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

Cauwels A, Rogge E, Janssen B, Brouckaert P - J. Mol. Med. (2010)

Bottom Line: 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.Also, in classical TNF or lipopolysaccharide-induced shock models, tempol protected significantly.Moreover, they may also explain why antioxidants other than tempol fail to provide survival benefit during shock.

View Article: PubMed Central - PubMed

Affiliation: Department for Molecular Biomedical Research, VIB, Technologiepark 927, 9052 Ghent, Belgium. anje@dmbr.UGent.be

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 (*)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 BK(Ca) channels, small-conductance SK(Ca) channels mediate vasodilation induced by EDHF. Interestingly, also SK(Ca) inhibition completely prevented the ROS-dependent shock. Our data thus indicate that intracellular (*)OH and SK(Ca) 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.

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The role of K+ channels and H2O2 in ROS-dependent zVAD + TNF shock. a Effect of different K+ channel inhibitors. Plotted is the percent survival of all mice used in up to five independent experiments; total numbers are indicated between brackets in the legend. ***P < 0.0001 compared with zVAD + TNF (black bar). b, c Effect of apamin on hypothermia (b) and mortality (c) induced by zVAD ± TNF in a representative experiment (n in the legend), *P < 0.05, **P = 0.0049, ***P < 0.001 compared with zVAD ± TNF. d, e Mean arterial pressure and HR were monitored in conscious radiotelemetred mice injected with zVAD ± TNF. Three mice were treated with apamin 2 h before TNF, plotted are the non-survivor and one of the two survivors. f Effect of catalase and PEG-catalase on protection by tempol, ***P < 0.001 compared with tempol + zVAD + TNF (diamonds); data shown are from one individual representative experiment
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Fig4: The role of K+ channels and H2O2 in ROS-dependent zVAD + TNF shock. a Effect of different K+ channel inhibitors. Plotted is the percent survival of all mice used in up to five independent experiments; total numbers are indicated between brackets in the legend. ***P < 0.0001 compared with zVAD + TNF (black bar). b, c Effect of apamin on hypothermia (b) and mortality (c) induced by zVAD ± TNF in a representative experiment (n in the legend), *P < 0.05, **P = 0.0049, ***P < 0.001 compared with zVAD ± TNF. d, e Mean arterial pressure and HR were monitored in conscious radiotelemetred mice injected with zVAD ± TNF. Three mice were treated with apamin 2 h before TNF, plotted are the non-survivor and one of the two survivors. f Effect of catalase and PEG-catalase on protection by tempol, ***P < 0.001 compared with tempol + zVAD + TNF (diamonds); data shown are from one individual representative experiment

Mentions: NO and PGI2 activate large-conductance BKCa and KATP channels [2, 8, 9]. Vascular smooth muscle BKCa channels may also be activated by EETs or H2O2, which have been suggested as EDHFs in certain systems [3]. In contrast, EDHF-dependent hyperpolarization specifically depends on endothelial SKCa channels, and not on BKCa or KATP channels [3, 4]. To study K+ channels, we used apamin (SKCa inhibitor), iberiotoxin (BKCa inhibitor), charybdotoxin (inhibits BKCa, IKCa, and certain voltage-gated Kv), glibenclamide (KATP inhibitor), and TEA (inhibits BKCa, KATP, and some Kv). Only apamin completely prevented hyperacute (within 6 h) zVAD + TNF-induced hypothermia and mortality (Fig. 4a–c). Furthermore, apamin also significantly protected against long-term TNF-induced mortality (Fig. 4a, c). To evaluate the cardiovascular effects of SKCa inhibition, blood pressure and heart rate were measured in radiotelemetred mice. In two of the three animals pretreated with apamin, hypotension and bradycardia were efficiently prevented (one representative mouse is shown in Fig. 4d, e), resulting in survival. In one mouse, apamin could not prevent but delayed hypotension, bradycardia, and mortality (Fig. 4d, e, dotted line)Fig. 4


