JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Plachinta, R. V.
Right arrow Articles by Rich, G. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Plachinta, R. V.
Right arrow Articles by Rich, G. F.
Related Collections
Right arrow Mechanisms
Right arrow Pharmacology

Anesth Analg 2004;99:556-561
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000124679.86069.AD

CRITICAL CARE AND TRAUMA

The Protective Effect of Protein Kinase C and Adenosine Triphosphate-Sensitive Potassium Channel Agonists Against Inflammation in Rat Endothelium and Vascular Smooth Muscle In Vitro and In Vivo

Roman V. Plachinta, MD*, Manuela J. M. de Klaver, MD*, John K. Hayes, PhD*, and George F. Rich, MD PhD*,{dagger}

Departments of *Anesthesiology and {dagger}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


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Pretreatment with isoflurane for 30 min before exposure to inflammatory cytokines protects endothelial and vascular smooth muscle (VSM) cells from inflammatory injury in vitro (1,2). In addition, isoflurane restores hyporesponsiveness to acetylcholine (ACH), an endothelium-dependent vasodilator, and decreases hypotension and tumor necrosis factor-{alpha} plasma levels resulting from lipopolysaccharide (LPS)-induced inflammation in vivo (3). Our previous studies are consistent with those of others, who have reported that volatile (4) and local (5) anesthetics 1) protect the vasculature from injury induced by ischemia/reperfusion (I/R) and inflammation and 2) improve cardiovascular function (4,6,7).

Anesthetic preconditioning may be important in pathologic conditions associated with systemic inflammation and endotoxemia (8). Endotoxemia is characterized by hypotension, hyporeactivity to vasoconstrictors, and decreased endothelial function (9,10). Pathophysiological changes in the pulmonary and systemic vasculature resulting from the release of cytokines (such as tumor necrosis factor-{alpha}, interleukin-1ß, and interferon-{gamma}) and endotoxins during systemic inflammation have been reported to play a significant role in the diminished response of systemic vasculature to vasoregulating drugs (9,10). Similar to cytokines, LPS, a bacterial endotoxin, alters endothelial function (11) and induces systemic vascular collapse (9,10).

The protective effects of volatile and/or local anesthetics against inflammatory and I/R injury are inhibited by the nonspecific protein kinase C (PKC) antagonist staurosporine, the catalytic domain-specific PKC antagonist chelerythrine, and the general and mitochondrial-specific adenosine triphosphate-sensitive potassium (KATP) channel antagonists glybenclamide and 5-hydroxydecoanate, respectively (4,6). These results indicate that PKC and mitochondrial KATP channels most likely are involved in the mechanistic pathway that mediates the protective effects of volatile (1,2) and local (12) anesthetics. However, the effects of PKC and KATP agonists against inflammatory injury remain unknown. We hypothesized that the PKC agonist phorbol 12-myristate 13-acetate (PMA) and the nonspecific KATP agonist cromakalim (CRK) may mimic the protective effects of volatile anesthetics. To test this hypothesis, we evaluated the possible protective effects of each agonist against LPS-induced cell death in vitro in endothelial and VSM cells. In a rat model, we determined the effects of systemic administration of each agonist on LPS-induced hypotension and alteration of endothelium-dependent vasodilation.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Rat VSM and rat aortic endothelial cells (AEC) were gifts from Lisa A. Palmer and Dr. J. Linden’s laboratories at the University of Virginia. VSM cells were grown in Dulbecco’s minimal essential medium (DMEM/HAM’s F12; Gibco, Rockville, MD) supplemented with 20% fetal bovine serum (Gibco). AECs were grown in bovine fibronectin (Sigma, St. Louis, MO)-coated flasks in molecular cellular and developmental biology medium (MCDB 131; Gibco) supplemented with L-glutamine 29.2 mg/mL, endothelial mitogen 0.15 mg/mL (BD Biosciences, Bedford, MA), heparin 90 g/mL (Sigma), and 15% fetal bovine serum. Confluent cell cultures of passages 3–10 were seeded with a density of 4 x 105/mL in 24-well plates and allowed to attach overnight.

