Impaired Myocardial Mitochondrial Function in an Experimental Model of Anaphylactic Shock

SIMPLE SUMMARY: Anaphylactic shock (AS) is the most severe allergic hypersensitivity reaction. In the early stage of shock, AS was associated with hemodynamic impairments: severe failure in arterial blood pressure and cardiac dysfunction. Mitochondrial disorders are associated with a high incidence of acute or chronic cardiac dysfunctions. The aim of the study was to evaluate mitochondrial involvement in cardiac dysfunction at the early stage of AS. In control (CON) and sensitized Brown Norway rats, anaphylactic shock (AS) was induced with ovalbumin iv bolus injection. Aortic abdominal blood flow (ABF), mean blood arterial pressure (MAP), and lactatemia were assessed during 15 min. The myocardial mitochondrial defect in AS was assessed by mitochondrial respiration, oxidative stress production, total superoxide dismutase activity (SODs), and oxidative damage. An ultrastructural evaluation of myocardial mitochondria was also performed using electronic microscopy. AS was associated with a rapid and dramatic decrease in MAP, ABF, and severe hyperlactatemia 15 min after AS induction. Non-phosphorylating mitochondrial respiration and OXPHOS states involving mitochondrial complex II were significantly impaired in the AS group. Oxidative stress was observed with a significant increase in SODs activity after AS induction. Moreover, in the AS group we observed an increase in oxidative damage via lipid peroxidation. No modifications of the mitochondrial ultrastructure were shown at the early stage of AS. In this experimental model, AS was associated with a rapid and significant myocardial mitochondrial dysfunction with oxidative damage that could explain cardiac anaphylaxis dysfunction. ABSTRACT: Anaphylactic shock (AS) is associated with a profound vasodilation and cardiac dysfunction. The cellular mechanisms underlying AS-related cardiac dysfunction are unknown. We hypothesized that myocardial mitochondrial dysfunction may be associated with AS cardiac dysfunction. In controls and sensitized Brown Norway rats, shock was induced by ovalbumin i.v bolus, and abdominal aortic blood flow (ABF), systemic mean arterial pressure (MAP), and lactatemia were measured for 15 min. Myocardial mitochondrial function was assessed with the evaluation of mitochondrial respiration, oxidative stress production by reactive oxygen species (ROS), reactive nitrogen species (RNS), and the measurement of superoxide dismutases (SODs) activity. Oxidative damage was assessed by lipid peroxidation. The mitochondrial ultrastructure was assessed using transmission electronic microscopy. AS was associated with a dramatic drop in ABF and MAP combined with a severe hyperlactatemia 15 min after shock induction. CI-linked substrate state (197 ± 21 vs. 144 ± 21 pmol/s/mg, p < 0.05), OXPHOS activity by complexes I and II (411 ± 47 vs. 246 ± 33 pmol/s/mg, p < 0.05), and OXPHOS activity through complex II (316 ± 40 vs. 203 ± 28 pmol/s/mg, p < 0.05) were significantly impaired. ROS and RNS production was not significantly increased, but SODs activity was significantly higher in the AS group (11.15 ± 1.02 vs. 15.50 ± 1.40 U/mL/mg protein, p = 0.02). Finally, cardiac lipid peroxidation was significantly increased in the AS group (8.50 ± 0.67 vs. 12.17 ± 1.44 µM/mg protein, p < 0.05). No obvious changes were observed in the mitochondrial ultrastructure between CON and AS groups. Our experimental model of AS results in rapid and deleterious hemodynamic effects and was associated with a myocardial mitochondrial dysfunction with oxidative damage and without mitochondrial ultrastructural injury.