Selective Inducible Nitric Oxide Synthase Inhibition During Long-Term Hyperdynamic Porcine Bacteremia

Abstract

We have recently demonstrated that selective inducible nitric oxide (NO) synthase (iNOS) inhibition with 1400W attenuated the hemodynamic and metabolic alterations affiliated with hyperdynamic porcine endotoxemia. In contrast to endotoxemia, limited evidence is available to document a relationship between NO and organ dysfunction in large animal bacteremic models. Therefore, using the same experimental setup, we investigated the role of selective iNOS blockade in porcine bacteremia induced and maintained for 24 h with a continuous infusion of live Pseudomonas aeruginosa. After 12 h of sepsis, animals received either vehicle (Control, n = 8) or continuous infusion of selective iNOS inhibitor, L-N6-(1-iminoethyl)-lysine (L-NIL; n = 8). Measurements were performed before, and 12, 18, and 24 h after P. aeruginosa infusion. L-NIL inhibited sepsis-induced increase in plasma nitrate/nitrite concentrations and prevented hypotension without affecting cardiac output. Despite comparable hepatosplanchnic macrocirculation, L-NIL blunted the progressive deterioration in ileal mucosal microcirculation and prevented mucosal acidosis. L-NIL largely attenuated mesenteric and hepatic venous acidosis, significantly improved P. aeruginosa-induced impairment of hepatosplanchnic redox state, and mitigated the decline in liver lactate clearance. Furthermore, the administration of L-NIL reduced the hepatocellular injury and prevented the development of renal dysfunction. Finally, treatment with L-NIL significantly attenuated the formation of 8-isoprostane concentrations, a direct marker of lipid peroxidation. Thus, selective iNOS inhibition with L-NIL prevented live bacteria from causing key features of metabolic derangements in porcine hyperdynamic sepsis. Underlying mechanisms probably include reduced oxidative stress with improved microcirculatory perfusion and restoration of cellular respiration.

Renal Hemodynamics in AKI

“…33 Therapeutic interventions aimed at maintaining the homeostatic balance between oxygen radicals, nitric oxide, and oxygen have been shown to be effective in several studies in rodent models of septic AKI [27][28][29][30][31] and ischemia-reperfusion injury 52 as well as in large animal models of septic AKI. 53,54 The lack of effective inducible nitric oxide synthase inhibitors for clinical use can be considered an important area for research.…”

Negative Regulation of Inducible Nitric-oxide Synthase Expression Mediated through Transforming Growth Factor-β-dependent Modulation of Transcription Factor TCF11

“…3). Selective iNOS inhibition has been shown to attenuate the hemodynamic alterations in sepsis models (4).…”

In Vivo Characterization of the Novel Imidazopyridine BYK191023 [2-[2-(4-Methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine], a Potent and Highly Selective Inhibitor of Inducible Nitric-Oxide Synthase

“…A large number of studies in animal models of acute and chronic inflammation have demonstrated beneficial effects of pharmacological intervention with nitric oxide production and activity or genetic deletion of the iNOS gene, suggesting that inhibition of iNOS could represent an interesting novel therapeutic principle (MacMicking et al, 1995;Cuzzocrea et al, 2001Cuzzocrea et al, , 2002Ichinose et al, 2003;Matejovic et al, 2004). During severe sepsis, uncontrolled excess synthesis and release of nitric oxide by iNOS are considered a potential contributor to pathological vasodilatation, eventually leading to severe hypotension with insufficient organ perfusion and consequently multiorgan failure (Titheradge, 1999;Cobb, 2001).…”