Endothelin A and B Receptors: Potential Targets for Microcirculatory-Mitochondrial Therapy in Experimental Sepsis.
Animals
Disease Models, Animal
Endothelin A Receptor Antagonists
/ therapeutic use
Endothelin B Receptor Antagonists
/ therapeutic use
Male
Microcirculation
/ drug effects
Microscopy, Video
Mitochondria, Liver
/ drug effects
Rats
Rats, Sprague-Dawley
Receptor, Endothelin A
/ agonists
Receptor, Endothelin B
/ agonists
Sepsis
/ drug therapy
Journal
Shock (Augusta, Ga.)
ISSN: 1540-0514
Titre abrégé: Shock
Pays: United States
ID NLM: 9421564
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
pubmed:
19
7
2019
medline:
15
5
2021
entrez:
19
7
2019
Statut:
ppublish
Résumé
The hypoxia-sensitive endothelin (ET) system plays an important role in circulatory regulation through vasoconstrictor ETA and ETB2 and vasodilator ETB1 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 ETA receptor (ETA-R) antagonist, ETB1 receptor (ETB1-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 i.p.) or a sham operation. Septic animals were treated with saline or the ETA-R antagonist ETR-p1/fl peptide (100 nmol kg i.v.), the ETB1-R agonist IRL-1620 (0.55 nmol kg 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 (ExO2), and CI-CII-linked OXPHOS capacities decreased. ETR-p1/fl treatment increased ExO2 (by >45%), CPR, and CII-linked OXPHOS capacity. The administration of IRL-1620 countervailed the sepsis-induced hypotension (by >30%), normalized ExO2, and increased CPR. The combined ETA-R antagonist-ETB1-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 ETA-R-ETB1-R-targeted therapy may offer a tool for a novel microcirculatory and mitochondrial resuscitation strategy in experimental sepsis.
Identifiants
pubmed: 31318833
doi: 10.1097/SHK.0000000000001414
pii: 00024382-202007000-00014
doi:
Substances chimiques
Endothelin A Receptor Antagonists
0
Endothelin B Receptor Antagonists
0
Receptor, Endothelin A
0
Receptor, Endothelin B
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
87-95Références
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