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© 1999 International Anesthesia Research Society
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Abstract |
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Polymorphonuclear neutrophils (PMN) play a crucial role in the initiation of reperfusion injury. In a previous study, we found that ketamine reduced the postischemic adherence of PMN to the intact coronary system of isolated guinea pig hearts. Because ketamine is a racemic mixture (1:1) of two optical enantiomers, we looked for possible differences in action between the stereoisomers. Seventy-six guinea pig hearts were perfused in the "Langendorff" mode under conditions of constant flow (5 mL/min) using modified Krebs-Henseleit buffer. After 15 min of global warm ischemia, freshly isolated human PMN (106) were infused as a bolus into the coronary system during the second minute of reperfusion. PMN adhesion was expressed as the numeric difference between PMN recovered in the effluent and those applied. Series A hearts received 5 µM S(+), 5 µM R(-), or 10 µM racemic ketamine starting 20 min before ischemia and during reperfusion. In Series B hearts, 10 µM nitro-L-arginine, an inhibitor of NO synthase, was added to the perfusate. In Series C, PMN were preincubated for 15 min with 5 µM S(+)- or R(-)-ketamine. Coronary vascular leak was assessed by measuring the rate of formation of transudate on the epicardial surface. Ischemia/reperfusion without anesthetics increased coronary PMN adherence from 25.5% ± 2.3% (basal) to 35.3% ± 1.5% of the number applied. S(+)-ketamine reduced postischemic adherence in each series (A, 25.5% ± 5.1%; B, 22.5% ± 1.7%; C, 25.3% ± 7.7%), as did racemate (A, 26.4% ± 3.7%). Although 5 µM R(-)-ketamine had no effect on adhesion (A, 30.5% ± 6.7%; B, 34.3% ± 5.1%; C, 34.3% ± 4.3%), it significantly increased vascular leak in the presence of NOLAG. These findings indicate stereoselective differences in biological action between the two ketamine isomers: S(+)-ketamine inhibited PMN adherence, R(-)-ketamine worsened coronary vascular leak in reperfused isolated hearts.
Implications: In this study, we demonstrated stereoselective differences in the biologic action of the two ketamine isomers in an animal model of myocardial ischemia. Polymorphonuclear neutrophil adherence to the coronary vasculature after ischemia was inhibited by S(+)-ketamine, whereas R(-)-ketamine increased coronary vascular fluid leak.
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Introduction |
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Ketamine, a widely used IV anesthetic, is a 1:1 racemic mixture of two optically active isomers that differ in their analgesic and psychomimetic effects: S(+)-ketamine is approximately 4 times as potent as R(-)-ketamine. These differences seem to reflect stereoselectivity toward membrane-receptors (1).
In a preliminary study in our laboratory, we found decreased postischemic adherence of polymorphonuclear neutrophils (PMN) in the presence of ketamine (2). Neutrophils play a crucial role in the development of cardiac reperfusion injury (3–6); one of the main consequences of PMN adherence in the heart is an increase in vascular leak (7). Therefore, inhibition of activation and/or adhesion of PMN in the coronary system has cardioprotective features (4,6). An anesthetic with such a capacity would be helpful in cardiac surgery.
Since the isolated optical isomers of ketamine have recently become available, we searched for differences in their effect on PMN adhesion and on the ensuing coronary leak between the two enantiomers and the racemate. Furthermore, we looked for effects of ketamine on PMN activation (expression of the integrin CD11b) during coronary passage and assessed the metabolic state of the hearts in the presence of ketamine isomers. For all these experiments, we used a highly standardized preparation: isolated guinea pig hearts with an intact coronary system and pure human PMN. After a controlled induction of myocardial ischemia, an intracoronary bolus of washed human PMN was applied during reperfusion in the presence or absence of the ketamine enantiomers, and the number of adherent PMN was determined from the arteriovenous difference.
Using human PMN instead of guinea pig PMN in our xenogenic model offered several advantages. We were able to reduce substantially the number of animals needed for the experiments, as no blood donor animals were required. Additionally, a monoclonal antibody against the integrin CD11b is available for human PMN but not for guinea pigs PMN. Furthermore, in previous experiments, we found that PMN from guinea pigs and humans show a quantitatively similar degree of adhesion in our model (8). PMN of both species provoke a postischemic increase in coronary leak, which is readily assessable in isolated heart preparations (7).
