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Anesth Analg 2005;101:349-355 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000154197.24763.EC
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Abstract |
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Sevoflurane preconditioning (SPC) in adult hearts reduces myocardial ischemia/reperfusion (I/R) injury, an effect that may be mediated by reductions in intracellular Ca2+ ([Ca2+]i) and/or mitochondrial Ca2+ ([Ca2+]m) accumulation during ischemia and reperfusion. Because the physiology, pharmacology, and metabolic responses of the newborn differ from adults, we tested the hypothesis that SPC protects newborn myocardium by limiting [Ca2+]i and [Ca2+]m by a KATP channel-dependent mechanism. Fluorescence spectrofluorometry and nuclear magnetic resonance spectroscopy were used to measure [Ca2+]i, [Ca2+]m, and adenosine triphosphate (ATP) in 4- to 7-day-old Langendorff-perfused rabbit hearts. Three experimental groups were used to study the effect of SPC on [Ca2+]m/[Ca2+]i, ATP, as well as hemodynamics and ischemic injury. The role of mitochondrial KATP channels was assessed by exposing the SPC hearts to the mitochondrial KATP channel blocker 5-hydroxydecanoic acid. Our results show that SPC significantly decreased [Ca2+]i and [Ca2+]m during I/R, as well as decreased creatine kinase release during reperfusion and resulted in higher ATP. 5-Hydroxydecanoic acid abolished the effect of SPC on [Ca2+], hemodynamics, ATP, and creatine kinase release. In conclusion, decreased [Ca2+]i and [Ca2+]m observed with SPC is associated with greater ATP recovery as well as diminished cell injury. Mitochondrial KATP channel blockade attenuates the SPC effect during I/R, suggesting that these channels are involved in the protective effects of SPC in the newborn.
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Introduction |
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Preconditioning with sevoflurane (SPC) or other inhaled anesthetics has been reported to provide myocardial protection against ischemia/reperfusion (I/R) injury in adult hearts (1). Many pathophysiological processes in cardiac I/R are associated with derangement of cellular ion homeostasis, with calcium overload likely having a key role in the impairment of ischemic and reperfused tissue (2,3). Given the important role of calcium overload, some have suggested that inhaled anesthetic preconditioning reduces I/R injury by activating adenosine triphosphate (ATP)-sensitive potassium channels (KATP), thereby decreasing intracellular calcium ([Ca2+]i) and mitochondrial Ca ([Ca2+]m) in adult hearts (1,4,5). However, the effect of inhaled anesthetic preconditioning on [Ca2+]m, as well as its efficacy in intact newborn hearts, has not been addressed. Because the physiology, pharmacology, and metabolic responses of the newborn heart differ from those of the adult heart (6), extrapolation of results from the adult heart is not necessarily warranted. To better understand the mechanism of I/R injury in the newborn heart, we tested the hypothesis that SPC opens mitochondrial KATP channels and decreases the driving force for Ca2+ influx, thus attenuating calcium overload during I/R in newborn myocardium.
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Methods |
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The study protocol was approved by the Animal Care Committee of the University of California, Davis and all experiments were conducted in accordance with guidelines of animal care from the National Institutes of Health.
New Zealand white rabbits (4–7 days old) were anesthetized with sodium pentobarbital (65 mg/kg) and heparinized (1000 USP U/kg). A total of 52 rabbits were used for this study. Hearts were removed, not paced, and perfusion pressure was set at 100 cm H2O at 37° ± 0.5°C. Left ventricular end-diastolic pressure (LVEDP) and left ventricular developed pressure (LVDP measured by isovolumic balloon) were measured continuously. LVEDPs were set between 7 to 10 cm H2O before ischemia. Ischemia started at time 0 (t = 0 min), lasted for 40 min, followed by 40 min of reperfusion. Control perfusate contained (mmole/liter): 133 NaCl, 4.75 KCl, 1.25 MgCl2, 1.82 CaCl2, 25 NaHCO3, 11.1 dextrose. Perfusates were equilibrated with 95% O2/5% CO2 which provided a pH of 7.35–7.45.
Three experiment protocols were used in this study. All the hearts were perfused for 30 min before acquiring any data. Control hearts were subjected to 30 min perfusion followed by 40 min of ischemia, and 40 min of reperfusion without pharmacologic interventions. Hearts in the SPC group were perfused for 10 min, then exposed to 2.5% sevoflurane for 10 min, followed by 10 min washout before 40 min of ischemia, and 40 min of reperfusion. Finally, hearts in the third group followed the SPC protocol and, in addition, were treated with the selective mitochondrial KATP channel inhibitor, 5-hydroxydecanoic acid (5-HD) (Sigma, St. Louis, MO), 100 µM, before ischemia. Hemodynamic variables, [ATP], creatine kinase (CK) release, [Ca2+]i and [Ca2+]m, were measured in all three groups as described below.
