Anesthetic Propofol Overdose Causes Vascular Hyperpermeability by Reducing Endothelial Glycocalyx and ATP Production

Abstract

Prolonged treatment with a large dose of propofol may cause diffuse cellular cytotoxicity; however, the detailed underlying mechanism remains unclear, particularly in vascular endothelial cells. Previous studies showed that a propofol overdose induces endothelial injury and vascular barrier dysfunction. Regarding the important role of endothelial glycocalyx on the maintenance of vascular barrier integrity, we therefore hypothesized that a propofol overdose-induced endothelial barrier dysfunction is caused by impaired endothelial glycocalyx. In vivo, we intraperitoneally injected ICR mice with overdosed propofol, and the results showed that a propofol overdose significantly induced systemic vascular hyperpermeability and reduced the expression of endothelial glycocalyx, syndecan-1, syndecan-4, perlecan mRNA and heparan sulfate (HS) in the vessels of multiple organs. In vitro, a propofol overdose reduced the expression of syndecan-1, syndecan-4, perlecan, glypican-1 mRNA and HS and induced significant decreases in the nicotinamide adenine dinucleotide (NAD+)/NADH ratio and ATP concentrations in human microvascular endothelial cells (HMEC-1). Oligomycin treatment also induced significant decreases in the NAD+/NADH ratio, in ATP concentrations and in syndecan-4, perlecan and glypican-1 mRNA expression in HMEC-1 cells. These results demonstrate that a propofol overdose induces a partially ATP-dependent reduction of endothelial glycocalyx expression and consequently leads to vascular hyperpermeability due to the loss of endothelial barrier functions.

A Mechanism by Which Propofol Induces Cytotoxicity

“…Lin et al reported that propofol significant decreases in the NAD+/ NADH ratio, in ATP concentrations, is also similar to our results, because the reduction of NAD+/NADH ratio indicates that failure of the electron transport system at mitochondria [40][41][42][43]. Tsuchiya et al reported that propofol induce mitochondrial pathway-dependent apoptosis in human promyelocytic leukemia (HL-60) cell lines [44] that is also similar to our results.…”

“…PRIS mostly occurs in younger children, and some of the main symptoms include acidosis, rhabdomyolysis, myoglobinuria, and subsequently multiple organ failure [37,38]. There are many reports of PRIS, mostly involving mitochondrial failure, with some reports noting intralipid involvement [39][40][41][42][43].…”

Effect of creatine phosphate sodium on bispectral index and recovery quality during the general anaesthesia emergence period in elderly patients: A randomized, double-blind, placebo-controlled trial

“…As a synthetic component of ATP, creatine phosphate sodium can increase the level of ATP in vivo , and thereby promote the metabolism of these drugs in the liver. 23 – 25 Experiments have shown that creatine phosphate sodium also buffers energy supplies and improves mitochondrial efficiency in the brain. 26 , 27 As an antioxidant, creatine phosphate sodium can protect brain and nerves.…”

Angiotensin-converting enzyme inhibitors attenuate propofol-induced pro-oxidative and antifibrinolytic effect in human endothelial cells

“…It is known that propofol, as a lipophilic agent, may disturb the continuity of cell membranes mechanically and reduce the glycocalyx barrier on endothelial cells. 40 Thus the direct effect of propofol on endothelial cells, depending strictly on its physicochemical properties, may further disturb the release of the endothelial mechanism of t-PA, PAI-1 and other factors. Moreover, there are some studies indicating a direct effect of propofol on shape and viscoelasticity of erythrocytes and platelets related to intercalation of propofol in the cell membrane.…”