To evaluate the effects of PKC and KATP channel agonists and antagonists, the cells were exposed to 12 different control or treatment protocols (n = 8 for each group): 1) control; 2) PMA (100 nM); 3) CRK (10 µM); 4) the PKC antagonist chelerythrine (CHR; 10 µg/mL); 5) the KATP antagonist glybenclamide GLB (10 µg/mL); 6) LPS (100 µg/mL); 7) PMA (0.1–10 µM) plus LPS; 8) CRK (0.01–1.0 mM) plus LPS; 9) CHR plus LPS; 10) GLB plus LPS; 11) PMA plus CHR plus LPS; and 12) CRK plus GLB plus LPS. After the 30-min pretreatment with agonists in the presence or absence of antagonists, the cells were incubated with fresh medium containing LPS (LPS groups) or medium alone (control group) for 6 h (37°C; 95% oxygen/5% CO2) and were then washed with phosphate-buffered normal saline and prepared for evaluation of cell survival.

Dead cells are incapable of excluding trypan blue; therefore, the uptake of this dye was used as a marker of cell death. Trypan blue (10 µL; Sigma) was mixed with 50 µL of cell suspension. For each sample, at least 100 cells per field were counted with a hemocytometer under a light microscope. The extent of cell survival was expressed as a percentage of the total number of cells per field.

The in vivo experiments were approved by the Animal Care and Use Committee at the University of Virginia. Male Sprague-Dawley rats weighing 450–550 g were anesthetized with sodium pentobarbital (40 mg/kg intraperitoneally [IP]), and anesthesia was maintained by continuous infusion of IV pentobarbital (3 mg · 100 g–1 · h–1). The rats were placed supine on a heating blanket and under a heating lamp to maintain a temperature of 37°C throughout the experiment. A tracheostomy was performed, and the rats were allowed to breathe spontaneously through a cone placed over the tracheostomy with 100% oxygen. A polyethylene catheter (PE-50) was placed in the carotid artery for monitoring mean arterial blood pressure (MAP). The MAP was recorded with a pressure transducer and a monitor. The arterial catheter was infused with saline at 0.5 mL/h. A PE-50 catheter was also inserted in the external jugular vein for the injection of drugs.

The rats were randomized to 1 of 10 groups (n = 8 each): 1) control; 2) CRK (150 µg/kg IV); 3) GLB (1 mg/kg IV); 4) PMA (0.5 mg/kg IP); 5) CHR (5 mg/kg IP); 6) LPS (10 mg/kg IV); 7) LPS plus CRK; 8) LPS plus GLB; 9) LPS plus PMA; or 10) LPS plus CHR. CRK and PMA were administered over 30 min before the administration of LPS or saline. LPS (10 mg/kg, salmonella; Sigma) dissolved in 0.5 mL of saline or saline alone was injected through the external jugular vein catheter. The experiments were conducted such that the agonists and/or antagonists were delivered at time 0; therefore, LPS was administered at 30 min.

Rats were evaluated hourly for changes in MAP, whereas the endothelium-dependent and -independent vasodilation was determined after 6 h by injections of ACH 1 µg/kg IV and sodium nitroprusside (SNP) 7.5 µg/kg IV. ACH and SNP were dissolved in 0.1 mL of saline and were injected in series only after the MAP had returned to baseline and stabilized for 1 min. Drug doses were based on previous experiments by our group (3,8).

