Live and let die: asymmetric dimethylarginine and septic shock
© BioMed Central Ltd 2006
Published: 03 November 2006
Nitric oxide (NO) is an important mediator of host defence and of vascular tone. In septic shock, upregulation of inducible NO synthase leads to the production of vast amounts of NO, which contribute to pathogen elimination but also to inappropriate vasodilation and to loss of vascular resistance. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthases shown to contribute to the regulation of vascular tone. ADMA was recently identified as a marker of organ dysfunction and mortality in intensive care patients and as a novel cardiovascular risk factor. In the present issue of Critical Care, a study by O'Dwyer and colleagues identifies ADMA as a potential regulator of NO production in septic shock. Being an inhibitor of NO production, ADMA may at least partly counteract pathological hypotension, but at the same time may impair the NO-dependent host defence. A mechanism is proposed by which the interplay between ADMA and inducible NO synthase activity is mediated. ADMA levels should be determined in future studies evaluating the regulation of NO in the intensive care setting.
In the previous issue of Critical Care, O'Dwyer and colleagues  report the results of a study in 47 patients with septic shock. Asymmetric dimethylarginine (ADMA) levels were elevated in these patients at the time of admission to the intensive care unit (ICU) as compared with a group of 10 healthy controls. ADMA levels in septic patients directly correlated with the Sequential Organ Failure Assessment scores, with the degree of acidaemia and lactaemia, and with vasopressor requirements. Interestingly enough, ADMA levels were higher in patients requiring vasoactive infusions than in those not requiring vasoactive infusions. ADMA levels further increased during the subsequent 7 days of ICU treatment. Nonsurvivors tended to have higher ADMA plasma levels on days 1 and 7 of ICU treatment as compared with survivors, although this trend was insignificant in the small patient group. The authors also demonstrated that a genetic polymorphism in the promoter region of the dimethylarginine dimethylaminohydrolase (DDAH) II gene was significantly associated with ADMA levels in these patients, suggesting that the genetically anchored dysfunction of the enzyme that metabolises ADMA may importantly regulate ADMA levels.
Standard therapy for patients with sepsis includes ICU admission, careful selection of antibiotic therapy, and, if needed, haemodynamic and ventilatory support . Despite the use of these intensive therapies, however, mortality from sepsis has remained at levels between 35% and 50% .
Nitric oxide (NO) is referred to as a key mediator of vasodilatation and catecholamine resistance in septic shock [3, 4]. Whereas in physiological conditions NO is mainly formed in the endothelium at low rates by the activity of the constitutive, endothelial isoform of the enzyme NO synthase, inflammatory stimuli such as bacterial lipopolysaccharides and cytokines released during sepsis result in a strong upregulation of an inducible isofom of NO synthase (iNOS). This isoform, once upregulated, releases huge amounts of NO during prolonged time intervals. The iNOS-derived NO contributes to pathogen elimination. NO-induced vasodilatation, however, also contributes to widespread vascular loss of tone and has been implicated in the cardiovascular failure in septic shock . There has been controversy about the pathophysiological roles of iNOS and NO in the development of septic shock after a phase III trial with NG-monomethyl-L-arginine, a nonselective NO synthase inhibitor, resulted in excess mortality . Indeed, experimental studies have suggested that iNOS-derived NO plays an important role in host defence and organ protection .
Previous evidence has linked elevated ADMA levels to reduced kidney and liver function and to multiple organ failure in ICU patients . Moreover, prospective clinical data point to the fact that ADMA may be a superior predictive marker of ICU death . We have recently shown that ADMA levels are prospectively associated with organ dysfunction and with the postoperative complication rate in patients undergoing major elective surgery (unpublished data).
In the battle between the invading pathogen and the host organism, NO generation has to be kept in a delicate balance between 'live' (keeping NO within boundaries for cardiovascular homeostasis) and 'let die' (upregulating NO to a sufficient degree for pathogen defence). Here, upregulation of ADMA levels may be another long ignored but important regulator.
With ADMA as a novel player in the game, understanding the role of NO in the 'live and let die' issue of septic shock has become even more complex. Measuring ADMA levels should certainly be considered in future studies on NO in critically ill patients.
intensive care unit
inducible NO synthase
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