Fluorescence measurements were performed, as previously described in detail, using a modified spectrofluorometer (model SLM8100; SLM Instruments, Rochester, NY) (7). After a 30-min equilibration period, baseline background fluorescence was measured and subtracted. Hearts were then loaded for 10 min by perfusion with Krebs-Henseleit buffer containing indo 1, acetoxymethyl ester (indo 1-AM) 6 µM, dissolved in dimethyl sulfoxide and Pluronic F-127, 20% wt/vol (Molecular Probes, Johnston City, OR) and 1% fetal bovine serum. Probenecid 0.1 mM (Sigma) was added to all perfusates to slow the extrusion of indo 1 from the myocytes (7). Residual indo 1-AM was washed out by perfusing with standard buffer for 25 min. To determine mitochondrial fluorescence, cytosolic fluorescence was quenched by adding MnCl2 at a final concentration of 17.5 µM to the perfusate 10 min before the 40-min ischemic period. Adequate quenching was verified by the loss of calcium transients after manganese loading. The addition of MnCl2 did not alter cardiac function (heart rate or developed pressure) (7).
[Ca2+]i was calculated using the standard equation for fluorescent calcium indicators, where R is the ratio of fluorescence at 385 and 456 nm and Rmin and Rmax are the fluorescence ratios at zero and saturating [Ca2+]i, respectively (7). [Ca2+]m was calculated using the same equation used to calculate total [Ca2+]i from the fluorescent intensity after manganese quenching.
Sevoflurane (Abbott Laboratories, North Chicago, IL) was delivered at 2.5% to the gas mixture via a standard Sevotec5 variable bypass vaporizer (Datex-Ohmeda, Milwaukee, WI). Samples of perfusate at coronary run-off were collected for measurement of sevoflurane concentration by gas chromatography (Varian, Walnut Creek, CA). The sevoflurane concentration was 0.4 ± 0.02 mM. Sevoflurane was not detected at the end of the washout period immediately before ischemia or during reperfusion.
A Bruker AMX400 nuclear magnetic resonance spectrometer (Bruker, Rheinstetten, Germany) was used for ATP measurement. 31P spectra were generated from the summed free induction decays of 148 excitation pulses (60°) using 4K word data files and ±4000 Hz sweep widths (Fig. 1). The ß-ATP peak height was used as an indicator for myocardial ATP (3,8).
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-, ß-, 
-ATP = Perfusates were collected during the baseline and reperfusion intervals, and a Shimadzu UV-VIS Recording Spectrophotometer (Shimadzu, Columbia, MD) was used to measure the time-integrated total CK release from the myocardium using a CK-10 kit (Sigma Diagnostics, St. Louis, MO). Units are expressed as international unit/gram dry weight (3,8).
The animals were randomly assigned to each group. Data presented are mean ± sem. Differences in data between groups were analyzed using analysis of variance. Two-tailed Student-Newman-Keuls post-test was used if the analysis of variance was significant. A value of P < 0.05 was considered statistically significant.
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Results |
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Consistent with previous measurements in adult hearts (7), SPC attenuated the increases in [Ca2+]i and [Ca2+]m during I/R. [Ca2+]i increased in both systole and diastole during I/R in control neonatal hearts (Figs. 2 and 3), with systolic [Ca2+]i (nanomolar) increasing significantly from 567 ± 63 before ischemia to 1304 ± 179 at the end of ischemia and recovering to 901 ± 136 at the end of reperfusion (P < 0.05). Diastolic [Ca2+]i was 256 ± 9 before ischemia, increased to 489 ± 25 at the end of ischemia (P < 0.05 versus baseline), and recovered to 291 ± 33 at the end of reperfusion. The increases in systolic [Ca2+]i in SPC-treated hearts were modest and significantly less than the control group (456 ± 12 before ischemia, 516 ± 18 at the end of ischemia, and 447 ± 2 at the end of reperfusion). The changes in diastolic Ca2+ were similar to those of systolic Ca2+, with increases in SPC-treated hearts significantly less than that of control hearts: 270 ± 11 before ischemia, 356 ± 14 at the end of ischemia (P < 0.05 versus control group), and 284 ± 6 at the end of reperfusion.
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). Sevoflurane preconditioning (SPC) significantly limited the increase in total calcium (
). *SPC versus control, P < 0.05. The mitochondrial KATP channel inhibitor, 5-hydroxydecanoic acid (5-HD), partially blunted the effect of SPC during reperfusion (
). **SPC + 5-HD versus SPC and #SPC + 5-HD versus control, each P < 0.05.
