title: Vascular BK channel deficiency exacerbates organ damage and mortality in endotoxemic mice.
abstract: We determined the contribution of vascular BK channels to endotoxin (lipopolysaccharide, LPS)-induced hypotension, organ damage, and mortality using smooth muscle BK channel deficiency (BK channel β1-subunit knockout, BK β1-KO) mice. BK β1-KO mice were more sensitive to LPS-induced mortality compared with wild-type mice. After LPS (20 mg/kg, intraperitoneally), BK β1-KO mice had a more rapid fall in heart rate and blood pressure (measured by radiotelemetry), shorter latency to mortality, and higher mortality rate than wild-type mice. Twenty-two hours after LPS treatment, wild-type and BK β1-KO mice had reduced norepinephrine reactivity and impaired constrictor responses to the BK channel blocker paxilline in mesenteric arteries in vitro and higher iNOS expression in the heart, but not in mesenteric arteries. Endotoxemic BK β1-KO mice also showed more severe lung and intestinal injury, higher myeloperoxidase activity and polymorphonuclear neutrophil infiltration in lung and liver. Endotoxemic BK β1-KO mice had higher plasma tumor necrosis factor α and interleukin 6 levels at 22 hours, but not 6 hours post-LPS. Exaggerated mortality in BK β1-KO mice also occurred in the cecal ligation/puncture model of septic shock. Reduced vascular BK channel function does not protect against hypotension in the early stage of septic shock; in the later stage, smooth muscle BK channel deficiency enhances organ damage and mortality.
authors: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA.
authors: Hui
authors: H
authors: Xu
authors: Youping
authors: Y
authors: Wang
authors: Hannah
authors: H
authors: Garver
authors: James J
authors: JJ
authors: Galligan
authors: Gregory D
authors: GD
authors: Fink
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000503:physiopathology*; D005260:Female; D006339:Heart Rate; D007022:Hypotension / Q000209:etiology; D015850:Interleukin-6 / Q000097:blood; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits / Q000235:genetics*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D012772:Shock, Septic / Q000503:physiopathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D015850:Interleukin-6; C543091:Kcnmb1 protein, mouse; D051038:Large-Conductance Calcium-Activated Potassium Channel beta Subunits; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009638:Norepinephrine