Treatment with senicapoc in a porcine model of acute respiratory distress syndrome.

Abstract

BACKGROUND:

Senicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio.

METHODS:

ARDS was induced in female pigs (42-49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h.

RESULTS:

Final senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of senicapoc on alveolar-capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid.

CONCLUSIONS:

In summary, senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.

• Authors: Asbjørn G Petersen, Peter C Lind, Anne-Sophie B Jensen, Mark A Eggertsen, Asger Granfeldt, Ulf Simonsen
• Journal: Intensive care medicine experimental (Intensive Care Med Exp) Vol. 9 Issue 1 Pg. 20 (Apr 19 2021) ISSN: 2197-425X [Print] Germany
• PMID: 33870468 (Publication Type: Journal Article)