Lipopolysaccharide‐induced nitric oxide production and hypotension in Mkp‐1 deficient mice depends on L‐arginine uptake

Abstract

Mitogen activated protein kinase phosphatase‐1 (MKP‐1) limits the pro‐inflammatory response to lipopolysaccharide (LPS). We hypothesized that Mkp‐1−/− mice would respond to low‐dose LPS with a fall in blood pressure (BP) due to augmented expression of inducible nitric oxide synthase (iNOS), which would depend on L‐arginine uptake. To test this hypothesis, Mkp‐1−/− mice and their wild‐type littermates were treated with 10 μg/kg LPS iv and mean BP and exhaled NO production (exNO) were measured. Wild‐type mice had no change in BP or exNO during the experimental period, while Mkp‐1−/− mice had a fall in BP (79 ± 5% of baseline (BL)) and an increase in exNO (266 ± 50% of BL) after 150 min. Tissue levels of iNOS were greater in Mkp‐1−/− mice than in wild‐type mice. In additional experiments, 60 min after LPS Mkp‐1−/− and wild type mice were given L‐lysine (a competitive inhibitor of L‐arginine uptake) and BP and exNO monitored for 90 min. Treatment with L‐lysine prevented the LPS‐induced increase in exNO and decrease in BP in Mkp‐1−/− mice. When L‐lysine was given 150 min after LPS, L‐lysine treatment reversed both the LPS‐induced fall in BP and increase in exNO in Mkp‐1−/− mice. These results demonstrate that deficiency of MKP‐1 results in an exaggerated hypotensive response to LPS mediated by augmented iNOS expression, and the LPS‐induced increase in NO production depends on uptake of extracellular L‐arginine.