Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice
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RESEARCH ARTICLE
Open Access
Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice Maurizio Turzo1, Karin Metzger1, Felix Lasitschka2, Markus A. Weigand1 and Cornelius J. Busch1*
Abstract 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 pressureflow 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 (ΔPAP 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 (ΔPAP 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. Keywords: Hypoxic pulmonary vasoconstriction, Kv3.4, BDS-I, Mouse lung
Background Hypoxic pulmonary vasoconstriction (HPV) regulates pulmonary blood flow to match ventilation and optimize oxygenation [1]. HPV is diminished in humans and animals with pneumonia, sepsis or ARDS [2–4]. This accounts for an increase of intrapulmonary shunt with subsequent hypoxia [1]. During endotoxemia, a number of vasoactive mediators including nitric oxide (NO) and arachidonic acid metabolites modulate HPV, but the exact mechanisms mediating HPV remain not entirely understood [5]. * Correspondence: [email protected] 1 Department of Anesthesiology, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany Full list of author information is available at the end of the article
Key regulators in HPV are voltage gated potassium channels, which also have been shown to regulate HPV in endotoxemia [4]. Nonspecific inhibition of voltage gated potassium channels with 4-AP increased HPV in an endotoxemic mouse model [4]. None of the analyzed potassium channels (Kv1.2, Kv1.5, Kv2.1, Kv3.1) in this study showed an increased expression, in fact, Kv1.2 was downregulated. So far there are 18 further voltage gate
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