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Methods |
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S(+)-ketamine, R(-)-ketamine, and ketamine racemate (preservative free) were provided by Parke-Davis (Freiburg, Germany). Magnetizable CD15 antibodies were obtained from Miltenyi Biotech GmbH (Bergisch Gladbach, Germany). Nitro-L-arginine (NOLAG) was purchased from Sigma Chemie (Deisenhofen, Germany) and was added to the perfusate at a concentration of 10-5 M. A monoclonal antibody against CD11b and the isotype control (mouse IgG1) were obtained from Guildhay (Guilford, UK).
The composition of Krebs-Henseleit buffer was (in mM): 126 NaCl, 24 NaHCO3, 4.7 KCl, 0.6 MgSO4, 1.25 CaCl2, 1.2 KH2PO4, 0.3 pyruvate, 5.5 glucose, and 5 IU/L insulin.
Phosphate-buffered saline (PBS), pH 7.4, contained (in mM): 120 NaCl, 2.7 KCl, 4 Na2HPO4, and 0.1% EDTA.
Tris-buffered Tyrode's solution, pH 7.4, was composed of (in mM): 137 NaCl, 2.6 KCl, 1 MgCl2, 3 CaCl2, 1 Tris, and 0.1% glucose.
Human neutrophils were isolated from 20 mL of venous blood that had been freshly obtained from five healthy volunteers. For anticoagulation, 0.1% EDTA was present. The blood was centrifuged for 15 min at 350g, and the buffy coat was removed. This was incubated for 15 min at 4°C with 20 µL of iron-tagged antibodies (mouse) against the PMN-specific epitope CD15. The labeled buffy coat was passed through a magnetizable column in which the labeled PMN were retained, whereas unbound cells were washed out with 3 x 600 µL of PBS. After removal of the column from the magnetic field, the retained cells were eluated by flushing the column with 1 mL of PBS. The obtained neutrophils were washed with 10 mL of PBS solution, centrifuged at 450g for 10 min, and resuspended in Tyrode's solution. The purity (98%) and viability (95%) were regularly controlled by flow cytometry analysis. The cell count was determined with a Coulter Counter ZM (Coulter Electronics, Luton, UK), and cells were diluted to a final concentration of 106/mL Tyrode's solution. This method of cell preparation yields relatively unstimulated PMN <1.5 h after sampling (9).
The care of the animals and all experimental procedures were in accordance with German animal protection laws and were approved by our institution's animal care committee.
Hearts were isolated from male guinea pigs (body weight 250–330 g). After cervical dislocation, median thoracotomy was performed, and the hearts were immediately arrested with cold saline. The aorta was cannulated, and the heart was perfused at 60 mm Hg as a "nonworking" Langendorff preparation with Krebs-Henseleit buffer equilibrated at 37°C with 94.4% oxygen and 5.6% carbon dioxide (pH 7.4 ± 0.05). The heart was rapidly excised, and the caval, azygos, and pulmonary veins were ligated. A steel cannula was inserted into the pulmonary artery to allow the collection of coronary effluent. The aortic perfusion pressure was continuously registered with a pressure transducer (P23 Db; Statham Instruments, Hato Rey, Puerto Rico).
After finishing the preparation, perfusion was continued at constant coronary flow of 5 mL/min for 30 min. Global myocardial ischemia was induced by interrupting the perfusion for 15 min, during which time the hearts were immersed in Tyrode's solution at 37°C. Reperfusion was started again with a 5-mL/min constant flow, which lasted for 30 min in all experiments. In the second minute of reperfusion, a 1-mL bolus of PMN (106 cells in 1 mL of Tyrode's solution) was applied continuously over 60 s into the coronary system via the aortic cannula by an infusion pump. For the minute of application, the coronary flow was increased to 6 mL/min. The coronary effluent was collected continuously during the bolus administration and in the following 60 s to count the PMN leaving the coronary system (PMN output). Previous studies in our laboratory showed that only a negligible amount of PMN (<1%) emerged after that sampling period (8). Immediately before each intracoronary application of a bolus of PMN, a test bolus of equal volume and duration (1 mL in 60 s) was sampled to determine the number of cells actually leaving the application syringe (PMN input). The percentage of PMN adhering to the endothelium was expressed by the following formula:
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To determine the major localization of the adherent PMN, electron microscopy of some hearts was performed after PMN application (Fig. 1).
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Ketamine isomers and racemate stock solutions were prepared with distilled water, divided into 5-mL aliquots, stored frozen at -15°C, and thawed for daily use. The following drug concentrations were tested: S(+)-ketamine 1 and 5 µM, R(-)-ketamine 5 and 15 µM, and racemate 10 µM. During ketamine anesthesia, the free plasma concentration of racemate is 3–10 µM (10). During anesthesia with S(+)-ketamine, the stable plasma concentration is approximately 5 µM (11).
In Experimental Series A, either no drugs (vehicle) or diluted drugs were administered into the aortic cannula at a constant flow rate of 50 µL/min for 20 min before ischemia, interrupted during ischemia, and applied again from the first minute of reperfusion until the end of the experiments (ischemia without anesthetic n = 10, S(+)-ketamine 5 µM n = 10, R(-)-ketamine 5 µM n = 10, 15 µM n = 4, racemate 10 µM n = 7).
To assess the possible role of endogenous NO in the effects of the ketamine stereoisomers, in Series B, an inhibitor of NO synthase, NOLAG (10-5 M), was added to the perfusate. These hearts were subjected to ischemia without anesthetic (n = 4) or in the presence of 5 µM S(+)-ketamine (n = 4) or 5 µM R(-)-ketamine (n = 4).
To investigate the influence of enantiomers on neutrophil function, in Series C, PMN instead of the hearts, were pretreated with ketamine. Freshly prepared PMN were incubated for 15 min at 37°C with 5 µM S(+)-ketamine (n = 7) or 5 µM R(-)-ketamine (n = 7), and these neutrophils (106) were infused into the coronary system in the second minute of reperfusion. The hearts did not receive any ketamine other than this bolus. However, because of dilution of the bolus and its ketamine content on infusion, the effective concentration of ketamine in the coronary system amounted to approximately 1 µM. Thus, we administered 1 µM S(+)-ketamine only during reperfusion and PMN without pretreatment in an additional four hearts.
Basal adhesion of PMN under preischemic conditions in the absence or presence of 10 µM ketamine racemate was also measured as described above.
Coronary effluent was collected for lactate and pyruvate measurements in the preischemic 10th and 30th minutes and in the postischemic 1st and 15th minutes of the study protocol.
Lactate and pyruvate were determined with the aid of high-performance liquid chromatography (HPLC) (12). Lactate release was assessed as the product of coronary effluent concentration and coronary flow. Pyruvate uptake was calculated from the difference of perfusate pyruvate supply (1.5 µmol/min) and the pyruvate efflux (effluent concentration x coronary flow rate). The ratio of lactate release to pyruvate consumption was calculated as a highly sensitive marker of myocardial ischemic stress (12).
The rate of formation of cardiac transudate was monitored in the preischemic 30th minute (basal) and in the postischemic 5th, 15th, and 30th minute of the experiments by collecting the epicardial free fluid (transudate) dripping from the apex of the isolated heart over 60-s intervals. For approximate determination of the volume of the transudate, the collected fluid was weighed. Transudate formation is a direct measure of net fluid filtration in the coronary bed and, under the given highly controlled experimental conditions, depends only on coronary perfusion pressure and paracellular endothelial permeability (7,8).
To evaluate the difference in the expression of CD11b between the PMN applied in the bolus and the PMN in the effluent, flow cytometry was performed. In brief, the expression of the adhesion molecule and activation marker CD11b was measured by analyzing the mean fluorescence intensity of PMN after staining with phycoerythrin-labeled CD11b antibody. The values were corrected for the fluorescence given by isotype control antibody (identically minimal in all cases). The effect of coronary passage was assessed by dividing the mean fluorescence intensity of PMN in the effluent by the mean fluorescence of the PMN in the bolus for each individual experiment. These values were then averaged, with ratios >1 indicating activation and ratios <1 indicating deactivation or selective retention of activated PMN.
The results are expressed as means ± SD. For comparisons among the groups, one-way analysis of variance was used. For comparison within the groups, one-way repeated-measures analysis of variance was applied. If the F-test proved to be positive, multiple comparisons were performed using the Student-Newman-Keul test. Differences were considered significant at P < 0.05.
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Results |
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Values of intracoronary adhesion of PMN of different experimental groups are depicted in Figures 2 and 3. Basal adherence of PMN in hearts without ischemia was 25.5% ± 2.3% of the applied 106 neutrophils. Application of 10 µM ketamine racemate had no influence on the extent of basal PMN adhesion (22% ± 7%). After 15 min of global warm ischemia (Series A), PMN adhesion increased significantly to 35.3% ± 1.5% (Fig. 2). The administration of 5 µM S(+)-ketamine inhibited the enhanced postischemic adhesion significantly; intracoronary retention returned to the basal level. The application of 5 µM R(-)-ketamine did not reduce the adherence of PMN after ischemia to a statistically significant extent, and 15 µM R(-)-ketamine also had no effect (40.0% ± 4.3%). However, treating the hearts with 10 µM racemic ketamine (containing 5 µM S[+]-ketamine) resulted in a significant decrease of the postischemic adhesion.
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Additional suppression of endogenous NO production with NOLAG (Series B) further increased postischemic adhesion of PMN to 39.5% ± 1.3% (P < 0.05 versus ischemia). Even in this situation, 5 µM S(+)-ketamine fully inhibited the postischemic increase in PMN adhesion (22.5% ± 1.7%), whereas 5 µM R(-)-ketamine exhibited no significant effect (Fig. 3, top). The postischemic values obtained with the two enantiomers differed significantly (P < 0.05).
In Series C, PMN were preincubated with the isomers for 15 min. Adding 5 µM S(+)-ketamine decreased postischemic adhesion to the basal level, whereas incubating the neutrophils with R(-)-ketamine had no beneficial effect (Fig. 3, bottom). Because of dilution of the PMN bolus in perfusate during the infusion, the actual concentration of ketamine in the coronary system was approximately 1 µM. Interestingly, 1 µM S(+)-ketamine administered with the perfusate only in the reperfusion phase successfully blocked the augmented postischemic adherence (n = 4, 21.8% ± 1.3%) as effectively as 5 µM S(+)-ketamine present from 20 min before ischemia (Figs. 2 and 3, bottom).
Data for transudate flow rates are presented in Table 1. Basal preischemic rates of transudate formation were on the order of 100 µL/min. There was no significant acute effect of application of any of the ketamine stereoisomers or of NOLAG. During reperfusion, transudate flow continuously increased. By the 30th minute of reperfusion, all values were significantly increased above the preischemic level. However, the infusion of NOLAG further worsened the coronary leakage. The administration of R(-)-ketamine, but not S(+)-ketamine, in the presence of NOLAG in the perfusate resulted in an additional significant increase in transudate flow compared with ischemia or NOLAG-ischemia controls.
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Preischemic coronary perfusion pressure (CPP) of the hearts was 20–30 mm Hg (Table 2). The data in Table 2 reveal a development of transient postischemic vasodilatation 5 min after ischemia (decrease in CPP), followed by significant vasoconstriction from the 15th minute of reperfusion until the end of the experiments. These changes were similar in all groups, although NOLAG tended to increase CPP. However, ketamine stereoisomers did not cause notable effects on CPP.
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Investigating the metabolic changes in Series A, lactate and pyruvate metabolism were compared in the preischemic phase (10th and 30th minute) and in postischemic hearts (1st and 15th minute of reperfusion). As shown in Table 3, lactate release was significantly higher in the 1st minute of reperfusion compared with the preischemic values in each group, but had decreased toward the normal range in the 15th minute of reperfusion. This can be taken as a sign of washout of accumulated lactate because pyruvate consumption was practically identical at all times measured. The ratio of lactate release to pyruvate uptake was significantly increased in all groups measured in the 1st minute of reperfusion. There were no differences among the groups for any of the metabolic variables at any time, which indicates that the ketamine stereoisomers did not significantly influence ischemic stress.
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The ratio of expression of integrin CD11b on PMN in the coronary effluent versus expression on PMN in the applied bolus was consistently greater than unity. In Series A, the ratio was 1.4–1.6; in Series B, it was 1.1–1.6; and in Series C, it was 1.6–1.8. In particular, there were no statistically significant differences between the groups with or without 5 µM S(+)- or R(-)-ketamine in all three series. Thus, equal activation of PMN occurred during passage through the coronary bed of the postischemic heart preparations under all conditions.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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S(+)-ketamine and racemate, administered 20 min before ischemia and during reperfusion, were able to reduce the enhanced postischemic adherence of neutrophils to the coronary endothelium. S(+)-ketamine also exerted its beneficial, inhibitory effect on postischemic adherence if the NO synthase system was blocked.
The expression of the CD11b integrin adhesion molecule of PMN, a marker of cell activation, increased during coronary passage, but was not different among the groups.
The action of ketamine was rapid. This is supported by the fact that S(+)-ketamine given only during reperfusion and starting just 1 min before PMN application also inhibited postischemic neutrophil adherence.
Ketamine stereoisomers and racemate did not influence myocardial metabolism, as judged by myocardial lactate release, pyruvate uptake, and lactate/pyruvate ratio. The latter variable accentuates any shift from aerobic to anaerobic metabolism.