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Ischemia increased [Ca2+]m in control hearts from 360 ± 28 before ischemia to 955 ± 104 at the end of ischemia, and to 623 ± 48 by the end of reperfusion (P > 0.05, compared with the baseline before ischemia) (Fig. 4). As with [Ca2+]i, SPC limited the increases in neonatal [Ca2+]m calcium during I/R: [Ca2+]m increased from 305 ± 25 before ischemia to 462 ± 32 at the end of ischemia and recovered to 353 ± 26 at the end of reperfusion, values which were significantly less than control group (P < 0.05). Thus, in comparison to control hearts, SPC significantly limited the increase in both [Ca2+]i and [Ca2+]m during I/R.
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Administration of the mitochondrial KATP channel antagonist, 5-HD, blunted the protective effect of SPC on [Ca2+]m and diastolic [Ca2+]i, during I/R (Figs. 2 and 3). With the addition of 5-HD to the SPC-treated hearts, [Ca2+]i in systole increased from 528 ± 37 before ischemia to 604 ± 55 at the end of ischemia, and recovered to 539 ± 26 at the end of reperfusion, a value significantly more than the SPC group (P < 0.05). [Ca2+]i in diastole increased from 272 ± 10 before ischemia, to 433 ± 20 (P < 0.05 compared with SPC) at the end of ischemia, and recovered to 268 ± 13 (P < 0.05) at the end of reperfusion. After adding 5-HD to the SPC-treated hearts, [Ca2+]m increased from 349 ± 7 before ischemia, to 779 ± 73 at the end of ischemia, and 460 ± 18 at the end of reperfusion, with the latter values significantly more than the SPC hearts (P < 0.05).
Figure 5 summarizes the results of experiments to determine the effects of SPC on high-energy phosphate metabolism and ischemic injury in newborn ischemic myocardium. After 40 min of reperfusion, ATP recovered to 36% ± 5% of baseline in control hearts and 59% ± 9% in the SPC hearts (P < 0.05). SPC decreased myocardial CK release during the first 10 min of reperfusion (Fig. 6) from 330 ± 47 (IU/g dry weight) in the control group to 10 ± 4 (IU/g dry weight) in the SPC-treated group (P < 0.05).
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Blockade of mitochondrial KATP channels using 5-HD effectively eliminated the protective effects of SPC on ATP and CK release. ATP recovery in SPC + 5-HD hearts was 33% ± 1% of baseline, compared with 36% ± 5% in control hearts and 59% ± 9% in the SPC hearts (P < 0.05). 5-HD partially blocked the protective effect of SPC on myocardial CK release during reperfusion (60 ± 23 IU/g dry weight) in the SPC + 5-HD group (P < 0.05 compared with SPC group).
In parallel with the protective effects of SPC on [Ca2+] and ATP recovery, SPC significantly improved left ventricular functional recovery (LVDP and LVEDP) during reperfusion compared with the control group (Table 1). Specifically, SPC improved reperfusion LVDP to 83% of the baseline value. As with its effects on [Ca2+] and ATP, the addition of 5-HD completely eliminated these beneficial effects.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It has been demonstrated that ischemia and reperfusion cause increases in [Ca2+]i and [Ca2+]m resulting in further Ca-dependent events leading to cell damage (3,7–11). Several studies have shown that a brief exposure to inhaled anesthetics before ischemia results in improved myocardial function and decreased infarct size in a manner similar to ischemic preconditioning (IPC) in adult hearts (1,4,5,12,13). One of the proposed mechanisms of IPC is the opening of mitochondrial KATP channels which results in K influx, expansion of the mitochondrial matrix volume, and a reduction of the inner mitochondrial membrane potential established by the proton pump. This change is expected to decrease the driving force for Ca2+ influx, therefore attenuating [Ca2+]m overload under conditions (such as I/R) in which cytosolic calcium is increased (14,15). A study in isolated rat mitochondria and intact rat cardiomyocytes supports this hypothesis, because KATP channel openers prevented [Ca2+]m overload by both reducing the driving force for Ca2+ uptake and by increasing Ca2+ efflux (16). Further evidence is provided in isolated perfused adult rat hearts, in which opening of KATP channels with diazoxide before ischemia reduced [Ca2+]m during I/R in a manner similar to IPC (7).
It is well documented that the newborn is not simply a smaller version of an adult. The physiology, pharmacology, and metabolic responses of the newborn heart differ from those of an adult. Although numerous studies have demonstrated that volatile anesthetic preconditioning is effective in protecting against ischemic damage in adult hearts (1,5,17), no studies have addressed the effects of inhaled anesthetic preconditioning in an intact newborn heart. The current study is the first to assess the effect of SPC on [Ca2+]i, [Ca2+]m, and high-energy phosphates in intact newborn hearts.