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

Cauwels A, Rogge E, Janssen B, Brouckaert P - J. Mol. Med. (2010)

The role of K+ channels and H2O2 in ROS-dependent zVAD + TNF shock. a Effect of different K+ channel inhibitors. Plotted is the percent survival of all mice used in up to five independent experiments; total numbers are indicated between brackets in the legend. ***P < 0.0001 compared with zVAD + TNF (black bar). b, c Effect of apamin on hypothermia (b) and mortality (c) induced by zVAD ± TNF in a representative experiment (n in the legend), *P < 0.05, **P = 0.0049, ***P < 0.001 compared with zVAD ± TNF. d, e Mean arterial pressure and HR were monitored in conscious radiotelemetred mice injected with zVAD ± TNF. Three mice were treated with apamin 2 h before TNF, plotted are the non-survivor and one of the two survivors. f Effect of catalase and PEG-catalase on protection by tempol, ***P < 0.001 compared with tempol + zVAD + TNF (diamonds); data shown are from one individual representative experiment
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Fig4: The role of K+ channels and H2O2 in ROS-dependent zVAD + TNF shock. a Effect of different K+ channel inhibitors. Plotted is the percent survival of all mice used in up to five independent experiments; total numbers are indicated between brackets in the legend. ***P < 0.0001 compared with zVAD + TNF (black bar). b, c Effect of apamin on hypothermia (b) and mortality (c) induced by zVAD ± TNF in a representative experiment (n in the legend), *P < 0.05, **P = 0.0049, ***P < 0.001 compared with zVAD ± TNF. d, e Mean arterial pressure and HR were monitored in conscious radiotelemetred mice injected with zVAD ± TNF. Three mice were treated with apamin 2 h before TNF, plotted are the non-survivor and one of the two survivors. f Effect of catalase and PEG-catalase on protection by tempol, ***P < 0.001 compared with tempol + zVAD + TNF (diamonds); data shown are from one individual representative experiment
Mentions: NO and PGI2 activate large-conductance BKCa and KATP channels [2, 8, 9]. Vascular smooth muscle BKCa channels may also be activated by EETs or H2O2, which have been suggested as EDHFs in certain systems [3]. In contrast, EDHF-dependent hyperpolarization specifically depends on endothelial SKCa channels, and not on BKCa or KATP channels [3, 4]. To study K+ channels, we used apamin (SKCa inhibitor), iberiotoxin (BKCa inhibitor), charybdotoxin (inhibits BKCa, IKCa, and certain voltage-gated Kv), glibenclamide (KATP inhibitor), and TEA (inhibits BKCa, KATP, and some Kv). Only apamin completely prevented hyperacute (within 6 h) zVAD + TNF-induced hypothermia and mortality (Fig. 4a–c). Furthermore, apamin also significantly protected against long-term TNF-induced mortality (Fig. 4a, c). To evaluate the cardiovascular effects of SKCa inhibition, blood pressure and heart rate were measured in radiotelemetred mice. In two of the three animals pretreated with apamin, hypotension and bradycardia were efficiently prevented (one representative mouse is shown in Fig. 4d, e), resulting in survival. In one mouse, apamin could not prevent but delayed hypotension, bradycardia, and mortality (Fig. 4d, e, dotted line)Fig. 4

Bottom Line: 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.Also, in classical TNF or lipopolysaccharide-induced shock models, tempol protected significantly.Moreover, they may also explain why antioxidants other than tempol fail to provide survival benefit during shock.

View Article: PubMed Central - PubMed

Affiliation: Department for Molecular Biomedical Research, VIB, Technologiepark 927, 9052 Ghent, Belgium. anje@dmbr.UGent.be

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 (*)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 BK(Ca) channels, small-conductance SK(Ca) channels mediate vasodilation induced by EDHF. Interestingly, also SK(Ca) inhibition completely prevented the ROS-dependent shock. Our data thus indicate that intracellular (*)OH and SK(Ca) 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.

Show MeSH
Related in: MedlinePlus