Xenon-induced inhibition of Ca²⁺-regulated transitions in the cell cycle of human endothelial cells

Abstract

 Xenon is an anesthetic with very few side-effects, yet its targets at the cellular level are still unclear. It interferes with many aspects of intracellular Ca²⁺ homeostasis, but so far no specific event or defined regulatory complex of the Ca²⁺-signaling system has been identified. Specific effects of xenon were found by investigating its effects on the cell cycle in human endothelial cells: there is a relationship between two cell cycle transition points, their regulation by Ca²⁺, and specific blocks induced by xenon. Within the group of substances studied (xenon, isoflurane, desflurane, helium, and N₂), only xenon blocks the cells almost completely at the G₂–M transition after a 2-h treatment; those cells that slip through this block are then arrested at metaphase. If xenon is removed, cells that have been accumulating at the G₂–M boundary move into mitosis, and cells blocked at metaphase complete their mitosis normally. No such specific block of the cell cycle was found with the other substances studied. An artificial increase of intracellular Ca²⁺ in the submicromolar range, using a very low dose of the Ca²⁺ ionophore ionomycin, or a threefold increase of the external Ca²⁺ concentration suffices to lift the xenon-induced metaphase block; the cells enter anaphase despite the presence of xenon and complete cell division. Thus, the specific but completely reversible inhibition by xenon of the G₂–M transition and the block at metaphase suggest an interaction with a Ca²⁺-dependent event involved in the control of these processes. The results are consistent with the hypothesis that suppression of Ca²⁺ signals can be considered as a common denominator of the effects of xenon on the cell cycle and on the neuronal system during anesthesia.