Propofol is a short-acting hypnotic agent used in human medicine for sedation and general anesthesia. Its administration can be associated with serious cardiovascular side-effects that include decrease in arterial blood pressure and cardiac output. The aim of the present study was to evaluate propofol effects on mitochondrial respiration, myocardial contractility and electrophysiology in the same samples isolated from the heart ventricles of adult rats. Mitochondrial oxygen consumption was
measured in permeabilized samples dissected from free walls of
both ventricles using high-resolution respirometry. State LEAK was determined with malate and glutamate. Active respiration was induced by ADP (state PI) and further by succinate, a Complex II substrate (PI+II). Rotenone was injected to measure state PII. Antimycin A, a Complex III inhibitor was used to determine residual oxygen consumption (ROX). N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride and ascorbate
were injected simultaneously for respirometric assay of cytochrome c oxidase activity (CIV). Isometric contractions and membrane potentials were determined on multicellular preparations isolated from right and left ventricles. Propofol concentrations used ranged from 0.005 to 0.5 mmol/l. All
respiratory parameters were significantly higher in the left control ventricles compared to the right ones. Propofol significantly decreased Complex I activity at concentration 0.025 mmol/l and papillary muscle contraction force at 0.1 mmol/l. Propofol did not affect action potential duration at any concentration studied. Our study suggests that mechanisms contributing to the impaired myocardial contraction during propofol anesthesia might include also mitochondrial dysfunction manifested by compromised
activity of the respiratory Complex I.
Hyperbaric oxygen (HBO) therapy, i.e. breathing pure oxygen
under increased environmental pressures serves as a treatment
for diverse medical conditions. However, elevated oxygen
concentration can be detrimental to central nervous system or
lungs. Our study aimed to evaluate the effects of repeated
exposure to HBO on mitochondrial respiration assessed by highresolution respirometry (HRR), cell viability estimated by
PrestoBlue® reaction, morphology analyzed by routine phase
contrast and fluorescent microscopy, and superoxide dismutase
(SOD) and citrate synthase (CS) activities using human lung
fibroblasts. The cells were exposed to HBO for 2 h per day for
5 consecutive days. One day after the last exposure, HBO cells
displayed significantly smaller area and perimeter, compromised
viability and elevated SOD activity. No changes were detected in
CS activity or quality of mitochondrial network. HRR revealed
impaired mitochondrial oxygen consumption manifested by
increased leak respiration, decreased activity of complex II and
compromised ATP-related oxygen consumption when fatty acids
were oxidized. Our findings document that in conditions
mimicking chronic intermittent exposure to HBO, lung fibroblasts
suffer from compromised mitochondrial respiration linked to
complex II and impaired cellular growth in spite of increased
antioxidant defense. Underlying mechanism of this HBO-induced
mitochondrial dysfunction should be further explored.
Ample experimental evidence suggests that sepsis could interfere
with any mitochondrial function; however, the true role of
mitochondrial dysfunction in the pathogenesis of sepsis-induced
multiple organ dysfunction is still a matter of controversy. This
review is primarily focused on mitochondrial oxygen consumption
in various animal models of sepsis in relation to human disease
and potential sources of variability in experimental results
documenting decrease, increase or no change in mitochondrial
respiration in various organs and species. To date, at least three
possible explanations of sepsis-associated dysfunction of the
mitochondrial respiratory system and consequently impaired
energy production have been suggested: 1. Mitochondrial
dysfunction is secondary to tissue hypoxia. 2. Mitochondria are
challenged by various toxins or mediators of inflammation that
impair oxygen utilization (cytopathic hypoxia). 3. Compromised
mitochondrial respiration could be an active measure of survival
strategy resembling stunning or hibernation. To reveal the true
role of mitochondria in sepsis, sources of variability of
experimental results based on animal species, models of sepsis,
organs studied, or analytical approaches should be identified and
minimized by the use of appropriate experimental models
resembling human sepsis, wider use of larger animal species in
preclinical studies, more detailed mapping of interspecies
differences and organ-specific features of oxygen utilization in
addition to use of complex and standardized protocols evaluating
mitochondrial respiration.