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

Xenon is an anesthetic with very few side-effects, yet its targets at the c ellular level are still unclear. It interferes with many aspects of intrace llular 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 huma n endothelial cells: there is a relationship between two cell cycle transit ion points, their regulation by Ca2+, and specific blocks induced by xenon. Within the group of substances studied (xenon, isoflurane, desflurane, hel ium, and N-2), only xenon blocks the cells almost completely at the G(2)-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 a ccumulating at the G(2)-M boundary move into mitosis, and cells blocked at metaphase complete their mitosis normally. No such specific block of the ce ll cycle was found with the other substances studied. An artificial increas e of intracellular Ca2+ in the submicromolar range, using a very low dose o f the Ca2+ ionophore ionomycin, or a threefold increase of the external Ca2 + concentration suffices to lift the xenon-induced metaphase block; the cel ls enter anaphase despite the presence of xenon and complete cell division. Thus, the specific but completely reversible inhibition by xenon of the G( 2)-M transition and the block at metaphase suggest an interaction with a Ca 2+-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 cycl e and on the neuronal system during anesthesia.