Potential interrelation of nitric oxide (NO) generation by inducible nitric oxide synthase (iNOS) and by asymmetric dimethylarginine (ADMA) and the pathophysiology of sepsis. 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 TEPP-46 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 TEPP-46 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 TEPP-46 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 Rabbit polyclonal to ATF2 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 . During the past decade knowledge has accumulated of endogenous compounds that inhibit NO synthase activity, and thereby regulate NO-dependent vascular function. The major molecule endogenously present in the circulation at concentrations sufficiently high to exert inhibitory effects on NO synthesis in vivo is ADMA. A structural analogue of NG-monomethyl-L-arginine, the long-known NO synthase inhibitor, and of L-arginine, ADMA is the endogenous substrate of NO synthase (Figure ?(Figure1).1). ADMA levels have been shown to regulate NO generation, endothelial function, and vascular resistance in animal models and in humans (for recent reviews, see [8-10]). Moreover, ADMA has evolved from prospective clinical trials as a novel cardiovascular risk marker . Open in a separate window Figure 1 Structural formulae. Schematic drawings of the structural formula of (a) L-arginine, the natural substrate of nitric oxide (NO) synthase, (b) NG-monomethyl-L-arginine, the NO synthase inhibitor used in clinical trials, and (c) asymmetric dimethylarginine, the endogenous inhibitor of NO synthases. The circle in (a) indicates the terminal guanidino nitrogen group, where NO is cleaved by NO synthase. 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 TEPP-46 be a superior predictive marker of ICU death . We have recently shown that ADMA levels are prospectively associated with organ TEPP-46 dysfunction and with the postoperative complication rate in patients undergoing major.