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Anesth Analg 2004;99:993-1000 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000131506.38512.7C
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Abstract |
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Isoflurane enhances myocardial functional recovery and improves energy levels after ischemia. We sought to determine whether isoflurane-induced cardioprotection is mediated by protein kinase C (PKC). The Langendorff model was used, and isolated perfused rat hearts were separated into untreated, isoflurane, chelerythrine (PKC inhibitor) plus isoflurane, and chelerythrine groups. All hearts were subjected to treatment before ischemia, followed by 30 min of ischemia and 60 min of reperfusion. We recorded hemodynamic variables, measured metabolites by high-performance liquid chromatography, and analyzed subcellular localization of PKC isoforms by Western blot analysis. Isoflurane significantly improved the recovery of left ventricular developed pressure, attenuated the depletion of myocardial adenosine triphosphate (ATP) and creatine phosphate at 15 min of ischemia, enhanced the recovery of myocardial ATP and creatine phosphate concentrations after ischemia, and was associated with the translocation of PKC-
and -
to the membrane. Chelerythrine suppressed the translocation of PKC- and - and blocked the improvement of cardiac function and ATP. We conclude that isoflurane delays the decrease in ATP during ischemia and improves the recovery of mechanical function and the energy state 60 min after ischemia. These effects of isoflurane are dependent on the activation of PKC. IMPLICATIONS: Protein kinase C activation is part of the mechanism by which isoflurane improves functional and metabolic recovery after ischemia in isolated rat hearts.
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Introduction |
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Isoflurane is widely used in patients with ischemic heart disease and has recently been shown to protect against ischemic myocardial injury (1–6). The role of isoflurane and protein kinase C (PKC) activation on energy levels during and after ischemia is unknown.
Myocardial high-energy phosphates are important for maintaining normal mechanical performance and cell viability. The depletion of adenosine triphosphate (ATP) during ischemia and reperfusion may trigger a series of intracellular events that lead to apoptosis or necrosis. Preventing the depletion of ATP during ischemia and increasing ATP resynthesis upon reperfusion is essential to prevent cardiac injury. Isoflurane enhances the recovery of function and maintains myocardial high-energy phosphate metabolism in the reperfused myocardium (1,7). The mechanism of the isoflurane-induced ATP-sparing effect, especially with regard to intracellular signal transduction, is unclear. Several studies have shown that the translocation of PKC isoforms is important for isoflurane’s cardioprotective effects against ischemia/reperfusion injury. Increasing PKC activity improves postischemic myocardial recovery (8), and PKC inhibitors eliminate the protective effect induced by isoflurane (3,4). In this study, we sought to determine whether isoflurane attenuates myocardial dysfunction and inhibits the depletion of ATP and whether these actions are mediated by PKC.
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Methods |
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Adult male Sprague-Dawley rats (300–400 g) were acclimatized in a quiet quarantine room for 1 wk before the experiments. The protocol was approved by the Institutional Animal Care and Use Committee of the State University of New York Downstate.
The rats were anesthetized with 2% isoflurane for 2 min and then decapitated. Their hearts were rapidly removed, submerged in cold (4°C) Krebs-Henseleit solution, attached to the perfusion apparatus via the aorta, and retrogradely perfused with Krebs-Henseleit solution (mM: NaCl 130, KCl 5.6, CaCl2 2.16, NaH2PO4 1.2, NaHCO3 25, MgSO4 0.56, glucose 11, and sucrose 13; pH 7.4 ± 0.2). The perfusate was equilibrated with 95% oxygen and 5% CO2, and myocardial temperature was maintained at 37°C throughout the experiment. The hearts were perfused using the Langendorff model.
