Neutral endopeptidase null mice are less susceptible to high altitude-induced pulmonary vascular leak.
Hypoxia increases pulmonary vascular leak, which is regulated in part by neutral endopeptidase (NEP). NEP is a cell-surface metalloprotease that degrades several vasoactive peptides, including endothelin-1 (ET-1) and atrial natriuretic peptide (ANP). We therefore hypothesized that NEP attenuates high altitude-induced pulmonary vascular leak. Wild-type and NEP null mice were exposed to a simulated high altitude (HA) of 6,728 m (22,000 ft; P(B) = 328 mmHg) or remained at the relatively low altitude (LA) of 1,500 m (4,920 ft; P(B) = 640 mmHg) for 24 h. Plasma ANP and ET-1 concentrations, right ventricular pressure (P(RV)), and indexes of lung injury were recorded. At HA, lung wet weight-to-body weight increased in all animals, but was greatest in the NEP wild-type mice. Vascular leak, as measured by Evans blue dye, increased only in the NEP wild-type mice at HA. P(RV) increased in both genotypes at HA. Plasma ANP concentrations increased at HA in both genotypes, but plasma ET-1 concentrations were elevated only in the NEP null mice at HA. Correlations between lung wet weight-to-body weight versus P(RV) (r = 0.56; p = 0.0136) and ANP versus P(RV) (r = -0.54; p = 0.02) were noted. We conclude that NEP null mice exposed to HA have a greater rise in ANP versus ET-1 plasma concentration, decreased pulmonary vascular pressure, and reduced high altitude-induced pulmonary vascular leak.
Irwin
David C
DC
Department of Biomedical Sciences, College of Veterinary and Biomedical Sciences, Colorado State University, Fort Collins, 80523, USA. Davidcirwin@earthlink.net
Patot
Martha Tissot Van
MT
Tucker
Alan
A
Bowen
Richard
R
D000532:Altitude Sickness / Q000378:metabolism*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood*; D019559:Capillary Leak Syndrome / Q000378:metabolism*; D002199:Capillary Permeability; D019332:Endothelin-1 / Q000097:blood*; D051379:Mice; D015260:Neprilysin / Q000097:blood*
D019332:Endothelin-1; D009320:Atrial Natriuretic Factor; D015260:Neprilysin