Cell counting was performed in a blinded manner. Comparisons between the different groups within each cell line were made with one-way analysis of variance (ANOVA) and the Student-Newman-Keuls post hoc test. Hemodynamic changes over time from baseline within each group were determined by repeated-measures ANOVA. Differences in MAP, endothelium-dependent and -independent vasodilation, and blood gases between the groups at each time point were evaluated by one-way ANOVA and a post hoc Tukey test. Statistical analysis was performed with SigmaStat 2.0 (Jandel Scientific Software, San Rafael, CA). The data are presented as the mean ± SEM. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
VSM and AEC control cultures showed a cell survival of >90%, and this was not altered in the presence of PMA, CHR, CRK, or GLB. LPS significantly decreased cell survival by 45% and 57% after 6 h of exposure to LPS in VSM and AEC cells, respectively (Fig. 1). Each concentration of PMA (0.1, 1.0, and 10 µM) significantly attenuated LPS-induced cell death compared with LPS only (0 µM). In VSM cells, PMA increased cell survival by approximately 28%–37% without any significant differences among the different concentrations. In contrast, in AEC there was a significant difference in cell survival between 0.1 µM PMA (increase of 39%) and 10 µM PMA (increase of 53%). The increase in cell survival secondary to PMA was partially was reversed by CHR in both cell lines.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 1. A, The effects of the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA) on cell survival in rat aortic endothelial cells (AEC) and rat vascular smooth muscle (VSM) cells after exposure to lipopolysaccharide (LPS) for 6 h in the presence (closed symbols) or absence (open symbols) of a specific PKC antagonist, chelerythrine (CHR). Control indicates cells incubated without LPS, agonists, or antagonists. *PMA significantly (P < 0.05) increased cell survival compared with LPS only; #CHR significantly (P < 0.05) attenuated the protective effect of PMA. B, The effects of the adenosine triphosphate-sensitive potassium (KATP) agonist cromakalim (CRK) on cell survival in rat AEC and VSM cells after exposure to LPS for 6 h in the presence (closed symbols) or absence (open symbols) of the KATP antagonist glybenclamide (GLB). Control indicates cells incubated without LPS, agonists, or antagonists. *CRK significantly increased cell survival compared with LPS only; #GLB significantly (P < 0.05) attenuated the protective effect of CRK. Data are mean ± SEM.

 
The small concentration (10 µM) of CRK did not alter cell survival after 6 h of LPS exposure in AEC cells, whereas 0.1 and 1 mM CRK increased cell survival by 14% and 22%, respectively. In contrast, all concentrations of CRK (0.01–1.0 mM) increased cell survival in VSM cells, with a significant difference between the smallest and largest concentrations (12% versus 24% increase). The KATP antagonist GLB inhibited these increases in cell survival in both cell lines.

Control rats, including those receiving PMA, CHR, or GLB, showed no significant change in MAP over the 6-h experiment; however, the rats receiving CRK showed a significant decrease in MAP at 1 and 2 h (data not shown). Rats receiving LPS alone showed a significant decrease in MAP (Fig. 2), which was less than control at 2, 5, and 6 h. Neither PMA nor CRK attenuated this decrease in MAP. Likewise, CHR and GLB did not alter the LPS-induced decrease in MAP (Fig. 2).



View larger version (28K):
[in this window]
[in a new window]
  		Figure 2. The effects of lipopolysaccharide (LPS) with and without protein kinase C and adenosine triphosphate-sensitive potassium agonist/antagonist pretreatment on mean arterial blood pressure (MAP) in rats. Groups are control (CON), LPS, LPS plus cromakalim (LPS-CRK), LPS plus glybenclamide (LPS-GLB), LPS plus phorbol 12-myristate 13-acetate (LPS-PMA), and LPS plus chelerythrine (LPS-CHR). #LPS significantly (P < 0.05) decreased MAP compared with control. Treatment groups were no different from LPS alone. Data are mean ± SEM.

 
Endothelium-dependent and -independent vasodilation with ACH and SNP did not vary significantly among the control groups (Table 1). LPS decreased endothelium-dependent and -independent vasodilation. The decrease in endothelium-dependent vasodilation associated with LPS was attenuated by PMA but not by CRK pretreatment. Endothelium-independent vasodilation was not altered by PMA or CRK pretreatment in LPS rats. GLB and CHR had no effect on endothelium-dependent and -independent vasodilation in LPS rats.


