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Anesth Analg 2000;90:17
© 2000 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Sevoflurane and Isoflurane Do Not Enhance the Pre- and Postischemic Eicosanoid Production in Guinea Pig Hearts

Bernhard Heindl, MD*, and Bernhard F. Becker, MD, PhD{dagger}

Departments of *Anesthesiology and {dagger}Physiology, Ludwig-Maximilians-University, Munich, Germany

Address correspondence and reprint requests to Dr. B. Heindl, Department of Anesthesiology, Nussbaumstr. 20, 80336 Munich, Germany. Address e-mail to heindl{at}ana.med.uni-muenchen.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 µM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2{alpha}. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%–60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5–8- and 2–4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane.

Implications: In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The eicosanoids prostacyclin and thromboxane A2 (TxA2) are formed from arachidonic acid (AA), when the cyclooxygenase pathway is stimulated, and are not stored in significant amounts. The content of unesterified AA in myocardium is very low, but ischemia and reperfusion release AA from membrane and plasma phospholipids (1). In the heart, eicosanoids are mainly released by endothelial cells, but also by cardiac myocytes and fibroblast-like cells (2). Their formation influences cardiac reperfusion injury. The protective effects attributed to prostacyclin include vasodilation and prevention of thrombus formation (3,4). In contrast, TxA2 aggravates injury by causing vasospasm and platelet activation during tissue reperfusion (5).

The cardioprotective effects of volatile anesthetics have been postulated in the ischemia/reperfusion situation. Several studies have shown beneficial effects of isoflurane on myocardial recovery (6–9), whereas little such data are available for sevoflurane (10,11). Because volatile anesthetics are "membrane active" (12), their protective effects may be based on increased prostacyclin and/or reduced thromboxane formation by endothelial cells and platelets. The influence of volatile anesthetics in clinically relevant concentrations on the production of eicosanoids is not yet well characterized. Only Hirakata et al. (13) have indicated that sevoflurane, but not isoflurane, inhibits platelet-dependent TxA2 formation.

Accordingly, we analyzed the effects of the two volatile anesthetics isoflurane and sevoflurane on the myocardial production of prostacyclin and TxA2 under basal and postischemic conditions, as well as during cyclooxygenase stimulation (infusion of exogenous AA). These metabolic effects were related to functional cardiac recovery after ischemia and reperfusion, by using a standardized, isolated heart model. Furthermore, the influence of volatile anesthetics on oxidative stress was investigated by measuring the level of the isoprostane 8-iso-PGF2{alpha} in the heart tissue after reperfusion (14–16).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Heart Preparation. The care of the animals was in full accordance with German animal protection laws, and the experiments were officially approved by our institutional animal care committee.

The hearts were isolated from male guinea pigs (body weight 200–300 g) after cervical dislocation, without the use of any anesthetics. After median thoracotomy the beating hearts were arrested rapidly by superfusion with ice cold saline. The ascending aorta was cannulated, and the hearts were excised. The isolated organs were perfused at 37°C by using a modified Krebs-Henseleit buffer (17), first in a nonworking Langendorff mode to allow further preparation. The veins entering the right atrium were ligated, and the pulmonary artery was cannulated to enable the collection of the coronary venous effluent. The left atrium was cannulated to allow natural filling and contraction. The hearts performed pressure-volume work at a left atrial filling pressure of 12 cm H2O and a mean aortic pressure of 80 cm H2O.

The heart rate and the perfusion pressure were continuously monitored with a pressure transducer (FMI GmbH, Egelsbach, Germany) in the aortic cannula, and aortic and coronary flows were recorded with an ultrasonic flow meter (Transsonic Systems Inc., Ithaca, NY).

Experimental Protocol for Working Hearts. The perfusion protocol is outlined in Figure 1. After an initial 20-min work phase (W1), the hearts were perfused for 15 min in a nonworking mode at a coronary flow of 5 mL/min. Thereafter, the hearts were subjected to 15 min of global stop-flow ischemia. Myocardial reperfusion was established at constant coronary flow of 5 mL/min for the next 20 min, after which work (W2) was performed again (20 min) under conditions identical to those of W1. To eliminate temperature effects, hearts in the nonworking phases were immersed in 37°C warm Tyrode’s solution.