SPC Decreases [Ca2+]i and [Ca2+]m During I/R
[Ca2+]i overload during myocardial I/R comes largely from extracellular Ca2+ via Na+-Ca2+ exchanger (3,10,11,18,19). However, mitochondria have distinct pathways for Ca2+ influx and efflux (7). The mitochondrial membrane potential driven uniporter is the primary influx pathway for calcium, whereas the mitochondrial permeability transition pore and Na+-Ca2+ exchanger are the main efflux pathways in mitochondria. Studies in adult hearts have shown that [Ca2+]i overload is closely correlated with myocardial damage and cell death (3,8,21). The results of the current study demonstrate similar findings in newborn hearts, namely that SPC diminishes the increase of [Ca2+]i/[Ca2+]m otherwise observed in newborn rabbit hearts during I/R (22,23).
SPC Preserves High-Energy Phosphates and Contractile Function and Decreases Myocardial Injury During Reperfusion
Although the above-described alterations in ion homeostasis are vitally important, changes in energy metabolism may also have an important role in the development of irreversible myocyte injury during I/R. It is generally accepted that I/R injury profoundly disrupts mitochondrial energy metabolism, and numerous studies have shown that mitochondria isolated from I/R hearts manifest reduced function, decreased membrane potential, and respiratory impairment (15).
As in adult rat hearts (13), exposure of newborn hearts to a volatile anesthetic preserved ATP during reperfusion. One postulate is that SPC could diminish use of ATP during reperfusion as a result of the relative decrease in [Ca2+]i and [Ca2+]m by decreasing Ca2+-dependent energy-consuming processes (e.g., Na/K adenosine triphosphatase [ATPase] and Ca2+ ATPase) in the cytosol and mitochondria.
A consequence of SPC decreasing [Ca2+]i and preserving high-energy phosphates would be preservation of myocardial function and reduction in myocardial injury secondary to less mitochondrial calcium and, hence, preservation of mitochondrial function. This postulate is supported by the findings in SPC hearts that LVDP recovered significantly in reperfusion, and myocardial compliance improved as reflected by lower LVEDP during reperfusion. Similarly, total CK release was much less in the SPC-treated group compared with the control group.
Inhibition of Mitochondrial KATP Channels Blunts the Protective Effects of SPC on [Ca2+]i/[Ca2+]m During I/R
It has been suggested that the activation of the mitochondrial KATP channels has an important role in myocardial protection during IPC and SPC (7,12,20). One mechanism could be the opening of mitochondrial KATP channels which reduces the driving force for Ca2+ influx, thus attenuating [Ca2+]m overload and preserving mitochondrial respiration and ATP synthesis (15,20,24,25). These studies in newborn hearts support the previous findings in adult hearts using either IPC or SPC (1,4,5,15), indicating that similar mechanisms are operative, independent of age.
One interesting finding from these studies is that 5-HD had its greatest effect on mitochondrial [Ca2+] during ischemia, essentially abolishing the effect of SPC (Fig. 4), whereas the effect on cytosolic [Ca2+] was only partial. The concurrence of the effect of 5-HD on mitochondrial [Ca2+] with changes in ATP, CK release, and function suggest that the accumulation of calcium by mitochondria, rather than in the cytosol, is a key event in determining cellular injury and survival (7,26). However, there is no proof of a causal role of higher [Ca2+]m in mediating injury in this setting.
Several limitations of this study should be noted. First, whereas these experiments focused on the pathway outlined in the hypothesis, there is more than one mechanism involved in anesthetic preconditioning (27). Second, only newborn rabbit hearts, equivalent to 21-day-old human hearts, were used and no adult hearts were studied for comparison. Thus, these data cannot be extrapolated to other species or ages. However, the literature shows significant consistency, suggesting common elements of protective mechanisms in mammals. Third, the sevoflurane concentration used in these studies was 2.5%, a concentration equivalent to 1 minimum alveolar concentration in a young adult animal; other concentrations may have greater or lesser effects. Fourth, measurements of ATP, [Ca2+]i, and [Ca2+]m were done in separate experiments.
These data provide further support for previous findings that newborn hearts respond to ischemia and reperfusion with an increase in [Ca2+]i and [Ca2+]m associated with myocardial cell damage and dysfunction. SPC in newborn rabbit hearts limits the increases in [Ca2+]i and [Ca2+]m during 40 minutes of warm I/R, a protective effect partially mediated by KATP channel opening. Finally, the observed decreases in [Ca2+]i and [Ca2+]m accumulation are associated with greater ATP recovery, decreased CK release, and improved recovery of left ventricular function during reperfusion.
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Footnotes |
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This work was supported in part by a "New Investigator Award" from the Foundation for Anesthesia Education Research, Mayo Clinic, Rochester, MN, the University of California Davis Health System Research Award, Davis, CA (HL), a National American Heart Association Grant-in-Aid (SS), and a Research Award from the Philip Morris External Research Program (SS). Nuclear magnetic resonance spectrometers were further supported through Grant RR08206 from the National Institutes of Health, Bethesda, MD.
Accepted for publication December 8, 2004.
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