View this table:
[in this window]
[in a new window]
  		Table 1. Endothelium-Dependent and -Independent Vasodilation
 
Arterial blood gas analysis demonstrated that LPS caused a significant base deficit and hypoglycemia (Table 2). Pretreatment with PKC and KATP agonists and antagonists had no significant effect on base deficit or hypoglycemia in control or LPS rats. Rats receiving CRK only had a lower pH and a higher potassium level. LPS decreased pH; however, treatment groups were no different from the LPS-alone group. The PaO2 and PaCO2 were not different among groups.


View this table:
[in this window]
[in a new window]
  		Table 2. Arterial Blood Gases
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
We previously demonstrated that isoflurane pretreatment has protective effects against inflammation-induced injury in vivo (3) and in vitro (1,2). The mechanisms associated with isoflurane-induced protection likely involve KATP channels and/or PKC-activated pathways (1,13). Therefore, we hypothesized that pretreatment with the PKC agonist PMA or the KATP channel agonist CRK may mimic the effects of isoflurane pretreatment in protecting the vasculature against LPS-induced inflammation. In this study, PMA and CRK increased cell survival in VSM and AEC in vitro. In vivo, PMA increased endothelium-dependent vasodilation; however, there were no other apparent protective effects on the vasculature by either agonist.

The administration of LPS to the cell culture medium resulted in a decrease in cell survival—a finding that is consistent with our previous study in which exposing the cells to cytokines also decreased cell survival. Pretreatment of VSM and AEC with PMA and CRK significantly decreased LPS-induced cell death in vitro after six hours. Evidence that protective effects are related to the activation of PKC and KATP channels is supported by the observation that the antagonists CHR and GLB attenuated the protective effect triggered by PMA and CRK pretreatment.

The protection provided by CRK in vitro is consistent with a study showing that activation of mitochondrial KATP channels with diazoxide prevents I/R-induced mitochondrial membrane transition and attenuated cell injury in rabbit cardiomyocytes through modulation of the mitochondrial membrane potential (13). Mitochondrial KATP channels, compared with sarcolemmal KATP channels, may play a more significant role in mediating the protection because diazoxide, a specific mitochondrial KATP channel agonist, mimics the protective effects induced by anesthetic and ischemic preconditioning in cardiomyocytes (6,14,15). Opening of mitochondrial KATP channels has been reported to enhance the activity of manganese superoxide dismutase (16), a free oxygen radical scavenger, thereby protecting cells against the oxidative stress associated with inflammatory injury. In addition, activation of the mitochondrial KATP channels may result in membrane depolarization, matrix swelling, optimization of energy production (17), reduced calcium overload (18), and increased gene expression of cytoprotective proteins (19). Furthermore, mitochondrial KATP channel opening may also preserve the mitochondrial morphology and functionality (20), both of which are compromised by the apoptotic cascade, which involves changes in chromatin condensation, cell shrinkage, and blebbing of the plasma membrane (11). Because the major pathways of LPS-induced cell death are thought to be through apoptosis (9,11,21), the increase in cell survival induced by the nonspecific KATP channel agonist CRK, as demonstrated in this study, is not surprising.

The PMA-induced increase in cell survival after LPS exposure in vitro is consistent with a study reporting that PMA (1 nM) administered to isolated rat hearts significantly decreased myocardial infarct size (22) and with another study showing that PMA (1 µM) attenuated the ischemia-induced cell death of rabbit cardiomyocytes (23). Activation of certain PKC isoforms by PMA may exert protection indirectly by activating KATP channels through phosphorylation and/or may activate other KATP-independent pathways downstream, which also may lead to cytoprotection (24). Activation of PKC-{delta} and -{epsilon} isoforms by PMA or volatile anesthetics has been reported to mediate an increase of endothelial-derived nitric oxide synthase (25). The subsequent increased bioavailability of nitric oxide may be another mechanism by which pretreatment with PMA preserves the regulation of vascular dilation, as demonstrated in this study by the improvement in ACH-dependent vasodilation in vivo.