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  		Figure 1. Schematic presentation of the experimental protocol for working hearts. Hearts performed pressure-volume-work for 20 min each at the beginning and at the end of the protocol. After work phase W1, coronary perfusion was changed to a volume-constant mode. The preischemic phase (5 mL/min) was successively followed by a global ischemia (no flow) and a reperfusion phase (5 mL/min). Sevoflurane or isoflurane was applied either only in the preischemic perfusion phase or in the preischemic and the first 10 min of the reperfusion phase. In the control group, no anesthetics were applied. {downarrow} = samples of the coronary venous effluent were collected for eicosanoid measurements. AA = facultative application of arachidonic acid.

 
Sevoflurane or isoflurane was added in clinically relevant concentrations of 1 minimum alveolar anesthetic concentration (MAC) (2 vol% sevoflurane, 1.2 vol% isoflurane) or 0.5 MAC (1 vol% sevoflurane) to the O2/CO2 gas mixture equilibrating the separate perfusate tank used for the nonworking mode. Application of anesthetics was either limited to the 15 min of preischemic, constant-volume perfusion or they were additionally present for the first 10 min of reperfusion (see Fig. 1). After this time, the perfusate was replaced by a fresh, warm, oxygenated perfusate to speed wash-out of volatile anesthetics from the heart. To exclude negative inotropic effects of sevoflurane and isoflurane on cardiac performance during W1 and W2, no anesthetics were applied during the work phases. The addition of the anesthetics to the perfusate was achieved by means of a calibrated vaporizer (Dräger, Lübeck, Germany), as described previously (18), and was monitored by gas detectors (Dräger) in the gas inflow. To ensure equilibration, the application of anesthetics to the perfusate began 30 min before its use.

To differentiate between whether sevoflurane inhibits the cyclooxygenase pathway or interferes with the liberation of AA from cell membranes, in an additional group of experiments, 1 µM exogenous AA was applied to the hearts for the last 5 min of the preischemic constant volume perfusion and the first 2 min of the reperfusion phase, either in the absence or presence of 2 vol% sevoflurane (Fig. 1).

The following experimental groups were investigated:

At the end of W1 and W2 coronary flow, aortic flow, heart rate, and ejection time of stroke volume were determined. External heart work (EHW) was calculated from these variables (17). Recovery of EHW was defined as the ratio of the values obtained in W2 and W1 and expressed in percent.

For measurements of myocardial release of prostacyclin and TxA2, 2-mL samples of the coronary effluent were collected on crushed ice in the 10th (basal value in the groups receiving AA) and 15th min of preischemic constant volume perfusion and in the 2nd, 5th, and 15th min of reperfusion (Fig. 1). Samples were immediately frozen in liquid nitrogen and stored at -80°C to await processing. As a measure of the severity of myocardial ischemia, cardiac lactate release and pyruvate consumption were measured in the 15th min of the preischemic perfusion, in the 2nd and 5th min of reperfusion, and at the end of W2. Lactate and pyruvate in the coronary effluent were determined simultaneously by using high-pressure liquid chromatography (19).

Measurement of Eicosanoids. After liberation from phospholipids of cell membranes, free AA is oxygenated in the cyclooxygenase pathway, two major end products being prostacyclin and TxA2. The production of prostacyclin and TxA2 is typically assessed by the measurement of the stable end products 6-keto-PGF1{alpha} (20) and thromboxane B2 (TxB2) (21), respectively.