All experiments lasted 145 min beginning with a 15-min period of stabilization perfusion before ischemia. Perfused hearts were randomly separated into 4 groups: 1) an untreated group (no drug was given before ischemia; n = 8); 2) an isoflurane group (2.2% isoflurane was given 30 min before ischemia; n = 8); 3) a chelerythrine (Chel) plus isoflurane group (5 µmol/L Chel was given 10 min before and during 30 min of isoflurane, and this was followed by ischemia; n = 8); and 4) a Chel group (5 µmol/L Chel was given 40 min before ischemia; n = 7). All hearts were subjected to 30 min of ischemia followed by 60 min of reperfusion. During ischemia, flow through the aortic cannula was stopped; this subjects the heart to global ischemia.
The biochemical experiments were stopped at specified times before, during, or after ischemia, and ventricular transmural tissue specimens were frozen in liquid nitrogen. Isoflurane was administered by placing an agent-specific vaporizer between the fresh gas supply and the perfusate. Chel was dissolved in the perfusate.
To obtain isovolumetric contractions, a latex balloon with a microtip manometer was inserted into the left ventricle via the left atrium. The balloon volume was adjusted with fluid to maintain the left ventricular end-diastolic pressure (LVEDP) between 0 and 5 mm Hg. This preload volume was held constant during the entire experiment to allow continuous recording of left ventricular pressure. The heart rate (HR), LVEDP, left ventricular systolic pressure, left ventricular developed pressure (end-systolic minus end-diastolic pressure), rate of left ventricular pressure development (+dP/dt), and rate of left ventricular relaxation (–dp/dt) were continuously recorded. Coronary flow (CF) was measured at 10-min intervals with a graduated cylinder. During ischemia, the time to the onset of ischemic contracture (minutes), the time between the beginning of ischemia and the maximal contracture (minutes), and the magnitude of the peak contracture (mm Hg) were recorded.
In separate experiments, ventricular transmural tissue specimens were sampled before ischemia, at 15 and 30 min during ischemia, and 60 min after ischemia. The tissue was frozen immediately in liquid nitrogen and stored at –75°C until analysis. The tissue was weighed, homogenized with an ultrasonic tissue disruptor in 0.4 mol/L ice-cold perchloric acid, and then centrifuged. The supernatant was adjusted to pH 7.0 with K2CO3 and centrifuged again. Twenty microliters of this supernatant was injected into a high-performance liquid chromatography system. ATP, adenosine diphosphate, adenosine monophosphate, and creatine phosphate (CrP) were obtained from Sigma (St. Louis, MO). Five standard concentrations of each were used to establish standard curves for quantitative measurements of tissue extracts, whereas one concentration was used for the systematic study of the retention time of standard solutions. Metabolites were measured with an ultraviolet detector and a ultra C18 column (Restek, PA) (9). The mobile phase contained potassium dihydrogen phosphate (215 mM), tetrabutylammonium hydrogen sulfate (2.3 mM), and acetonitrile (3.5%). Chromatography was performed at ambient temperature with the spectrophotometer set at 206 nm; the flow rate was maintained at 0.9 mL/min.
The frozen heart samples were minced and homogenized in homogenization buffer (20 mM Tris-HCl, 0.33 M sucrose, 5 mM EDTA, 0.5 mM EGTA, 1 mM phenylmethylsulfonyl fluoride, 5 mM benzamidine, 0.0003% aprotinin, and 0.005% leupeptin; pH 7.4). Homogenates were then centrifuged at 24,000 g for 20 min to collect cytosolic (supernatant) and particulate (membrane) fractions.
