Drug Discovery Opinion

Septic shock, characterised by refractory hypotension and resulting end-organ dysfunction, is a major cause of death in intensive care units. Systemic inflammation leads to increased production of nitric oxide (NO), an important regulator of vascular tone, which was believed to play a key role in the pathogenesis of septic shock. In support of this hypothesis, early animal studies and small scale clinical trials appeared to show that nitric oxide synthase inhibitors were beneficial in septic shock. Disappointingly, however, outcome studies with the non-selective nitric oxide synthase inhibitor, tilarginine, found that treatment was associated with excess mortality in septic shock and provided no benefit in cardiogenic shock.

A team led by scientists at VIB and Ghent University have now shown that, rather than contributing to damage in septic shock, NO may instead be beneficial. When mice with septic shock induced by a lethal TNF challenge were treated with nitrite – which can serve as a source of NO – hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction and mortality were all attenuated. Nitrite also provided protection against toxicity induced by Gram-negative lipopolysaccharide, although higher doses were needed. Until recently, nitrite was believed to be an inert metabolite of NO but is now considered to be a central homeostatic molecule in NO biology and to serve as an important signalling molecule and regulator of gene expression in its own right. The protection afforded by nitrite treatment was largely abolished in mice lacking the soluble guanylate cyclase 1 subunit, an important intracellular NO receptor and signal transducer. Although the mechanisms underlying the protective effects of nitrite in septic shock are not yet fully understood, the study provides new information about the role of NO in septic shock and suggests new opportunities for treatment.

The study is published in the Journal of Experimental Medicine.

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