Coronary effluent samples were analyzed with the corresponding ELISA kits (R+D-Systems, Wiesbaden, Germany). Samples (100 µL) were incubated with 50 µL of specific conjugate and antibody solution for 2 h at room temperature. After a washing procedure, 200 µL of substrate solution was added to determine the bound enzyme activity. After 45 min, the development of color was stopped, and the extinction was measured at 405 nm. The kit can detect as little as 1.4 pg/mL 6-keto-PGF1{alpha}, and 8 pg/mL TxB2, and there is negligible cross-reactivity between 6-keto-PGF1{alpha} and TxB2 with other eicosanoids. Detected concentrations of standard samples exposed to 1 MAC of sevoflurane or isoflurane were not different from those not preexposed to anesthetics.

Tissue Extraction and Measurement of 8-Iso-Prostaglandin F2{alpha}. Isoprostanes are a group of bioactive prostaglandin-like substances, which are produced in vivo mainly by free radical-catalyzed peroxidation of AA. In the ischemia-control groups and the experimental groups receiving 1 MAC isoflurane or sevoflurane during the pre- and postischemic perfusion, 5–6 hearts each were shock frozen at the end of W2. The frozen ventricular tissue was stored at -80°C until processed further. Frozen tissue was pulverized under liquid nitrogen, and a portion of the powdered tissue was used to determine the dry/wet weight ratio. Extraction of 8-iso-PGF2{alpha} from approximately 100 mg of frozen tissue was achieved with 3 mL of 0.5 M perchloric acid. After centrifugation and neutralization of the supernatant with 1 M NaOH, levels of 8-iso-PGF2{alpha} were measured by ELISA, the analytical procedure and principle corresponding to that described for eicosanoids. The recovery of 8-iso-PGF2{alpha} standard was 82%; all values were corrected by this amount.

Statistical Methods. The results were expressed as mean ± SEM. For comparison of groups, analysis of variance was first performed to detect any possible overall differences. Whenever a significant result was obtained, multiple comparisons were made between groups by using the Dunn test (different number of experiments per group) or the Student-Newman-Keuls test (identical number of experiments per group). For comparison of perfusion pressures before and after the start of the AA infusion (preischemic phase), the paired t-test was used. Differences between data were considered significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Production of Eicosanoids. Basal production of prostacyclin showed a high variability between individual hearts and groups (Table 1). In the second min of reperfusion, release of prostacyclin by control hearts was increased approximately 5–8 fold. The prostacyclin concentration in the coronary effluent decreased continuously thereafter, regaining the preischemic level after approximately 15 min of reperfusion. Application of isoflurane and 1 vol% sevoflurane had no statistically significant effect on the production of prostacyclin in the preischemic phase and during reperfusion in the intergroup comparison. In the presence of 2 vol% sevoflurane in the reperfusion phase, the increase of prostacyclin was only modest (see Table 1) and, in comparison with all other groups, not significantly elevated above the preischemic value.


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  		Table 1. Myocardial Production of Prostacyclin and Thromboxane A2 with Application of Isoflurane (Iso) or Sevoflurane (Sevo), Either Only Before (pre) or Before and After Ischemia (pre + post)
 
Basal release of TxA2 from guinea pig hearts was comparable to that of prostacyclin, both with respect to amount and variability (Table 1). Release of TxA2 of ischemia-control hearts increased in the second min of reperfusion, albeit only 2–4 fold. After 15 min of reperfusion, TxA2 levels were similar to the preischemic range. As in the case of prostacyclin, only sevoflurane applied pre- and postischemically at 2 vol% mitigated the increased production of TxA2 during early reperfusion.

Infusion of 1 µM AA resulted in a 200-fold increase of prostacyclin production, both before and after ischemia. In contrast, AA augmented the production of TxA2 only modestly by a factor of 2–3, and there was no further increase after ischemia. The presence of sevoflurane did not influence the time course or extent of release of either prostacyclin or TxA2 induced by AA (Table 1). The enhancement of eicosanoid formation was rapidly reversible, disappearing within 10 min of washout.

Coronary Perfusion Pressure. The time course of the coronary perfusion pressure measured during reperfusion is outlined in Table 2. In all groups, coronary perfusion pressure decreased in the early reperfusion phase in comparison with the preischemic values and increased again in the course of the reperfusion. No statistically significant differences between groups were detected at any time. Approximately 1 min after the start of the infusion of AA in the preischemic phase, the coronary perfusion pressure decreased by 6 ± 4 cm H2O (P < 0.05 in the paired t-test) and tended to be lower in the early reperfusion phase. This effect dissipated rapidly during washout of AA.