Protein was measured by using a commercial assay based on the bicinchoninic acid assay (Pierce, IL). The cytosolic- and particulate-associated proteins prepared from isolated perfused rat hearts were assayed, and samples were adjusted to equal protein concentrations (20 µg of protein was loaded per lane) before being subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (7.5% polyacrylamide gels) under reducing conditions. Proteins were then transferred to a nitrocellulose membrane (Bio-Rad, CA), and primary antibodies were incubated overnight. The following antibodies were used: PKC-
(GIBCO BRL, MD), PKC-, polyclonal rabbit antibody and PKC-, and monoclonal mouse antibody (Santa Cruz, CA). The nitrocellulose membrane was washed in Tris-buffered saline with Nonidet P-40 substitute (Sigma) and incubated in anti-rabbit (Sigma) or mouse (Promega, WI) IgG conjugated with alkaline phosphatase (AP) for 1 h. The membrane was then developed with 5-bromo-4-chloro-3-indoyl-phosphate/nitroblue tetrazolium one-component phosphatase substrate (Kirkegaard & Perry Laboratories, MD). Quantitative analysis of the band density was performed with the National Institutes of Health Image program after scanning with an XRS OmniMedia scanner.
All values are expressed as the mean ± SE. Functional variables and biochemical data were compared among groups by using a one-way analysis of variance followed by the Newman-Keuls test. For all statistical analyses, P < 0.05 was considered significant.
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Results |
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Isoflurane reduced and Chel increased LVEDP before ischemia (Table 1). All of the treated groups had significantly increased left ventricular developed pressure and CF. Chel caused a significant increase of +dp/dt compared with the untreated and isoflurane groups. When given before and during isoflurane, Chel significantly attenuated the isoflurane-induced reduction of LVEDP.
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Isoflurane significantly delays the onset of ischemic contracture and the time until maximum LVEDP (Table 2). The peak value of LVEDP during ischemia was significantly less in the isoflurane-treated group compared with the untreated group. Chel blocked the effects of isoflurane.
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Pretreatment with 2.2% isoflurane resulted in significantly improved recovery of left ventricular developed pressure (57% ± 3%) compared with untreated hearts (33% ± 4%) 60 min after ischemia (Fig. 1A). The administration of Chel with isoflurane before ischemia significantly reduced the recovery of left ventricular developed pressure (30% ± 2%) compared with isoflurane alone (57% ± 3%) (Fig. 1B). The recovery of +dp/dt and –dp/dt, which are indices of myocardial contractility and relaxation, respectively, were also improved with isoflurane (Fig. 1, C and D). Chel (5 µmol/L) significantly reduced the improvement of left ventricular developed pressure, +dP/dt, and –dp/dt induced by isoflurane, but Chel by itself did not significantly alter the recovery of left ventricular developed pressure, +dp/dt, or –dp/dt compared with untreated hearts (Figure 1B–D).
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There was no significant difference in the recovery of HR at the end of reperfusion between the untreated and isoflurane groups. Chel by itself and with isoflurane significantly reduced the recovery of HR compared with the untreated and isoflurane groups (Fig. 1E).
Isoflurane significantly improved the recovery of CF 60 min after ischemia compared with the untreated group. Chel blocked this improvement in CF with isoflurane and significantly reduced CF to a level less than in the untreated group (Fig. 1F).
There was no significant difference in the concentrations of ATP, total adenine nucleotide phosphates (
AP), and CrP after drug application but before ischemia (Fig. 2). In all of the groups, ischemia decreased the tissue concentrations of ATP, AP, and CrP. Although the tissue concentrations of ATP and CrP in the isoflurane group were reduced at 15 min of ischemia, they were significantly larger than the concentration in untreated hearts at this time point. When isoflurane was administered with Chel, the tissue concentrations of ATP were significantly decreased compared with isoflurane alone at 15 min of ischemia. There were no significant differences in the concentrations of ATP and CrP among any of the groups at 30 min of ischemia. Postischemic reperfusion allowed the tissue concentrations of ATP and CrP to incompletely recover in the untreated group. Isoflurane enhanced the recovery of tissue ATP and CrP concentrations during reperfusion. Chel pretreatment blocked these improvements with isoflurane. The change of the AP was reduced equally in all groups at 30 min of ischemia. However, the isoflurane group had significantly improved recovery compared with the other groups 60 min after ischemia (Fig. 2B).
