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Reactive oxygen species and small-conductance calcium-dependent potassium channels are key mediators of inflammation-induced hypotension and shock

Anje Cauwels (UGent) , Elke Rogge (UGent) , Ben Janssen and Peter Brouckaert (UGent)
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Abstract
Septic shock is associated with life-threatening vasodilation and hypotension. To cause vasodilation, vascular endothelium may release nitric oxide (NO), prostacyclin (PGI2), and the elusive endothelium-derived hyperpolarizing factor (EDHF). Although NO is critical in controlling vascular tone, inhibiting NO in septic shock does not improve outcome, on the contrary, precipitating the search for alternative therapeutic targets. Using a hyperacute tumor necrosis factor (TNF)-induced shock model in mice, we found that shock can develop independently of the known vasodilators NO, cGMP, PGI2, or epoxyeicosatrienoic acids. However, the antioxidant tempol efficiently prevented hypotension, bradycardia, hypothermia, and mortality, indicating the decisive involvement of reactive oxygen species (ROS) in these phenomena. Also, in classical TNF or lipopolysaccharide-induced shock models, tempol protected significantly. Experiments with (cell-permeable) superoxide dismutase or catalase, N-acetylcysteine and apocynin suggest that the ROS-dependent shock depends on intracellular center dot OH radicals. Potassium channels activated by ATP (K-ATP) or calcium (K-Ca) are important mediators of vascular relaxation. While NO and PGI2-induced vasodilation involves K-ATP and large-conductance BKCa channels, small-conductance SKCa channels mediate vasodilation induced by EDHF. Interestingly, also SKCa inhibition completely prevented the ROS-dependent shock. Our data thus indicate that intracellular center dot OH and SKCa channels represent interesting new therapeutic targets for inflammatory shock. Moreover, they may also explain why antioxidants other than tempol fail to provide survival benefit during shock.
Keywords
HYDROGEN-PEROXIDE, OXIDATIVE STRESS, ENOS-DERIVED NO, ENDOTHELIUM-DEPENDENT HYPERPOLARIZATION, NITRIC-OXIDE SYNTHASE, Apamin, Shock, Hypotension, ROS, Potassium channels, Nitric oxide, SEPTIC SHOCK, ANTIOXIDANT, INHIBITION, K+ CHANNELS, IN-VIVO

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Chicago
Cauwels, Anje, Elke Rogge, Ben Janssen, and Peter Brouckaert. 2010. “Reactive Oxygen Species and Small-conductance Calcium-dependent Potassium Channels Are Key Mediators of Inflammation-induced Hypotension and Shock.” Journal of Molecular Medicine-jmm 88 (9): 921–930.
APA
Cauwels, Anje, Rogge, E., Janssen, B., & Brouckaert, P. (2010). Reactive oxygen species and small-conductance calcium-dependent potassium channels are key mediators of inflammation-induced hypotension and shock. JOURNAL OF MOLECULAR MEDICINE-JMM, 88(9), 921–930.
Vancouver
1.
Cauwels A, Rogge E, Janssen B, Brouckaert P. Reactive oxygen species and small-conductance calcium-dependent potassium channels are key mediators of inflammation-induced hypotension and shock. JOURNAL OF MOLECULAR MEDICINE-JMM. 2010;88(9):921–30.
MLA
Cauwels, Anje, Elke Rogge, Ben Janssen, et al. “Reactive Oxygen Species and Small-conductance Calcium-dependent Potassium Channels Are Key Mediators of Inflammation-induced Hypotension and Shock.” JOURNAL OF MOLECULAR MEDICINE-JMM 88.9 (2010): 921–930. Print.
@article{1029823,
  abstract     = {Septic shock is associated with life-threatening vasodilation and hypotension. To cause vasodilation, vascular endothelium may release nitric oxide (NO), prostacyclin (PGI2), and the elusive endothelium-derived hyperpolarizing factor (EDHF). Although NO is critical in controlling vascular tone, inhibiting NO in septic shock does not improve outcome, on the contrary, precipitating the search for alternative therapeutic targets. Using a hyperacute tumor necrosis factor (TNF)-induced shock model in mice, we found that shock can develop independently of the known vasodilators NO, cGMP, PGI2, or epoxyeicosatrienoic acids. However, the antioxidant tempol efficiently prevented hypotension, bradycardia, hypothermia, and mortality, indicating the decisive involvement of reactive oxygen species (ROS) in these phenomena. Also, in classical TNF or lipopolysaccharide-induced shock models, tempol protected significantly. Experiments with (cell-permeable) superoxide dismutase or catalase, N-acetylcysteine and apocynin suggest that the ROS-dependent shock depends on intracellular center dot OH radicals. Potassium channels activated by ATP (K-ATP) or calcium (K-Ca) are important mediators of vascular relaxation. While NO and PGI2-induced vasodilation involves K-ATP and large-conductance BKCa channels, small-conductance SKCa channels mediate vasodilation induced by EDHF. Interestingly, also SKCa inhibition completely prevented the ROS-dependent shock. Our data thus indicate that intracellular center dot OH and SKCa channels represent interesting new therapeutic targets for inflammatory shock. Moreover, they may also explain why antioxidants other than tempol fail to provide survival benefit during shock.},
  author       = {Cauwels, Anje and Rogge, Elke and Janssen, Ben and Brouckaert, Peter},
  issn         = {0946-2716},
  journal      = {JOURNAL OF MOLECULAR MEDICINE-JMM},
  keywords     = {HYDROGEN-PEROXIDE,OXIDATIVE STRESS,ENOS-DERIVED NO,ENDOTHELIUM-DEPENDENT HYPERPOLARIZATION,NITRIC-OXIDE SYNTHASE,Apamin,Shock,Hypotension,ROS,Potassium channels,Nitric oxide,SEPTIC SHOCK,ANTIOXIDANT,INHIBITION,K+ CHANNELS,IN-VIVO},
  language     = {eng},
  number       = {9},
  pages        = {921--930},
  title        = {Reactive oxygen species and small-conductance calcium-dependent potassium channels are key mediators of inflammation-induced hypotension and shock},
  url          = {http://dx.doi.org/10.1007/s00109-010-0633-2},
  volume       = {88},
  year         = {2010},
}

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