Vascular BK channel deficiency exacerbates organ damage and mortality in endotoxemic mice

摘要

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 to 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 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.