Kinetic characteristics of propofol-induced inhibition of electron-transfer chain and fatty acid oxidation in human and rodent skeletal and cardiac muscles

Abstract

IntroductionPropofol causes a profound inhibition of fatty acid oxidation and reduces spare electron transfer chain capacity in a range of human and rodent cells and tissues–a feature that might be related to the pathogenesis of Propofol Infusion Syndrome. We aimed to explore the mechanism of propofol-induced alteration of bioenergetic pathways by describing its kinetic characteristics.MethodsWe obtained samples of skeletal and cardiac muscle from Wistar rat (n = 3) and human subjects: vastus lateralis from hip surgery patients (n = 11) and myocardium from brain-dead organ donors (n = 10). We assessed mitochondrial functional indices using standard SUIT protocol and high resolution respirometry in fresh tissue homogenates with or without short-term exposure to a range of propofol concentration (2.5–100 μg/ml). After finding concentrations of propofol causing partial inhibition of a particular pathways, we used that concentration to construct kinetic curves by plotting oxygen flux against substrate concentration during its stepwise titration in the presence or absence of propofol. By spectrophotometry we also measured the influence of the same propofol concentrations on the activity of isolated respiratory complexes.ResultsWe found that human muscle and cardiac tissues are more sensitive to propofol-mediated inhibition of bioenergetic pathways than rat’s tissue. In human homogenates, palmitoyl carnitine-driven respiration was inhibited at much lower concentrations of propofol than that required for a reduction of electron transfer chain capacity, suggesting FAO inhibition mechanism different from downstream limitation or carnitine-palmitoyl transferase-1 inhibition. Inhibition of Complex I was characterised by more marked reduction of Vmax, in keeping with non-competitive nature of the inhibition and the pattern was similar to the inhibition of Complex II or electron transfer chain capacity. There was neither inhibition of Complex IV nor increased leak through inner mitochondrial membrane with up to 100 μg/ml of propofol. If measured in isolation by spectrophotometry, propofol 10 μg/ml did not affect the activity of any respiratory complexes.ConclusionIn human skeletal and heart muscle homogenates, propofol in concentrations that are achieved in propofol-anaesthetized patients, causes a direct inhibition of fatty acid oxidation, in addition to inhibiting flux of electrons through inner mitochondrial membrane. The inhibition is more marked in human as compared to rodent tissues.

Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome

“…The unsaturated fatty acids decreased and saturated fatty acids increased, and were relatively unaffected by addition of propofol (1.75 to 17.5 μgl −1 ) in in vitro analysis (Appendix B, http://links.lww.com/EJA/A604). Previous in vitro studies on human skeletal and heart muscle cell bioenergetics have shown a profound inhibitory effect of propofol on fatty acid oxidation (FAO) 37,38 . On the basis of previous research, after an overnight fast, FAO may account for up to 70% of total body energy expenditure 39 .…”

“…Previous in vitro studies on human skeletal and heart muscle cell bioenergetics have shown a profound inhibitory effect of propofol on fatty acid oxidation (FAO). 37,38 On the basis of previous research, after an overnight fast, FAO may account for up to 70% of total body energy expenditure. 39 In theory, a disruption of fatty acid utilisation could lead to changes in the circulating lipid profile.…”

Developing In Vitro Models to Define the Role of Direct Mitochondrial Toxicity in Frequently Reported Drug-Induced Rhabdomyolysis

“…Propofol has been shown to impair mitochondrial function via the inhibition of complex II + III activity in an in vivo rat model [69]. Moreover, propofol can inhibit fatty acid oxidation and the flux of electrons through the inner mitochondrial membrane, which is more pronounced in human than rat tissue [70] and can attenuate mitochondrial membrane potential in differentiated C2C12 cells [71]. In contrast, pregabalin has not previously been cited as causing mitochondrial dysfunction in vivo or in vitro skeletal muscle.…”

Circulating oxylipin and bile acid profiles of dexmedetomidine, propofol, sevoflurane, and S-ketamine: a randomised controlled trial using tandem mass spectrometry

“… 45 In vitro , clinically relevant concentrations of propofol directly inhibited FAO and mitochondrial respiration in human heart and skeletal muscle. 46 Physiologically, elevated 12,13-DiHOME in response to exercise increased fatty acid uptake to skeletal and cardiac myocytes, increasing FAO. 28 In high concentrations, DiHOMEs induce mitochondrial dysfunction.…”