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CARDIOVASCULAR ANESTHESIA

Anesthetic Preconditioning Attenuates Mitochondrial Ca²⁺ Overload During Ischemia in Guinea Pig Intact Hearts: Reversal by 5-Hydroxydecanoic Acid

Matthias L. Riess, MD^*, Amadou K. S. Camara, PhD^*, Enis Novalija, MD^*, Qun Chen, MD^*, Samhita S. Rhodes, MS, and David F. Stowe, MD PhD^*&Verbar||¶

Anesthesiology Research Laboratory, Departments of *Anesthesiology and Physiology, and &Verbar||Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin; Department of Anesthesiology and Intensive Care Medicine, University Hospital Münster, Münster, Germany; Department of Biomedical Engineering, Marquette University, Milwaukee, Wisconsin; and ¶Research Service, Veterans Affairs Medical Center, Milwaukee, Wisconsin

Address correspondence and reprint requests to David F. Stowe, MD, PhD, M4280, 8701 Watertown Plank Rd., Medical College of Wisconsin, Milwaukee, WI 53226. Address e-mail to dfstowe{at}mcw.edu

	Abstract

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Cardiac ischemia/reperfusion (IR) injury is associated with mitochondrial (m)Ca²⁺ overload. Anesthetic preconditioning (APC) attenuates IR injury. We hypothesized that mCa²⁺ overload is decreased by APC in association with mitochondrial adenosine triphosphate-sensitive K⁺ (mK_ATP) channel opening. By use of indo-1 fluorescence, m[Ca²⁺] was measured in 40 guinea pig Langendorff-prepared hearts. Control (CON) hearts received no treatment for 50 min before IR; APC hearts were exposed to 1.2 mM (8.8 vol%) sevoflurane for 15 min; APC + 5-hydroxydecanoate (5-HD) hearts received 200 µM 5-HD from 5 min before to 15 min after sevoflurane exposure; and 5-HD hearts received 5-HD for 35 min. Sevoflurane was washed out for 30 min and 5-HD for 15 min before 30 min of global ischemia and 120 min of reperfusion. During ischemia, the peak m[Ca²⁺] accumulation was decreased by APC from 489 ± 37 nM (CON) to 355 ± 28 nM (P < 0.05); this was abolished by 5-HD (475 ± 38 nM m[Ca²⁺]). APC resulted in improved function and reduced infarct size on reperfusion, which also was blocked by 5-HD. 5-HD pretreatment alone did not affect m[Ca²⁺] (470 ± 34 nM) or IR injury. Thus, preservation of function and morphology on reperfusion is associated with attenuated mCa²⁺ accumulation during ischemia. Reversal by 5-HD suggests that APC may be triggered by opening mK_ATP channels.

IMPLICATIONS:Myocardial ischemia/reperfusion injury is associated with mitochondrial Ca²⁺ overload. Mitochondrial [Ca²⁺] and function were measured in guinea pig isolated hearts. Anesthetic preconditioning attenuated mitochondrial Ca²⁺ overload during ischemia, improved function, and reduced infarct size. Reversal by 5-hydroxydecanoate suggests that anesthetic preconditioning may be triggered by mitochondrial adenosine triphosphate-sensitive K channel opening.

	Introduction

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Volatile anesthetics are routinely used for general anesthesia. Experimentally they protect the myocardium against ischemia/reperfusion (IR) injury when administered either before or after prolonged ischemia (1,2). The unique discovery that short periods of ischemia before prolonged ischemia precondition the myocardium to attenuate IR injury, called ischemic preconditioning (IPC) (3), was followed by studies showing that temporary exposure to volatile anesthetics before prolonged ischemia also preconditioned against IR injury. This phenomenon, called "anesthetic preconditioning" (APC), reduced infarct size in dogs (4) and improved vascular, mechanical, and metabolic function, reduced cytosolic Ca²⁺ overload and nicotinamide-adenine dinucleotide (NADH) accumulation, and improved drug-induced endothelial nitric oxide release in guinea pig isolated hearts (5–7).

The precise triggering mechanism of APC is not well understood. Attenuation of APC by the adenosine triphosphate (ATP)-sensitive K⁺ (K_ATP) channel antagonist glibenclamide (4,5) suggested that volatile anesthetics trigger APC, in part, by opening K_ATP channels. Evidence that K_ATP channels in the mitochondrial (m) inner membrane might also play an important role in preconditioning was first presented by Garlid et al. (8).

Mitochondria transport Ca²⁺ to regulate m[Ca²⁺], which controls the activation of Ca²⁺-sensitive dehydrogenases and oxidative phosphorylation (9). Overload of mCa²⁺ occurs during ischemia and on reperfusion and has been causally implicated in IR injury (10–12). IPC reduces mCa²⁺ overload during IR, an effect that was blocked by the putative mK_ATP channel antagonist 5-hydroxydecanoate (5-HD) (13). Mitochondrial K_ATP channel opening is thought to reduce the driving force for intracellular Ca²⁺ into the mitochondria (11,14). The possible influence of altered mCa²⁺ in APC and the effect of opening mK_ATP channels on mCa²⁺ have not been examined.

We hypothesized that anesthetic exposure before ischemia decreases subsequent mCa²⁺ overload and attenuates IR injury in part by opening mK_ATP channels. Use of the Langendorff heart preparation with real-time measurement of mCa²⁺ fluorescence (F) allowed us to follow the development of functional variables, as well as mCa²⁺, before, during, and after ischemia in guinea pig intact hearts. We examined whether APC is evidenced by reduced mCa²⁺ during IR and whether 5-HD reverses the cardioprotection afforded by APC.

	Methods

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The investigation conformed to the Guide for the Care and Use of Laboratory Animals (US National Institutes of Health No. 85-23, revised 1996) and was approved by the animal studies committee. Our methods have been described previously (2,5–7,12). In brief, 40 hearts were isolated from decapitated guinea pigs and perfused retrograde through the aorta at a constant pressure of 55 mm Hg and at 37°C. The Krebs-Ringer solution (KR) perfusate (pH 7.40 ± 0.01; PO₂, 570 ± 10 mm Hg) had the following composition (in mM, non-ionized): Na⁺ 138, K⁺ 4.5, Mg²⁺ 1.2, Ca²⁺ 2.5, CI^- 134, HCO₃ 14.5, H₂PO₄ 1.2, glucose 11.5, pyruvate 2, mannitol 16, probenecid 0.1, EDTA 0.05, and insulin 5 (U/L).

Heart rate, left ventricular pressure (LVP), and coronary inflow (ultrasonic flowmeter) were measured as described previously (2,5–7,12). Characteristic data from LVP were systolic (sys), diastolic, and developed LVP, as well as dLVP/dt_max and dLVP/dt_min (indices of contractility and relaxation, respectively). Coronary inflow and coronary venous Na⁺, K⁺, Ca²⁺, PO₂, pH, and PCO₂ were measured off-line. Sevoflurane was bubbled into the perfusate for 15 min by using an agent-specific vaporizer placed in the oxygen/CO₂ gas mixture line. Coronary perfusate was collected from a port in the aortic cannula and from the pulmonary catheter to measure sevoflurane concentrations by gas chromatography. The inflow sevoflurane concentration was 1.24 ± 0.02 mM, or 8.80 ± 0.14 vol%, at 37°C (n = 20). This concentration, which is too large for maintenance of clinical anesthesia but can be used temporarily during mask induction (15), was chosen to unmask any possible effect of sevoflurane on mCa²⁺ during exposure to sevoflurane as well as during IR. To block mK_ATP channels (8), 200 µM 5-HD was infused alone or before, during, and after sevoflurane exposure.

At the end of 120 min of reperfusion, hearts were removed and ventricles cut into transverse sections of 3-mm thickness. Sections were immediately stained with 1% 2,3,5-triphenyletrazolium chloride in 0.1 M KH₂PO₄ buffer (pH 7.4, 38°C) for 5 min (7). All slices were digitally imaged, and the infarcted areas were measured in a blinded fashion by planimetry with National Institutes of Health (Bethesda, MD) software (Image 1.62). Infarcted areas of individual slices were averaged on the basis of their weight to calculate the total infarct size of both ventricles as a percentage.

The m[Ca²⁺] was measured by the indo-1 F technique (16) adapted for use in the intact heart (12,17,18). Each experiment was performed in a light-blocking Faraday cage. The distal end of a bifurcated fiberoptic cable (6.8 mm² per bundle) was placed gently against the left ventricular anterior wall. A net was applied around the heart to ensure optimal contact with the fiberoptic tip. The two proximal ends of the fiberoptic cable were connected to a modified luminescence spectrophotometer (Photon Technology International [PTI], London, Ontario, Canada).

F was excited with light from a 75-W xenon arc lamp. The light was filtered at 350 nm (Delta RAM; PTI), and the beam was focused onto the fibers entering the optic bundle. The arc lamp shutter was opened for only 2.5-s recording intervals to prevent photobleaching. F collected by the second limb of the cable was separated by a dichroic beamsplitter at 430 nm and filtered at 405 ± 15 nm and 460 ± 10 nm. Intensities were measured by photomultipliers (Photomultiplier Detection System 814; PTI). After a 30-min equilibration period, background F was determined for each heart. Indo-1-AM (6 µM) was prepared (2,6,12) and perfused for 30 min. This loading increased F approximately 10-fold.

After washout of residual interstitial indo-1-AM for 20 min, cytosolic Ca²⁺ was quenched from cytosolic indo-1 by perfusion with 100 µM MnCl₂ for 15 min. The remaining F originates predominantly from mitochondrial sources (18) and lacks the phasic character of cytosolic Ca²⁺ F (12,13). Figure 1 displays a representative original F tracing before and after indo-1 loading, after quenching with MnCl₂, and 200 min later in a nonischemic control heart. Although both F₄₀₅ and F₄₆₀ declined over time, the F₄₀₅/F₄₆₀ ratio remained stable during the course of our studies (6,12).

View larger version (31K): [in this window] [in a new window]   Figure 1. Representative original tracings of fluorescence (F) emissions (in arbitrary fluorescence units) from one nonischemic time-control experiment at 405 and 460 nm and their fluorescence ratio (F405/F460) before (A) and after (B) loading with indo-1, after MnCl2 perfusion (C), and 200 min later (D) in a guinea pig intact heart. Note the 10-fold increase in F405 and F460 with indo-1 loading and the phasic character of F405, F460, and their ratio (F405/F460), representing intracellular Ca2+ transients. MnCl2 decreased F405 and F460 by 60% and abolished the transient. Although both F405 and F460 decreased slightly over 200 min, their ratio, F405/F460, representing mitochondrial Ca2+, remained stable. LVP = left ventricular pressure.

where S₄₆₀ is the ratio of F intensities at 460 nm at zero and saturated Ca²⁺, K_d is the dissociation constant of indo-1, R_m is the actually measured F₄₀₅/F₄₆₀ ratio, R_min is the F₄₀₅/F₄₆₀ ratio at zero Ca²⁺, and R_max is the F₄₀₅/F₄₆₀ ratio at saturated Ca²⁺. In calibration experiments, K_d was calculated as 249 nM (12), S₄₆₀ as 2.29, R_min as 0.57, and R_max as 6.22 at the chosen photomultiplier settings; m[Ca²⁺] is given in nanomolar. Perfusion and washout of indo-1 decreased LVP by approximately 25% (Fig. 1); this effect is due to the vehicle and to intracellular Ca²⁺ buffering by indo-1 (6). MnCl₂ quenching increased LVP to approximately 85% of preloading values; this is likely due to reversal of indo-1 buffering of Ca²⁺ by substitution with Mn²⁺. LVP and m[Ca²⁺] remained stable during the experiments (Fig. 1).

All analog signals were digitized (PowerLab/16 SP; ADInstruments, Castle Hills, Australia) and recorded at 200 Hz (Chart & Scope Version 3.6.3; ADInstruments) on a Power Macintosh^® G4 (Apple Computer, Inc., Cupertino, CA) for later analysis with MATLAB^® (The MathWorks, Natick, MA) and Microsoft Excel^® (Microsoft Corp., Redmond, WA) software. All variables were averaged over the sampling period of 2.5 s.

After 95 min for equilibration, loading, washout, and MnCl₂ perfusion, each protocol lasted 200 min, beginning at 0 min (Fig. 2). Hearts were assigned randomly to one of four different groups: 1) untreated ischemic control hearts (CON, n = 10) were not subjected to preconditioning or given 5-HD; 2) preconditioned hearts (APC, n = 10) were exposed to 1.2 mM (8.8 vol%) sevoflurane for 15 min, followed by a 30-min washout period before ischemia; 3) APC + 5-HD hearts (n = 10) were perfused with 200 µM 5-HD from 5 min before to 15 min after sevoflurane exposure, and this was followed by a 15-min washout of 5-HD before ischemia; and 4) 5-HD hearts (n = 10) received 200 µM 5-HD for 35 min, followed by a 15-min washout before ischemia. There was no difference in sevoflurane concentration between APC and APC + 5-HD hearts. Sevoflurane was almost undetectable (0.05 ± 0.01 mM) in the effluent 30 min after its washout before ischemia. All hearts underwent 30 min of global no-flow ischemia by clamping the aortic inflow; this was followed by 120 min of reperfusion.

View larger version (27K): [in this window] [in a new window]   Figure 2. Schema for the protocol used in four randomized groups of guinea pig hearts (n = 10 per group). After indo-1 loading and washout, MnCl2 was infused to quench cytosolic Ca2+ fluorescence before beginning the study. Anesthetic preconditioning (APC) was elicited by exposing hearts to 1.2 mM sevoflurane; 200 µM 5-HD was perfused alone or before, during, and after sevoflurane administration. All hearts underwent 30 min of global no-flow ischemia and 120 min of reperfusion. CON = control; 5-HD = 5-hydroxydecanoic acid.

	Results

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As shown in Figure 3, m[Ca²⁺] increased continuously during ischemia in each group. This increase was less in APC hearts than in other groups. Perfusion with 5-HD during sevoflurane exposure abrogated this difference, whereas 5-HD alone caused no difference compared with CON.

View larger version (22K): [in this window] [in a new window]   Figure 3. Indo-1 fluorescence-determined mitochondrial (m) Ca2+ for each group before, during, and after ischemia. Note the continuous increase in mCa2+ during ischemia in all groups and the lesser accumulation in the anesthetic preconditioning (APC) group during ischemia; this was abolished by 5-hydroxydecanoic acid (5-HD). 5-HD alone did not alter mCa2+ accumulation. Ischemia/reperfusion values for each group were different from the preischemia values except at after 90 and 120 min of reperfusion (P < 0.05). Symbols for P < 0.05 among groups are *CON versus APC; APC versus APC + 5-HD; and #APC versus 5-HD. CON = control.

View larger version (38K): [in this window] [in a new window]   Figure 4. A, Systolic (sys) and diastolic (dia) left ventricular pressure (LVP) for each group before, during, and after ischemia. Sevoflurane (sevo) exposure with and without 5-hydroxydecanoic acid (5-HD) caused a completely reversible decrease in sysLVP. 5-HD alone did not change sysLVP. On reperfusion, sysLVP recovered better in anesthetic preconditioned (APC) hearts than in control (CON) hearts but did not reach preischemic values in either group (P < 0.05). DiaLVP increased similarly during ischemia in all groups and remained significantly increased throughout reperfusion compared with baseline values (P < 0.05). Sys-dia LVP was improved throughout reperfusion in APC hearts compared with all others (P < 0.05). B, The dLVP/dtmax (contractility) and dLVP/dtmin (relaxation) for each group before, during, and after ischemia. Sevoflurane exposure with and without 5-HD caused a completely reversible decrease in dLVP/dtmax and dLVP/dtmin. During reperfusion, the contraction and relaxation indices were improved more in APC hearts than in all other hearts but did not return to preischemic values (P < 0.05). Symbols for P < 0.05 among groups are *CON versus APC; CON versus APC + 5-HD; APC versus APC + 5-HD; #APC versus 5-HD; and ¶APC + 5-HD versus 5-HD. For other symbols, refer to Figure 3.

Sevoflurane reversibly altered heart rate from 245 ± 4 bpm in CON hearts to 181 ± 14*# bpm in APC hearts. This was not blocked by 5-HD (191 ± 14¶ bpm). Heart rate recovered fully on washout of sevoflurane before ischemia. 5-HD alone caused no difference compared with CON (243 ± 7 bpm). At all other perfusion periods, there was no difference in heart rate among the four groups (data not displayed).

Coronary flow (CF; mL · min^-1 · g^-1) was not different among groups before ischemia (average, 6.8 ± 0.0). Sevoflurane exposure and 5-HD perfusion caused no significant change in CF. At early reperfusion, each group exhibited a postischemic flow response. CF was significantly higher in the APC group than in the other groups at 5 min of reperfusion: 4.6 ± 0.2* for CON, 6.0 ± 0.3 for APC, 5.0 ± 0.3 for APC + 5-HD, and 5.2 ± 0.2# for 5-HD. Throughout reperfusion, CF recovered better in the APC group than in the other groups but did not reach preischemic values at 120 min of reperfusion, when CF was 4.7 ± 0.2* for CON, 5.6 ± 0.2 for APC, 4.8 ± 0.3 for APC + 5-HD, and 4.7 ± 0.2# for 5-HD.

Infarct size (percentage of total ventricular tissue) was decreased significantly only in APC hearts. This decrease was blocked by 5-HD, which, by itself, had no effect on infarct size: 54.9% ± 1.8%* for CON, 31.1% ± 2.0% for APC, 53.0% ± 2.6% for APC + 5-HD, and 54.3% ± 2.3%# for 5-HD.

	Discussion

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This is the first study to indicate that APC triggered by sevoflurane exposure before global ischemia is associated with attenuated mCa²⁺ overload during IR and that this effect on mCa²⁺ overload is reversed by 5-HD, a putative blocker of mK_ATP channels. As in our previous report on mNADH (7), this study supports the thesis that APC initiates a sequence of events characterized by observable changes in mitochondrial function during ischemia. The mK_ATP channel opening may be an important factor in this sequence.

Myocardial preconditioning is a phenomenon whereby brief periods of ischemia (IPC) (3) or brief administration of a variety of drugs, (20) including volatile anesthetics (4–7), before prolonged ischemia trigger mechanisms that protect the myocardium against subsequent IR injury. Mitochondria likely play a central role as both triggers and effectors of preconditioning (7,21,22).

Volatile anesthetics are thought to trigger APC, in part, by opening K_ATP channels (4,5,8). K_ATP channels are abundant on mitochondrial inner membranes (23,24). The putative mK_ATP channel opener diazoxide mimics IPC on infarct size (8) and attenuates IR injury (21,25). The opening of mK_ATP and subsequent K⁺ influx leads to mitochondrial membrane depolarization, matrix swelling, slowing of ATP synthesis, and accelerated respiration (26). Sufficient mitochondrial membrane depolarization may reduce the driving force for Ca²⁺ influx through the Ca²⁺ uniporter (27), thus attenuating mCa²⁺ overload during ischemia and on reperfusion (14). This is supported by the findings that diazoxide attenuated mCa²⁺ overload in isolated mitochondria (28), myocytes (29), and isolated rat hearts (13). IPC, as APC, leads to decreased cytosolic Ca²⁺ (6) and mCa²⁺ overload (13) and to similar changes in NADH (7), which suggests common pathways elicited by APC and IPC.

Our study demonstrates that the APC-induced preservation of function and tissue viability and the attenuated mCa²⁺ overload are reversed by the concomitant administration of 5-HD. This suggests an important link between mK_ATP channel function and mCa²⁺ handling in the cardioprotection by APC and indicates attenuated mCa²⁺ overload as an observable marker for reduced IR injury. Because IPC and APC both cause a decrease in cytosolic Ca²⁺ overload during IR (6), lower mCa²⁺ loading may also result in part from a lower influx of cytosolic Ca²⁺.

