Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice

Jahn, Nora; Lamberts, Regis R.; Busch, Cornelius; Voelker, Maria Theresa; Busch, Thilo; Koel-Simmelink, Marleen; Teunissen, Charlotte E.; Oswald, Daniel D.; Loer, Stephan A.; Kaisers, Udo X.; Weimann, Jörg

doi:10.1186/s12931-015-0274-7

Cited by 8 publications

(8 citation statements)

References 57 publications

(96 reference statements)

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“…In line with other studies, a strong HPV was found in buffer-perfused isolated mouse lungs of healthy animals [ 14 , 15 ]. Consistent with previous experiments, a distinctive reduction of HPV was observed in lungs of endotoxemic mice [ 4 , 16 ]. It has been shown that HPV is modulated by several vasoactive mediators including nitric oxide and arachidonic acid metabolites, but the precise mechanisms mediating HPV are still incompletely understood [ 15 – 19 ].…”

Section: Discussionsupporting

confidence: 92%

“…Consistent with previous experiments, a distinctive reduction of HPV was observed in lungs of endotoxemic mice [4,16]. It has been shown that HPV is modulated by several vasoactive mediators including nitric oxide and arachidonic acid metabolites, but the precise mechanisms mediating HPV are still incompletely understood [15][16][17][18][19]. Increased activity of NOS2 [13] results in elevated sGC activity with subsequent induction of the effector proteins of sGC in smooth muscle cells.…”

Section: Discussionsupporting

confidence: 83%

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Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice

et al. 2020

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Background Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. The aim of the study was to identify a voltage gated potassium channel involved in dysregulated HPV during endotoxemia. Methods Lungs of male C57BL/6 mice with and without endotoxemia (n = 6 ea. group) were analyzed for Kv3.4 gene and protein expression. HPV was examined in isolated perfused lungs of mice with and without endotoxemia and with and without selective Kv3.4 blocker BDS-I (n = 7 ea. group). Pulmonary artery pressure (PAP) and pressure-flow curves were measured during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation. HPV was quantified as the increase in perfusion pressure in response to hypoxia in percent of baseline perfusion pressure (ΔPAP) in the presence and absence of BDS-I. Results Kv3.4 gene (3.2 ± 0.5-fold, p < 0.05) and protein (1.5 ± 0.1-fold p < 0.05) expression levels were increased in endotoxemic mouse lungs. Endotoxemia reduced HPV (∆PAP control: 121.2 ± 8.7% vs. LPS 19.5 ± 8.0%, means ± SEM) while inhibition of Kv3.4 with 50 nM BDS-I augmented HPV in endotoxemic but not in control lungs (∆PAP control BDS-I: 116.6 ± 16.0% vs. LPS BDS-I 84.4 ± 18.2%, means ± SEM). Conclusions Kv3.4 gene and protein expressions are increased in endotoxemic mouse lungs. Selective inhibition of Kv3.4 augments HPV in lungs of endotoxemic mice, but not in lungs of control mice.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 83%

Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice

et al. 2020

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“…NFκB expression can by down-regulated by CO in LPS stimulated mouse peritoneal macrophages [ 37 ]. Thus, restoration of HPV by inhaled CO (iCO) in endotoxemic mice [ 38 ] might be attributable to anti-inflammatory effects of iCO via NFκB expression.…”

Section: Discussionmentioning

confidence: 99%

Role of ATP-sensitive potassium channels on hypoxic pulmonary vasoconstriction in endotoxemia

et al. 2018

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BackgroundATP-regulated potassium channels (KATP) regulate pulmonary vascular tone and are involved in hypoxic pulmonary vasoconstriction (HPV). In patients with inflammation like sepsis or ARDS, HPV is impaired, resulting in a ventilation-perfusion mismatch and hypoxia. Since increase of vascular KATP channel Kir6.1 has been reported in animal models of endotoxemia, we studied the expression and physiological effects of Kir6.1 in murine endotoxemic lungs. We hypothesized that inhibition of overexpressed Kir6.1 increases HPV in endotoxemia.MethodsMice (C57BL/6; n = 55) with (n = 27) and without (n = 28) endotoxemia (35 mg/kg LPS i.p. for 18 h) were analyzed for Kir6.1 gene as well as protein expression and HPV was examined in isolated perfused mouse lungs with and without selective inhibition of Kir6.1 with PNU-37883A. Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation were obtained. HPV was quantified as the increase in perfusion pressure in response to hypoxic ventilation in mmHg of baseline perfusion pressure (ΔPAP) in the presence and absence of PNU-37883A.ResultsEndotoxemia increases pulmonary Kir6.1 gene (+ 2.8 ± 0.3-fold) and protein expression (+ 2.1 ± 0.3-fold). Hypoxia increases HPV in lungs of control animals, while endotoxemia decreases HPV (∆PAP control: 9.2 ± 0.9 mmHg vs. LPS: 3.0 ± 0.7 mmHg, p < 0.05, means ± SEM). Inhibition of Kir6.1 with 1 μM PNU-37883A increases HPV in endotoxemia, while not increasing HPV in controls (∆PAP PNU control: 9.3 ± 0.7 mmHg vs. PNU LPS: 8.3 ± 0.9 mmHg, p < 0.05, means ± SEM).ConclusionEndotoxemia increases pulmonary Kir6.1 gene and protein expression. Inhibition of Kir6.1 augments HPV in murine endotoxemic lungs.

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“…Compelling evidence has demonstrated that each member of this triad of gasotransmitter can influence each other. For example, the inhibition of the NO synthesis might increase the CO production [ 129 ], while low-dose CO has been showed to decrease the eNOS mRNA expression [ 130 ].…”

Section: Crosstalk Between No and The Other Gasotransmittersmentioning

confidence: 99%

Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases

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Damato

et al. 2016

Oxidative Medicine and Cellular Longevity

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Within the family of endogenous gasotransmitters, nitric oxide (NO) is the smallest gaseous intercellular messenger involved in the modulation of several processes, such as blood flow and platelet aggregation control, essential to maintain vascular homeostasis. NO is produced by nitric oxide synthases (NOS) and its effects are mediated by cGMP-dependent or cGMP-independent mechanisms. Growing evidence suggests a crosstalk between the NO signaling and the occurrence of oxidative stress in the onset and progression of vascular diseases, such as hypertension, heart failure, ischemia, and stroke. For these reasons, NO is considered as an emerging molecular target for developing therapeutic strategies for cardio- and cerebrovascular pathologies. Several natural derived compounds, such as polyphenols, are now proposed as modulators of NO-mediated pathways. The aim of this review is to highlight the experimental evidence on the involvement of nitric oxide in vascular homeostasis focusing on the therapeutic potential of targeting NO with some natural compounds in patients with vascular diseases.

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Inhaled carbon monoxide protects time-dependently from loss of hypoxic pulmonary vasoconstriction in endotoxemic mice

Cited by 8 publications

References 57 publications

Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice

Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice

Role of ATP-sensitive potassium channels on hypoxic pulmonary vasoconstriction in endotoxemia

Targeting Nitric Oxide with Natural Derived Compounds as a Therapeutic Strategy in Vascular Diseases

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