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  		Table 2. Time Course of Coronary Perfusion Pressure
 
Production of Lactate and Consumption of Pyruvate. Rates of lactate production and of pyruvate consumption are displayed in Table 3. In each case, lactate release increased dramatically in the second min of reperfusion in comparison with the preischemic values. This normalized rapidly during reperfusion, and no statistically significant intra- and intergroup differences were detectable at the end of W2. Pyruvate consumption decreased during reperfusion in all groups, but recovered again to the preischemic control level in W2, except for the groups that received AA. Aerobic metabolism was continuously suppressed after AA infusion, as evidenced by the ratio of lactate production to pyruvate consumption. This ratio increases with falling contribution of aerobic metabolism. At the end of W2, the ratios after application of AA were significantly (P < 0.05) increased (ischemia-control + AA: 3.2 ± 0.4, sevoflurane (pre + post) + AA: 2.5 ± 0.3) in comparison with the ischemia-control group (0.9 ± 0.2).


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  		Table 3. Lactate Production and Pyruvate Consumption
 
Recovery of EHW. The hemodynamic data of the working hearts are presented in Figure 2 and Table 4. Time-control hearts maintained myocardial function at approximately 90%, whereas recovery of EHW of ischemia-control hearts was reduced to approximately 57% (Fig. 2). The application of 1 MAC isoflurane or 0.5 and 1 MAC sevoflurane had no influence on recovery. The infusion of AA reduced postischemic recovery of EHW substantially. In contrast, AA in the presence of sevoflurane caused an intermediate impairment: recovery of EHW was neither significantly lower than that in the ischemia control group nor higher than that in the control hearts receiving AA. The reductions in coronary flow seen during W2 in comparison with W1 were in accordance with the changes in performance of EHW (Table 4). There were no substantial alterations in spontaneous heart rate.



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  		Figure 2. Recovery of external heart work (EHW). Time-control hearts were not subjected to global ischemia. The ischemia-control group was subjected to global ischemia without anesthetics. Pre- or pre- and postischemic application of isoflurane or sevoflurane did not result in an improved recovery of EHW. Arachidonic acid (AA, 1 µM) significantly reduced recovery of EHW. #P < 0.05 versus all groups without application of AA. *P < 0.05 versus time-control group. Values are mean ± SEM, n = 6–7 each.

 

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  		Table 4. Preischemic (W1) and Postischemic (W2) Hemodynamic Parameters of Hearts Subjected to 15 min of Global Ischemia and 20 min of Reflow in the Absence or Presence of Volatile Anesthetics
 
The tissue content of the isoprostane 8-iso-PGF2{alpha} in hearts after ischemia and reperfusion was not significantly different under any condition. Values (in pg/mg dry weight) were ischemia-control: 12.7 ± 2.5, isoflurane (pre + post) 1 MAC: 13.9 ± 5.5, sevoflurane (pre + post) 1 MAC: 21.4 ± 12.5, ischemia-control + AA: 9.1 ± 2.4, sevoflurane (pre + post) + AA: 19.5 ± 9.2.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In our study, prostacyclin and TxA2 were produced in approximately equal amounts by hearts under basal conditions and showed a parallel increase in the early reperfusion phase, returning to preischemic values within 10–15 minutes of reperfusion. These observations are in accordance with results of Tosaki et al. (22) obtained in isolated rat hearts. After stimulation with 1 µM exogenous AA, we detected a dramatic (200-fold) increase in production only for prostacyclin, signifying a high latent activity for cyclooxygenase and the enzyme prostacyclin synthetase as opposed to thromboxane synthetase.

