Introduction
In septic shock, iNOS activation and nitric oxide (NO) overproduction contribute to vascular hyporeactivity to adrenergic vasopressors. The consequent hypotension often necessitates high doses of catecholamine administration. However, this may lead to detrimental effects on tissue perfusion, immune function and myocardial function. Asymmetric dimethlyarginine (ADMA), an endogenous inhibitor of NO synthase, is extensively metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Competitive inhibition of the DDAH-1 isoform should thus reverse hypotension but, as this isoform is absent in immune cells, it should not compromise the immune effects of NO. Hence, we investigated whether L257, a novel DDAH-1 inhibitor, could spare norepinephrine dosing in a rat endotoxic shock model.