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There was no difference in the energy charge (EC) before ischemia among the four groups (Table 3). There was a reduction of the EC in all groups at 15 and 30 min of ischemia. Isoflurane significantly attenuated the decrease in EC at 15 min of ischemia compared with the untreated rat hearts, and Chel blocked this attenuation. In the isoflurane group 60 min after ischemia, the EC returned to its preischemia value. It was significantly more than in either the untreated or the Chel plus isoflurane–treated groups.
Isoflurane significantly increased the content of PKC- and - in the membrane fraction and decreased that in the cytosolic fraction compared with the untreated group (Fig. 3). This indicates translocation and activation of PKC. Chel suppressed the effect of isoflurane on the translocation of PKC- and -. There were no significant differences in the translocation of PKC- in any group.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The protective effects of isoflurane against myocardial ischemic injury have been described in several studies (1–6). One important mechanism by which isoflurane protects against ischemic injury is to open ATP-sensitive potassium channels (KATP channels) (6). Several studies have suggested that PKC might link mediators released during ischemia to the activation of the KATP channel (10). Toller et al. (3) have reported that PKC plays a role in the isoflurane-induced functional recovery of stunned canine myocardium; however, its effect on metabolism is unclear. In this study, we demonstrate that the cardioprotection and the ATP-sparing effects of isoflurane are mediated by the PKC pathway.
Previous studies have suggested that isoflurane could slow the rate of ATP depletion and, thus, attenuate ischemia/reperfusion injury (1,7). We provide evidence for the involvement of PKC in this energy-sparing effect. Isoflurane induced a translocation of PKC- and - from the cytosolic to the membrane fraction. Increased translocation of PKC- and - to the membrane fraction was associated with improvement of postischemic cardiac function and ATP preservation in the isoflurane-treated hearts. Chel blocks PKC activation by inhibiting its phosphorylation, and it is also possible that Chel inhibits the translocation of PKC to the membrane (11). The translocation of these isoforms by isoflurane was suppressed by Chel pretreatment, and this also abolished the improvement in functional high-energy phosphate metabolism. These results indicate that PKC activation plays an important role in the ATP-sparing effect of isoflurane. This finding is in agreement with studies demonstrating that PKC plays a pivotal role in ischemic and anesthetic preconditioning (5). We could not demonstrate activation of PKC- in our experiments. Kawamura et al. (12) reported that translocation of PKC- was transient and that it rapidly dissociated from the membrane. Zhong and Su (13) suggested that the novel PKCs (e.g., PKC- and -), but not the conventional PKCs (e.g., PKC-), were activated by isoflurane in cultured vascular smooth muscle cells. This is in agreement with our results and explains why we did not find changes of PKC- with 60 min of reperfusion after ischemia. Isoflurane delays myocardial ATP depletion during ischemia and increases the recovery of ATP upon reperfusion. The improved postischemic physiologic recovery was associated with these larger ATP concentrations. Compared with isoflurane treatment alone, isoflurane with the PKC inhibitor Chel accelerated ATP depletion during ischemia and attenuated the recovery of ATP after ischemia. Chel also blocked the physiologic improvement with isoflurane. These results indicate that the cardioprotection by isoflurane may be related to the slower rate of ATP depletion during ischemia and that the decreased rate of decreases in ATP is due to PKC activation.
The PKC activation in response to isoflurane may be a signal for contractile quiescence, because PKC regulates cytoskeletal contractile proteins and because its activation causes a downregulation of contractile activity during ischemia (14). This inactivation of cytoskeletal contractile proteins may serve as an energy-conserving defense mechanism against ischemia. The opening of KATP channels may also play an important role in the protection found with volatile anesthetics (6). The protective effect caused by sarcolemmal KATP and/or mitochondrial KATP channel activation may be mediated by the PKC signaling pathway (15,16). The opening of the sarcolemmal KATP channels would hyperpolarize the cardiac myocyte, reduce myocyte action potential duration, and partially inhibit voltage-dependent calcium channel activity. Subsequent reductions in myocardial contractility and intracellular Ca2+ overload may preserve intracellular energy stores for more vital processes during ischemia and reperfusion (17). The consequences of opening the mitochondrial KATP channel include depolarization of the intramitochondrial membrane as K+ enters, which would reduce mitochondrial Ca2+ overload (18) and mitochondrial matrix swelling. This may enhance production of ATP by optimizing oxidative phosphorylation (19). The decreased mitochondrial Ca2+ overload during ischemia may not only preserve myocardial ATP, because calcium transport consumes ATP, but also limit mitochondrial damage, thus providing better conditions for ATP production after ischemia (20).