The protective effects of KATP and PKC agonists against LPS-induced death in endothelial cells and VSM cells are consistent with evidence that these agonists protect against I/R injury in cardiomyocytes (13,23). Furthermore, these results are consistent with our previous studies demonstrating that the protective effects of isoflurane pretreatment against cytokine-induced cell death are attenuated by PKC and KATP antagonists (1,2). This supports growing evidence that anesthetic preconditioning is mediated through PKC and KATP channels and supports evidence that activation of these mediators is protective against inflammation.

In vivo, LPS-induced inflammation is associated with a loss of vascular tone that results in a decrease in MAP and endothelium-dependent vasodilation (3,4,9,10). Pretreatment with CRK (150 µg/kg IV) had no protective effects against LPS-induced injury. The results of this study contrast with a study in rat myocardium in which CRK (40–150 µg/kg) attenuated the ischemia-induced decrease in aortic flow and increased left ventricular end-diastolic pressure (26). Similarly, another study demonstrated that CRK (100 µg/kg) improved skeletal muscle function after I/R, as measured by postischemic maximal force, contraction index, and force after one minute of stimulation (27). The discrepancy between these studies and our results may be due to the differences in models of injury; LPS induces a systemic inflammatory response, whereas the I/R injury was localized and was perhaps more likely to be attenuated by preconditioning with CRK.

In our in vivo model, rats pretreated with PMA (0.5 mg/kg IP) 30 min before LPS demonstrated increased endothelium-dependent vasodilation. Increased endothelium-dependent vasodilation may indicate that PMA protected the endothelium from the effects of inflammation. PMA did not appear to protect the VSM, as suggested by the lack of effect on endothelium-independent vasodilation. A similar dose of PMA was used in an endotoxic shock model in rats (28), but it had no apparent protective effects. No other studies have reported protective effects of PMA against I/R- or inflammatory-induced injury in vivo.

PMA increased endothelium-dependent vasodilation but did not alter acidosis or LPS-induced hypotension or hypoglycemia. CRK did not have any protective effects. In contrast, our previous in vivo experiments demonstrated that isoflurane pretreatment attenuated the LPS-induced decrease in MAP, the decrease in endothelium-dependent vasodilation, the acidosis, and the hypoglycemia (3). Despite these contrasting effects, it is likely that isoflurane-induced endothelial protection, as demonstrated in our previous studies (1–3), is related to the activation of certain PKC isoforms and mitochondrial KATP channels (13,24). It is possible that the systemic administration of CRK or PMA deposits the agonists at different sites than where isoflurane activates PKC and KATP channels. It is also not known whether systemic administration provides adequate concentrations to increase PKC or KATP channel activity at the cellular level or whether the potential increase in PKC or KATP channel activity is equivalent to that achieved with isoflurane pretreatment. Although the effects of KATP and PKC agonists may be concentration dependent, larger doses of PMA and CRK result in decreased survival in control rats (unpublished data). Further studies are necessary to determine whether pretreatment with more specific PKC-{delta} and -{epsilon} agonists may be protective in vivo or whether different methods to deliver the agonists to very specific intracellular targets may enhance vascular protection against inflammatory injury.

The vascular endothelium plays a crucial role in many physiological functions, such as regulation of blood flow, coagulation, angiogenesis, barrier formation, and leukocyte interactions with extravascular tissues (29). Exposure of the endothelial cells to circulating inflammatory mediators, such as cytokines and LPS, results in compromised hemodynamics in septic patients, as well as in trauma patients and patients undergoing major cardiopulmonary surgery (30). Protection of the vasculature against inflammation-induced injury could prevent many complications associated with major trauma or surgery (29). Therefore, it is important to further evaluate possible protective effects of volatile anesthetics, PKC, and KATP agonists against inflammatory injury.

