Rutai 2019 Crit Care
|Rutai A, Fejes R, Tallósy SZ, Poles M, Juhász L, Mészáros A, Boros M, Kaszaki J (2019) Potential role of endothelin receptors in the therapy of experimental sepsis. Crit Care.|
Event: Crit Care
The endothelin system plays important roles in circulatory regulation through vasoconstrictor ET-A and ET-B2 receptors and vasodilator ET-B1 receptors (ETAr; ETBr, respectively). Tissue hypoxia during the progression of sepsis is associated with microcirculatory and mitochondrial disturbances. Our aim was to investigate the possible influence of ETAr antagonist, ETBr agonist or combined treatments on oxygen dynamics, microcirculatory and mitochondrial respiration parameters in experimental sepsis.
Male Sprague-Dawley rats (n=8/group) were subjected to faecal peritonitis (0.6 g/kg faeces ip) or sham-operation. Septic animals were treated with sterile saline solution, or received the ETAr antagonist ETR-p1/fl peptide (100 nmol/kg iv), ETBr agonist IRL-1620 (0.55 nmol/kg iv) or same doses as combination therapy, 22 hr after sepsis induction. Invasive hemodynamic monitoring and blood gas analyses were performed during a 90-min observational window. Intestinal microcirculation (perfusion rate, red blood cell velocity -RBCV) was investigated by intravital videomicroscopy. Complex I and II-linked (CI; CII,) mitochondrial respiration (oxidative phosphorylation -OxPhos) was evaluated by high resolution respirometry (O2k, Oroboros, Austria).
The septic reaction was characterized by significant hypotension and decreased microperfusion, oxygen extraction and CI -CII-linked OxPhos values. The ETAr antagonist treatment significantly increased the oxygen extraction, RBCV and CII-linked OxPhos capacity. The ETBr agonist treatment prevented the sepsis-induced hypotension, decrease in oxygen extraction, and significantly increased the perfusion rate. The combined therapy amplified the beneficial mitochondrial and microcirculation effects of selective ETAr antagonist and ETBr agonist compounds.
The combination of ETAr antagonism and ETBr agonism may offer a novel tool for a simultaneous microcirculatory and mitochondrial resuscitation strategy in sepsis.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Sepsis
Coupling state: OXPHOS Pathway: N, S HRR: Oxygraph-2k
Affiliations and Support
- Univ Szeged, Inst Surgical Research, Szeged, Hungary
Grant supports: NKFIH K116689