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Departments of *Anesthesiology and
Biomedical Engineering, University of Virginia Health System, Charlottesville, Virginia
Address correspondence and reprint requests to George F. Rich, MD, PhD, Department of Anesthesiology, PO Box 800710, University of Virginia Health System, Charlottesville, VA 22908-0710. Address e-mail to gfr2f{at}virginia.edu
Volatile anesthetic pretreatment protects the vasculature from inflammation-induced injury via mechanisms involving the activation of adenosine triphosphate-sensitive potassium (KATP) channels and/or protein kinase C (PKC). Therefore, we hypothesized that KATP 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 KATP 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 µM) 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 KATP agonists appear to protect AEC and VSM cells against inflammation in vitro, but the systemic administration of PKC and KATP agonists appeared to exert minimal or no protection in our in vivo model.
IMPLICATIONS: Volatile anesthetics protect the vasculature via mechanisms involving protein kinase C (PKC) and adenosine triphosphate-sensitive potassium (KATP) channels. In this study, we showed that PKC and KATP agonists attenuate lipopolysaccharide-induced injury of endothelial and vascular smooth muscle cells in vitro, whereas this protection is minimal in vivo after systemic administration. Protection of the vasculature from endotoxemia-associated injury may preserve important physiological endothelial and vascular smooth muscle functions.
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