Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4 mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42 ± 0.06 versus 0.73 ± 0.2 μmol/L, respectively; p < 0.001). Both ADMA (B = 3.5; 95% CI: 0.5-6.5; p = 0.023) and SDMA (B = 1.7; 95% CI: 0.7-2.7; p = 0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p = 0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p = 0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed.

ADMA, Arginine, Critical illness, MOF, Multiple organ failure, Nitric oxide, Rosiglitazone,
Pharmacological Research
Erasmus MC: University Medical Center Rotterdam

Richir, M.C, Ellger, B, Teerlink, T, Siroen, M.P.C, Visser, M, Spreeuwenberg, M.D, … van Leeuwen, P.A.M. (2009). The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients. Pharmacological Research (Vol. 60, pp. 519–524). doi:10.1016/j.phrs.2009.06.007