A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

Abstract

The nitric oxide pathway plays a critical role in vascular homeostasis. Increased levels of systemic nitric oxide (NO) are observed in preclinical models of sepsis and endotoxemia. This has led to the postulation that vasodilation by inducible nitric oxide synthase (iNOS) generated NO may be a mechanism of hypotension in sepsis. However, contrary to the expected pharmacological action of a nitric oxide synthase (NOS) inhibitor, clinical studies with L-NAME produced adverse cardiac and pulmonary events, and higher mortality in sepsis patients. Thus, the potential adverse effects of NO in human sepsis and shock have not been fully established. In recent years, the emerging new understanding of the NO pathway has shown that an endogenously produced inhibitor of NOS, asymmetric dimethylarginine (ADMA), a host response to infection, may play an important role in the pathophysiology of sepsis as well as organ damage during ischemia–reperfusion. ADMA induces microvascular dysfunction, proinflammatory and prothrombotic state in endothelium, release of inflammatory cytokines, oxidative stress and mitochondrial dysfunction. High levels of ADMA exist in sepsis patients, which may produce adverse effects like those observed with L-NAME. Several studies have demonstrated the association of plasma ADMA levels with mortality in sepsis patients. Preclinical studies in sepsis and ischemia–reperfusion animal models have shown that lowering of ADMA reduced organ damage and improved survival. The clinical finding with L-NAME and the preclinical research on ADMA “bed to bench” suggest that ADMA lowering could be a potential therapeutic approach to attenuate progressive organ damage and mortality in sepsis. Testing of this approach is now feasible by using the pharmacological molecules that specifically lower ADMA.

Endothelial dysfunction and immunothrombosis in sepsis

“…Some studies suggest that NO production increases during sepsis and this is associated with poor prognosis, while others support that NO levels are lower in sepsis patients compared to healthy controls (48)(49)(50)(51). New evidence suggests that increased NO bioavailability in sepsis may be beneficial for the host without deteriorating vasodilation and subsequent hypotension, as has been proposed in previous studies (52). Overall, the dysregulation of the NO pathway during sepsis merits further investigation.…”

Early adjunctive methylene blue in patients with septic shock: a randomized controlled trial

“…Sparing the constitutive isoform is important to maintain homeostasis even in sepsis; for instance, to improve microcirculatory flow, increase blood flow to ischemic areas, scavenge oxygen-free radicals, and enhance microbial killing by macrophages [31]. It has been postulated that a global inhibition of NO is associated with detrimental effects in sepsis that can result in accelerated organ damage [32]; thus, a more downstream inhibition within the NO cascade as provided by MB could be a better approach. In line with these assumptions, MB was associated with a reduction in mortality in a recent systematic review and meta-analysis pooling observational and RCT studies [33].…”

Preeclamptic programming unevenly perturbs inflammatory and renal vasodilatory outcomes of endotoxemia in rat offspring: modulation by losartan and pioglitazone

“…The observation that gestational therapies failed to modify the hypotensive response to LPS in male offspring of PE dams despite the suppression of the concomitant inflammatory signal deserves a comment. Admittedly, the hypotensive response to endotoxemia is often set off by the developed state of systemic inflammation, which begins with the LPS-mediated upregulation of the TLR-4/NFκB/ TNFα/iNOS cascade and consequent overproduction of NO, diminution of vascular resistance, and widespread systemic vasodilation (El-Mas et al, 2008;Singh et al, 2022). Since the inflammatory response was obliterated by gestational therapies Frontiers in Pharmacology frontiersin.org particularly the combined losartan/pioglitazone regimen, it is likely that factors other than the inflammatory milieu might be responsible for the persistent fall in blood pressure.…”