This study demonstrates that lidocaine attenuates cytokine-induced injury of endothelial and vascular smooth muscle cells via mechanisms involving adenosine triphosphate-sensitive potassium channels. Protection of the vasculature from cytokine-induced inflammation may preserve important physiological endothelial and vascular smooth muscle functions.
Thirty minutes of isoflurane attenuates cytokine-induced cell death and increases cell viability in VSMs for 96 h and in HUVECs for 72 h. Isoflurane must be administered less than 2 h prior to or simultaneously with the cytokines to be protective. These initial inhibitor studies suggest involvement of PKC and K(ATP) channels in isoflurane and halothane protection against both cytokine- and H(2)O(2)-induced cell death of VSMs and HUVECs.
Isoflurane pretreatment has immediate and delayed protective effects against cytokine-induced injury in endothelial and vascular smooth muscle cells that seem to be modulated by mitochondrial adenosine triphosphate-sensitive potassium channels. The time course of immediate and delayed protection is similar but not identical for each cell type.
Lidocaine attenuates cell injury induced by ischemic-reperfusion and inflammation, although the protective mechanisms are not understood. We hypothesized that lidocaine and other amide local anesthetics protect against endothelial cell injury through activation of the mitochondrial adenosine triphosphate-sensitive potassium (mitoK(ATP)) channels. We determined the effects of amide local anesthetics (lidocaine, ropivacaine, and bupivacaine), ester local anesthetics (tetracaine and procaine), one amide analog (YWI), and two non-amide local anesthetic analogs (JDA and ICM) on viability of human microvascular endothelial cells after exposure to lipopolysaccharide (LPS) in the absence or presence of the mitoK(ATP) channel antagonist 5-hydroxydecaonate. Flavoprotein fluorescence was used to investigate the effects of local anesthetics on diazoxide-induced activation of mitoK(ATP) channels. Lidocaine, ropivacaine, bupivicaine, YWI, JDA, and ICM attenuated by 60% to 70% the decrease in cell viability caused by LPS. Amide local anesthetics and YWI protection was inhibited by 5-hydroxydecaonate, whereas the protection induced by JDA and ICM was not. Tetracaine and procaine did not protect against LPS-induced injury. The amide local anesthetics and the amide analog (YWI) enhanced diazoxide-induced flavoprotein fluorescence by 5% to 20%, whereas ester local anesthetics decreased diazoxide-induced flavoprotein fluorescence by 5% to 60% and the non-amide local anesthetic analogs had no effect. In conclusion, amide local anesthetics and the amide analog (YWI) attenuate LPS-induced cell injury, in part, through activation of mitoK(ATP) channels. In contrast, tetracaine and procaine had no protective effects and inhibited activation of mitoK(ATP) channels. The non-amide local anesthetic analogs induced protection but through mechanisms independent of mitoK(ATP) channels.
Volatile anesthetic pretreatment protects the vasculature from inflammation-induced injury via mechanisms involving the activation of adenosine triphosphate-sensitive potassium (K(ATP)) channels and/or protein kinase C (PKC). Therefore, we hypothesized that K(ATP) and PKC agonists may mimic the protective effects of volatile anesthetics in vitro and in vivo. In vitro, rat vascular smooth muscle cells (VSM) and aortic endothelial cells (AEC) were used to evaluate whether pretreatment with a K(ATP) agonist, cromakalim (CRK), or a PKC agonist, phorbol 12-myristate 13-acetate (PMA), decreases lipopolysaccharide (LPS)-induced cell injury. Cell survival was determined by trypan blue staining after 6 h. In vivo, rats received systemic LPS or saline with or without pretreatment with PMA or CRK. Mean arterial blood pressure, the response to endothelium-dependent (acetylcholine; ACH) and -independent (sodium nitroprusside) vasodilators, and arterial blood gases were determined after 6 h. Cell survival in VSM and AEC control cultures was more than 90%, which was not altered in the presence of PMA or CRK, whereas LPS significantly decreased cell survival. PMA (0.1-10 microM) significantly attenuated the LPS-induced decrease in cell survival by 28%-37% in VSM and 39%-53% in AEC, and CRK (1 mM) increased cell survival by 24% in VSM and 22% in AEC. In vivo, PMA and CRK pretreatment had no significant effect on measured variables in control rats. LPS decreased mean arterial blood pressure and vasodilation to ACH and sodium nitroprusside and caused hypoglycemia. PMA, but not CRK, increased ACH-dependent vasodilation (46%) at 6 h, but neither agonist altered the other detrimental effects of LPS. In conclusion, PKC and K(ATP) agonists appear to protect AEC and VSM cells against inflammation in vitro, but the systemic administration of PKC and K(ATP) agonists appeared to exert minimal or no protection in our in vivo model.
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