Deficiency of mitogen-activated protein kinase phosphatase-1 results in iNOS-mediated hypotension in response to low-dose endotoxin.
Mitogen-activated protein kinase phosphatase-1 (MKP-1) is essential in limiting the proinflammatory response to lipopolysaccharide (LPS). We hypothesized that Mkp-1(-/-) mice would respond to low-dose LPS with a fall in blood pressure due to augmented expression of inducible nitric oxide (NO) synthase (iNOS). To test this hypothesis, Mkp-1(-/-) mice and their wild-type littermates were treated with 10 microg/kg iv LPS, and mean arterial blood pressure (MAP) and exhaled NO production (exNO) were measured. Tissues were harvested for an assessment of iNOS protein levels. Wild-type mice had no change in MAP or exNO during the experimental period, whereas Mkp-1(-/-) mice had a fall (P < 0.005) in MAP [79 +/- 5% of baseline (BL)] and an increase (P < 0.01) in exNO (266 +/- 50% of BL) after 150 min. The tissue levels of iNOS were greater in Mkp-1(-/-) than in wild-type mice. In additional experiments, 60 min after LPS treatment, Mkp-1(-/-) and wild-type mice were given N(omega)-nitro-l-arginine methyl ester (l-NAME) or aminoguanidine, and MAP and exNO were monitored for 90 min. Treatment with l-NAME prevented the LPS-induced increase in exNO and decrease in MAP but resulted in decreased exNO and elevated MAP in wild-type mice. Aminoguanidine prevented the increase in exNO and the fall in MAP caused by LPS in Mkp-1(-/-) mice, without significantly affecting MAP or exNO in wild-type mice. These results demonstrate that a deficiency of MKP-1 results in an exaggerated hypotensive response to LPS mediated by augmented iNOS expression. We speculate that defects in the Mkp-1 gene may increase susceptibility for the development of septic shock.
Calvert
Thomas J
TJ
The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Chicoine
Louis G
LG
Liu
Yusen
Y
Nelin
Leif D
LD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001944:Breath Tests; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D007022:Hypotension / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D006146:Guanidines; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; C091861:spermine nitric oxide complex; D013096:Spermine; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester