In:
Shock, Ovid Technologies (Wolters Kluwer Health), Vol. 54, No. 1 ( 2020-07), p. 87-95
Kurzfassung:
The hypoxia-sensitive endothelin (ET) system plays an important role in circulatory regulation through vasoconstrictor ET A and ET B2 and vasodilator ET B1 receptors. Sepsis progression is associated with microcirculatory and mitochondrial disturbances along with tissue hypoxia. Our aim was to investigate the consequences of treatments with the ET A receptor (ET A -R) antagonist, ET B1 receptor (ET B1 -R) agonist, or their combination on oxygen dynamics, mesenteric microcirculation, and mitochondrial respiration in a rodent model of sepsis. Sprague Dawley rats were subjected to fecal peritonitis (0.6 g kg −1 i.p.) or a sham operation. Septic animals were treated with saline or the ET A -R antagonist ETR-p1/fl peptide (100 nmol kg −1 i.v.), the ET B1 -R agonist IRL-1620 (0.55 nmol kg −1 i.v.), or a combination therapy 22 h after induction. Invasive hemodynamic monitoring and blood gas analysis were performed during a 90-min observation, plasma ET-1 levels were determined, and intestinal capillary perfusion (CPR) was detected by intravital videomicroscopy. Mitochondrial Complex I (CI)- and CII-linked oxidative phosphorylation (OXPHOS) was evaluated by high-resolution respirometry in liver biopsies. Septic animals were hypotensive with elevated plasma ET-1. The ileal CPR, oxygen extraction (ExO 2 ), and CI–CII-linked OXPHOS capacities decreased. ETR-p1/fl treatment increased ExO 2 (by 〉 45%), CPR, and CII-linked OXPHOS capacity. The administration of IRL-1620 countervailed the sepsis-induced hypotension (by 〉 30%), normalized ExO 2 , and increased CPR. The combined ET A -R antagonist–ET B1 -R agonist therapy reduced the plasma ET-1 level, significantly improved the intestinal microcirculation (by 〉 41%), and reversed mitochondrial dysfunction. The additive effects of a combined ET A -R–ET B1 -R-targeted therapy may offer a tool for a novel microcirculatory and mitochondrial resuscitation strategy in experimental sepsis.
Materialart:
Online-Ressource
ISSN:
1073-2322
,
1540-0514
DOI:
10.1097/SHK.0000000000001414
Sprache:
Englisch
Verlag:
Ovid Technologies (Wolters Kluwer Health)
Publikationsdatum:
2020
ZDB Id:
2011863-6
