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

Abstract

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.

Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice

“…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].…”

Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS)

“…This beneficial effect of HPV has been shown to be inhibited in experimental models of oleic acid, bleomycin, or endotoxin-induced ALI (Sylvester et al, 2012 ), underscoring the important role that HPV has in matching ventilation/perfusion. Herein, studies in mice have revealed that inhibition of ATP-regulated potassium channel Kir6.1, which is elevated after endotoxemia, was able to restore HPV in mice; however, the effects on lung inflammation were not assessed (Turzo et al, 2018 ). However, prolonged HPV can lead to the development of PH and high-altitude induced pulmonary edema (HAPE) which is characterized by patchy peripheral distribution of edema (Bartsch, 1999 ).…”

Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome

“…Inhibitors of voltage-dependent potassium (K v ) channels, such as 4-aminopyridine, are possible sensitisers of hypoxic K v -channel inhibition and restored HPV in isolated lungs in LPS-preconditioned mice [31]. Inhibition of the vasodilatory K ATP channels with PNU-37883A was found to restore HPV in isolated lungs from endotoxaemic mice, while HPV among non-endotoxaemic controls was not altered [32]. However, a previous clinical trial with the K ATP channel inhibitor glibenclamide, focussing on systemic hypotension, failed [33].…”