A cell’s EC is indicative of its ability to perform anabolic processes (21). Isoflurane attenuated the decrease in EC during ischemia and improved its recovery upon reperfusion. These effects were blocked by Chel. The myocardium demonstrated improved energetics after ischemia with isoflurane compared with either ischemia alone or ischemia with isoflurane plus Chel. This indicates that mitochondrial function, a major contributor to cellular energy production, is preserved by isoflurane via a PKC-dependent pathway. One potential mechanism for this is via PKC activation of the mitochondrial KATP channels.
Adenosine nucleotide phosphates are required for the production of ATP. If total adenosine phosphates (AP) are reduced, then ATP levels will be reduced, even if energetics and mitochondrial function recover. The depletion of the AP in all groups during ischemia is due to the breakdown and/or efflux of adenosine from the cells and the reduction in its synthesis (22). The decrease of the AP paralleled the depletion of ATP during ischemia; at 30 minutes of ischemia, all groups showed a similar depletion of ATP and AP. The improved energetics upon reperfusion in the isoflurane group, as indicated by the return of the EC to nearly normal levels, may enhance adenosine nucleotide phosphate synthesis and explain the increased AP and ATP levels in this group. However, even though EC and CrP recovered fully, both the AP and the ATP showed only partial recovery. This may be due to the short time after ischemia for adenosine biosynthesis.
Isoflurane preserved the CrP concentration during ischemia and improved its recovery upon reperfusion, and Chel blocked its effects. CrP serves as an "energy buffer" and is important for the rapid transport of energy between intracellular compartments (23). These results indicate that isoflurane improves the ability of cells to resynthesize high-energy phosphates during reperfusion, and this process is related to activation of PKC.
In this study, there was better recovery of CF in the isoflurane-treated hearts than in the untreated hearts during reperfusion. Isoflurane is a both a systemic and a coronary vasodilator (24); it increases CF before ischemia. However, during reperfusion, isoflurane was not present, yet the recovery of CF was improved. This result may be an indirect effect of isoflurane. An increase in the number of surviving cells would improve heart function and metabolism. Additionally, the increased CF may improve the supply of oxygen and energy to surviving myocytes in the subendocardial and subepicardial layers and enhance the recovery of myocardial function and energy resynthesis. The administration of isoflurane with Chel and Chel alone attenuated the recovery of CF.
Isoflurane leads to better recovery of LVEDP after ischemia and reperfusion (Fig. 1A). This indicates that isoflurane improves the function of the ventricle during the end-diastolic phase. Chel increased LVEDP and +dp/dt before ischemia (Table 1). Pongo et al. (25) found a similar effect of Chel on hemodynamic variables. This indicates that Chel might interfere with the regulation of baseline PKC activity in the myocardium or may have a direct effect on the ventricle.
Our data demonstrate that isoflurane improves function by activating PKC. The delayed energy loss during, and the metabolic recovery after, ischemia are associated with this PKC activation.
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Acknowledgments |
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Supported by Brooklyn Anesthesia Research P.C.
We gratefully acknowledge Todd Sacktor, MD, John Crary, Andrew Tcherepanov, and Matt Relly (Department of Physiology and Pharmacology, State University of New York Downstate Medical Center) for assistance with the immunoblot analysis of PKC.
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