Neither isoflurane nor sevoflurane increased cardiac eicosanoid formation under pre- or postischemic conditions. Thus, the cardioprotective effects of volatile anesthetics, seen under some experimental conditions, cannot be ascribed to increased prostacyclin production. Sevoflurane, given at a concentration of 1 MAC, but not at 0.5 MAC, prevented the increased eicosanoid formation in the early reperfusion phase. In the presence of 1 MAC sevoflurane, there was no statistically significant increase of either prostacyclin or TxA2 production in the second minute of reperfusion. However, because of the high variability of eicosanoid formation among individual hearts, even under basal conditions, the test power is too small to completely ensure the suppressing effect of sevoflurane on cardiac eicosanoid formation. Interestingly, Hirakata et al. (13) have also described a suppressing effect of sevoflurane on TxA2 formation in blood platelets starting at 0.5 vol% and higher, which was not detectable for isoflurane up to 1.8 vol%.

An inhibiting effect of sevoflurane on eicosanoid release could arise from the inhibition of cyclooxygenase or, alternatively, from the inhibition of the liberation of endogenous AA from membrane lipids during reperfusion (1), e.g., by blocking the activity of phospholipases A2. This would reduce the substrate supply for eicosanoid production. Hirakata et al. (13) postulated a cyclooxygenase-inhibiting effect of sevoflurane in blood platelets. However, in our model, infusion of exogenous AA into the hearts in the presence of sevoflurane increased eicosanoid production in quantitatively the same manner as when sevoflurane was absent. Thus, there was no detectable inhibition of cyclooxygenase by sevoflurane. Although we have used a rather small concentration of exogenous AA (1 µM) it was still applied in a relative excess, and the occurrence of competitive inhibition of the enzyme by sevoflurane cannot be excluded completely. Nevertheless, the intriguing possibility that sevoflurane interferes with the increased liberation of endogenous AA in reperfused myocardium bears consideration (1).

The reduced eicosanoid production in the presence of sevoflurane in the early reperfusion phase did not improve or impair recovery of EHW in our study. This does not exclude a cardioprotective effect of volatile anesthetics, as described by others and our group, under different conditions (6,7,23). The experimental setup (crystalloid buffer versus presence of blood cells) and the protocol (duration of ischemia, species examined, etc.) may have an important influence on the cardioprotective potential of volatile anesthetics. Furthermore, the increase of both prostacyclin and TxA2 production was inhibited in our isolated hearts, and thus, two "antagonistically" acting substances were influenced in the same direction.

Directly on reperfusion, myocardial lactate release increased dramatically in all groups. Neither the application of volatile anesthetics nor the infusion of AA exerted a relevant influence on lactate, indicating an identical severity of ischemic conditions. Pyruvate consumption, however, was reduced transiently in the reperfusion phase, as well as during and after the application of AA (W2). The increased ratio of lactate production to pyruvate consumption in W2 after the AA application is additional, convincing evidence of a shift to anaerobic metabolism of these hearts. AA has been shown to induce mitochondrial dysfunction (24), which would explain the reduced aerobic metabolism in W2. This long-lasting metabolic effect might be the cause for the reduced recovery of heart work after ischemia and reperfusion seen in hearts treated with AA. After ischemia and reperfusion, the tissue content of 8-iso-PGF2{alpha} did not differ significantly between groups. Our findings therefore suggest sevoflurane and isoflurane do not markedly influence heart metabolism and free radical activity during reperfusion.

In conclusion, neither isoflurane nor sevoflurane increased cardiac eicosanoid formation, either pre- or postischemically. Sevoflurane, at a concentration of 1 MAC during reperfusion, suppressed the production of prostacyclin and TxA2 in the early reperfusion phase. The effect of sevoflurane on cardiac eicosanoid production was probably caused by interference with the increased liberation of AA associated with ischemia and reperfusion, an effect not observed with isoflurane.


   Acknowledgments
 
Supported by the Friedrich-Baur-Foundation of the University of Munich, Munich, Germany.

The authors thank Stefan Zahler for helpful discussions and Denice Deck, Dora Kiesl and Evi Musiol for their valuable technical assistance.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication September 13, 1999.





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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