In conclusion, this study showed that pretreatment with PMA and CRK attenuated LPS-induced cell death in AEC and VSM cells in vitro. Although we were not able to observe protective effects of pretreatment with CRK in vivo, PMA increased endothelium-dependent vasodilation. These data and our previous studies suggest that directly targeting PKC and/or KATP channels or activating these mediators with volatile or local anesthetics may attenuate the detrimental consequences of vascular inflammation.


   Acknowledgments
 
Funded by the Department of Anesthesiology, University of Virginia Health System, and the Society of Cardiovascular Anesthesiologists.

We would like to thank Lisa A. Palmer, PhD, Associate Professor of Anesthesiology and Pediatrics, and J. Linden, PhD, Professor of Internal Medicine, University of Virginia Health System, for generously donating the endothelial and VSM cells.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. De Klaver MJM, Manning L, Palmer LA, Rich GF. Isoflurane pretreatment inhibits cytokine-induced cell death in rat smooth muscle cells and human endothelial cells. Anesthesiology 2002; 97: 24–32.[ISI][Medline]
  2. De Klaver MJM, Buckingham M-G, Rich GF. Isoflurane pretreatment has immediate and delayed protective effects against cytokine-induced injury in endothelial and vascular smooth muscle cells. Anesthesiology 2003; 99: 896–903.[ISI][Medline]
  3. Plachinta RV, Hayes JK, Cerilli LA, Rich GF. Isoflurane pretreatment inhibits lipopolysaccharide-induced inflammation in rats. Anesthesiology 2003; 98: 89–95.[ISI][Medline]
  4. Cope DK, Impastato WK, Cohen MV, et al. Volatile anesthetics protect the ischemic rabbit myocardium from infarction. Anesthesiology 1997; 86: 699–709.[ISI][Medline]
  5. Hollmann MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication. Anesthesiology 2000; 93: 858–75.[ISI][Medline]
  6. Kersten JR, Schemling TJ, Pagel PS, et al. Isoflurane mimics ischemic preconditioning via activation of KATP channels: reduction of myocardial infarct size with an acute memory phase. Anesthesiology 1997; 87: 361–70.[ISI][Medline]
  7. Roscoe AK, Christensen JD, Lynch IC. Isoflurane, but not halothane, induces protection of human myocardium via adenosine A1 receptors and adenosine triphosphate-sensitive potassium channels. Anesthesiology 2000; 92: 1692–701.[ISI][Medline]
  8. Strunk V, Hahnenkamp K, Schneuing M, et al. Selective iNOS inhibition prevents hypotension in septic rats while preserving endothelium-dependent vasodilation. Anesth Analg 2001; 92: 681–7.[Abstract/Free Full Text]
  9. Szabo C, Cuzzocrea S, Zingarelli B, et al. Endothelial dysfunction in a rat model of endotoxic shock. J Clin Invest 1997; 100: 723–35.[ISI][Medline]
  10. Boyle EMJ, Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 1997; 63: 277–84.[Abstract/Free Full Text]
  11. Bannerman DD, Goldblum SE. Mechanisms of bacterial lipopolysaccharide-induced endothelial apoptosis. Am J Physiol Lung Cell Mol Physiol 2003; 284: L899–914.[Abstract/Free Full Text]
  12. De Klaver M, Buckingham M-G, Rich GF. Lidocaine attenuates cytokine-induced injury in endothelial and vascular smooth muscle cells. Anesth Analg 2003; 97: 465–70.[Abstract/Free Full Text]
  13. Kersten JR, Schemeling TJ, Pagel PS, et al. Mechanism of myocardial protection by isoflurane: role of adenosine triphosphate-regulated potassium (KATP) channels. Anesthesiology 1996; 87: 794–807.
  14. Kohro S, Hogan QH, Nakae Y, et al. Anesthetic effects on mitochondrial ATP-sensitive K channel. Anesthesiology 2001; 95: 1435–40.[ISI][Medline]
