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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 .
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 ,
nitric oxide ( no ) is referred to as a key mediator of vasodilatation and catecholamine resistance in septic shock .
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 n - 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 n - monomethyl - l - arginine , the long - known no synthase inhibitor , and of l - arginine
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 .
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 .
upregulation of inos leads to the release of huge amounts of no and superoxide , which , by forming peroxynitrite , can nitrosylate proteins and thereby damage tissues .
s - nitrosylation of ddah ii has been shown to downregulate this enzyme 's activity , leading to accumulation of adma .
this may explain why adma levels were actually higher in patients with more vasopressor need in the study by o'dwyer and colleagues : vasopressor need identified patients with greater inos induction , which , in turn , may have resulted in ddah nitrosylation  and thereby inactivation  which finally resulted in higher adma levels that blocked the activities of both constitutive and inducible no synthases ( figure 2 ) .
alternatively , compromised kidney and liver function secondary to tissue malperfusion may have led to reduced metabolic clearance of adma by ddahs .
the study did not , however , report any data to support or refute any of these hypotheses .
adma may interfere , by nonspecific inhibition of no synthases , with critical physiological functions , eventually giving rise to a cascade of organ dysfunction that may be fatal to the critically ill patient .
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 .
adma = asymmetric dimethylarginine ; ddah = dimethylarginine dimethylaminohydrolase ; icu = intensive care unit ; inos = inducible no synthase ; no = nitric oxide .
rhb is named as an inventor on patents relating to endogenous inhibitors of the nitric oxide pathway and receives royalties from licenses thereof .
structural formulae . schematic drawings of the structural formula of ( a ) l - arginine , the natural substrate of nitric oxide ( no ) synthase , ( b ) n - 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 . potential interrelation of nitric oxide generation and the pathophysiology of sepsis .
potential interrelation of nitric oxide ( no ) generation by inducible nitric oxide synthase ( inos ) and by asymmetric dimethylarginine ( adma ) and the pathophysiology of sepsis .
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 .