly increased after LPS injection. Both the urine and serum stimulation was significantly prevented by the NO synthesis inhibitor, N,,-nitro-L-arginine methyl ester (L-NAME). L-Arginine, given with LPS + L-NAME significantly restored the NO2/NO3 levels in the urine. Ex vivo incubation oftissues from rats treated with LPS demonstrated NO production by the aorta, whole kidney, and glomeruli, but not cortical tubules. Histological examination of kidneys from rats given either LPS or L-NAME alone revealed that 2 and 4.5% of the glomeruli contained capillary thrombosis, respectively. In contrast, rats given LPS + L-NAME developed thrombosis in 55% of glomeruli (P < 0.001), which was significantly prevented when L-arginine was given concomitantly. We conclude that LPS stimulates endogenous production of NO in vivo and that this NO is critical in preventing LPS-induced renal thrombosis. (J. Clin. Invest. 1992. 90:1718-1725

Administration of anti-CD3 monoclonal antibody during experimental Chagas’ disease induces CD8+ cell-dependent lethal shock

“…L-NAME was given 30 min before, simultaneously with, and 2, 4 and 6 h after anti-CD3 MoAb injection. This protocol was previously shown to efficiently inhibit NO release in models of septic shock [26,29]. As previously observed in those models, L-NAME administration in T. cruzi-infected mice did not prevent and even appeared to increase anti-CD3 MoAb-induced lethality: lethality rates were 12/14 in L-NAME-injected mice versus 9/14 in mice injected with anti-CD3 MoAb alone.…”

“…Although NO was involved in the haemodynamic changes occurring during septic shock [28], the vasoactive properties of NO as well as its ability to inhibit platelet aggregation and adhesion might protect vital organs from the prothrombotic properties of IFN-and TNF- [37,38]. Indeed, inhibition of the constitutive and inducible forms of NOS by agents such as L-NAME was previously shown to increase the toxicity of bacterial toxins [26,29]. It is therefore not surprising that in this model, too, L-NAME administration appeared to enhance lethality.…”

Prevention and Treatment of Acute Renal Failure in Sepsis

“…NO thus appears to be cytotoxic to renal tubular cells. In contrast to the protective effects in isolated renal tubules, L-NAME resulted in an increase in proteinuria, a decline in renal function and a marked fibrin deposition and glomerular thrombosis during in vivo endotoxemic injury (58). Escherichia coli bacteremia in the rat increased cardiac output and caused renal hypoperfusion due to preglomerular vasoconstriction.…”

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

“…However, the administration of NOS inhibitors, which are not selective for the inducible isoforms of NOS, also causes a concomittant inhibition of the constitutive NOS in the endothelium and may increase the incidence of organ ' Author for correspondence. ischaemia, microvascular thrombosis and mortality (Hutcheson et al, 1990;Harbrecht et al, 1992;Shultz & Raij, 1992;Wright et al, 1992). Moreover, the non-selective NOS inhibitor N0-nitro-L-arginine methyl ester (L-NAME) causes detrimental haemodynamic effects in pigs with septic shock (Robertson et al, 1994).…”