  15. Zaugg M, Lucchinetti E, Spahn D, et al. Differential effects of anesthetics on mitochondrial KATP channel activity and cardiomyocyte protection. Anesthesiology 2002; 97: 15–23.[ISI][Medline]
  16. Tanaka T, Kurabayashi M, Aihara Y, et al. Inducible expression of manganese superoxide dismutase by phorbol 12-myristate 13-acetate is mediated by Sp1 in endothelial cells. Thromb Vasc Biol 2000; 20: 392–401.[Abstract/Free Full Text]
  17. Kowaltowski AJ, Seetharaman S, Paucek P, Garlid KD. Bioenergetic consequences of opening the ATP-sensitive K(+) channel of heart mitochondria. Am J Physiol Heart Circ Physiol 2001; 280: H649–57.[Abstract/Free Full Text]
  18. Murata M, Akao M, O’Rourke B, Marban E. Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca(2+) overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection. Circ Res 2001; 89: 891–8.[Abstract/Free Full Text]
  19. Bolli R. The late phase of preconditioning. Circ Res 2000; 87: 972–83.[Abstract/Free Full Text]
  20. Akao M, Ohler A, O’Rourke B, Marban E. Mitochondrial ATP-sensitive potassium channels inhibit apoptosis induced by oxidative stress in cardiac cells. Circ Res 2001; 88: 1267–75.[Abstract/Free Full Text]
  21. Lindner H, Holler E, Ertl B, et al. Peripheral blood mononuclear cells induce programmed cell death in human endothelial cells and may prevent repair: role of cytokines. Blood 1997; 89: 1931–8.[Abstract/Free Full Text]
  22. Hedayati N, Schomisch SJ, Carino JL, et al. Cardioprotection by St. Thomas’ solution is mediated by protein kinase C and tyrosine kinase. J Surg Res 2003; 113: 121–7.[ISI][Medline]
  23. Batthish M, Diaz RJ, Zeng HP, et al. Pharmacological preconditioning in rabbit myocardium is blocked by chloride channel inhibition. Cardiovasc Res 2002; 55: 660–71.[Abstract/Free Full Text]
  24. Uecker M, da Silva R, Grampp T, et al. Translocation of protein kinase C isoforms to subcellular targets in ischemic and anesthetic preconditioning. Anesthesiology 2003; 99: 138–47.[ISI][Medline]
  25. Gelinas DS, Bernatchez PN, Rollin S, et al. Immediate and delayed VEGF-mediated NO synthesis in endothelial cells: role of PI3K, PKC and PLC pathways. Br J Pharmacol 2002; 137: 1021–30.[ISI][Medline]
  26. Gan X, Cook M, Moffat M, Karmazyn M. Protective effects against hydrogen peroxide-induced toxicity by activators of the ATP-sensitive potassium channels in isolated rat hearts. J Mol Cell Cardiol 1998; 30: 33–41.[ISI][Medline]
  27. Gurke L, Mattei A, Chaloupka K, et al. Mechanisms of ischemic preconditioning in skeletal muscle. J Surg Res 2000; 94: 18–27.[ISI][Medline]
  28. Inaba H, Filkins JP. Augmentation of endotoxic lethality and glucose dyshomeostasis by phorbol ester. Am J Physiol 1991; 260: R494–502.
  29. Laude K, Beauchamp P, Thuillez C, Richard V. Endothelial protective effects of preconditioning. Cardiovasc Res 2002; 55: 466–73.[Abstract/Free Full Text]
  30. Wan S, LeClerc J-L, Vincent J-L. Inflammatory response to cardiopulmonary bypass. Chest 1997; 112: 676–92.[Abstract/Free Full Text]
Accepted for publication February 9, 2004.





This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via ISI Web of Science (1)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Plachinta, R. V.
Right arrow Articles by Rich, G. F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Plachinta, R. V.
Right arrow Articles by Rich, G. F.
Related Collections
Right arrow Mechanisms
Right arrow Pharmacology

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press