Sevoflurane exposure before ischemia caused a marked but fully reversible reduction in contractility and heart rate; however, this temporary cardiac depression per se cannot be responsible for APC because it was not blocked by 5-HD. It is interesting that despite the temporary cardiac depression, mCa²⁺ did not change during sevoflurane exposure. Diazoxide perfusion also does not appear to alter mCa²⁺ under normoxic conditions (13). Therefore, sevoflurane exposure without ischemia may not open mK_ATP channels directly but rather may "prime" (30) them directly or indirectly to open faster and/or more during subsequent ischemia. Volatile anesthetics, as well as diazoxide, cause small but significant changes in mitochondrial energetics (7,31). Furthermore, we have demonstrated a role for APC in attenuating mNADH accumulation during ischemia (7). Thus, the attenuation of mCa²⁺ by APC may be the result of a partial preservation of mitochondrial bioenergetics rather than their cause.

The higher mCa²⁺ signals on reperfusion for each group persisted until approximately 30 minutes of reperfusion and then reached preischemic values during the last 90 minutes of reperfusion. Thus, we did not observe a continuously increased mCa²⁺ signal or an attenuated mCa²⁺ signal in preconditioned hearts, as was reported with shorter reperfusion protocols in intact rat hearts (13) or isolated rabbit ventricular myocytes (29). Infarction in our model was concentric and subepicardial; thus, infarcted cells, as well as viable cells, underlie the fiberoptic probe. The overall F measured in our study is therefore likely a product of average mCa²⁺ signals per cell and the number of viable cells contributing to the observed F. We suggest that lower mCa²⁺ in a larger number of viable cells in preconditioned hearts may balance out higher mCa²⁺ in a smaller number of viable cells in nonpreconditioned hearts so that the overall F signal during reperfusion is similar among groups. If this is so, the mCa²⁺ measurements obtained on reperfusion must be interpreted in context with the fraction of viable cells on reperfusion, i.e., the percentage of noninfarcted tissue.

Possible limitations of our study are that the use of a high-PO₂, blood-free perfusate causes a greater use of CF reserve and that volatile anesthetics may modify neutrophil function related to IR injury in in vivo hearts. Moreover, the isolated heart is devoid of autonomic and hormonal input, which could influence IR injury. Although many investigators use the rat heart as a model for APC, the guinea pig is closer in design to the human heart, as we (2,6) and others (32–34) have observed. We used only one pulse of a large concentration of sevoflurane to induce APC. However, from our studies in the same preparation, we know that APC can also be induced with two pulses of smaller concentrations (5,6) and that there is a concentration-dependent effect of APC induced by sevoflurane (7). It is important to note that conclusions on the role of mK_ATP channel opening in APC depend on the selectivity of 5-HD as a blocker of mK_ATP channels.

In summary, we have shown that APC not only afforded cardioprotection against mechanical dysfunction and tissue necrosis on reperfusion after myocardial ischemia, but also attenuated mCa²⁺ overload during ischemia and on reperfusion. Reversal of these effects by the putative mK_ATP channel blocker 5-HD suggests that direct or indirect mK_ATP channel opening is part of the triggering mechanism of APC. This study extends our knowledge of the triggering mechanism of volatile anesthetics to protect against myocardial IR injury. APC could prove advantageous in patients undergoing surgery who are at risk for cardiac ischemia.

	Acknowledgments

 
Supported in part by Grant HL58691 (DFS and AKSC) from the National Institutes of Health (Bethesda, MD), Grant 0020503Z (EN) from the American Heart Association (Dallas, TX), and Grant Ri 610005 (MLR) from the Medical Faculty of the Westfälische-Wilhelms-Universität (Münster, Germany).

The authors thank James Heisner for technical assistance and Dr. Srinivasan Varadarajan, Dr. Ming Tao Jiang, Dr. Jianzong An, Anita Tredeau, and Mary Ziebell for their valuable contributions to this study.

	Footnotes

 
Presented in abstract form at the Experimental Biology meeting, New Orleans, LA, April 20–24, 2002.

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