R(-)-ketamine perturbed vascular integrity in the presence of NOLAG, as assessed by transudate formation. This deleterious effect on coronary leakage occurred in addition to the failure to reduce the amount of adherent-activated PMN.
PMN adhesion in the coronary system during reperfusion is deleterious for the heart. Thus, inhibition of PMN adhesion protects the reperfused heart (4,5). A prerequisite for the adhesion of PMN is their close interaction with endothelial cells, which can be mediated by two different pathways: capillary plugging, as a nonspecific physical process ensuing from narrowed capillary lumina after edema formation or reduced leukocyte elasticity, and specific interaction of adhesion molecules, such as CD11b/CD18, with the endothelial ligand ICAM-1.
To explain why S(+)- but not R(-)-ketamine induced a marked decrease in postischemic neutrophil adherence, the first consideration was whether the ketamine isomers differentially affect the coronary perfusion pressure, i.e., grossly influence intravascular shear stress. Graf et al. (13) investigated the cardiovascular responses of the ketamine isomers and racemate in untreated, catecholamine-depleted, or opioid-blocked isolated guinea pig hearts. They found that both stereoisomers possess cardiac-depressant properties and that S(+)-ketamine increased availability of catecholamines in the adrenergic neuroeffector junction. Such an action could elicit vasoconstriction. However, in our experiments, we did not see any remarkable differences in the CPP of hearts receiving stereoisomers. Nevertheless, these observations do not exclude discrete influences of ketamine enantiomers on the distribution of flow. If ketamine influences the microcirculation, one would assume an effect on basal adhesion, not only during postischemic perfusion. There was no evidence for such an action, which in vivo would give rise to symptoms of coronary steal, which are not described for ketamine. Furthermore, the application of the vasodilator iloprost in our model changed neither the basal nor the postischemic adhesion rate of PMN (14). Thus, flow does not seem to be critical for PMN adhesion. Furthermore, any induction of marked heterogenicity of flow would likely have led to changes in the lactate to pyruvate ratio, which did not occur. Thus, altered intravascular shear rates can largely be excluded as a cause of different extents of adhesion.
A second possible explanation could have been that a negative inotropic effect of R(-)-ketamine (15) mitigates ischemia and, thus, the severity of reperfusion injury. Our observation of unchanged lactate release and pyruvate uptake during reperfusion does not support this theory.
Considering these findings, the reduced adhesion of PMN in the presence of S(+)-ketamine seems to result from specific interference of the anesthetic with the adhesion event. In controls, expression of the integrin adhesion molecule CD11b on the surface of neutrophils increased during coronary passage. This enforces sticking to the endothelium and is a marker of the degree of PMN activation (16). Inhibition of the adhesion complex CD11b/CD18 or the endothelial ligand ICAM-1 by monoclonal antibodies prevents PMN adhesion to the coronary endothelium (4,5). However, ketamine did not influence the extent of CD11b activation during coronary passage. Nevertheless, we cannot exclude that ketamine has a direct effect on PMN. Not only the upregulation of CD11b expression, but also the regulation of the affinity of integrin CD11b, can influence the adhesion event (17). The receptor affinity of CD11b could not be measured with our methods; therefore, ketamine may interact with the affinity regulation of CD11b/CD18.
Another explanation would be an inhibitory effect of S(+)-ketamine on the endothelial binding site of PMN. For example, ketamine may influence the affinity of ICAM-1, the endothelial ligand of ß2-integrins of PMN. In this context, it is notable that S(+)-ketamine was able to block the augmented postischemic adherence when given with the onset of reperfusion, 1 min before the application of PMN. This suggests—but does not prove—an endothelial site of action. Moreover, ketamine could influence the production of NO by the endothelium, which is known to have an inhibitory effect on PMN adhesion (7). In our experiment, when endogenous NO synthase was blocked by adding NOLAG to the perfusate, S(+)-ketamine and R(-)-ketamine fully retained their disparate effects. Thus, inhibition of postischemic neutrophil adherence by S(+)-ketamine cannot originate from enhancement of endothelial NO production.
R(-)- and S(+)-ketamine may have opposing influences on the endothelium, as suggested by our finding that only R(-)-ketamine heightened postischemic coronary leakage, especially in hearts deprived of endogenous NO. We have no explanation for this finding. Because S(+)-ketamine and racemate did not induce such an increase in coronary permeability, these drugs may be more beneficial for postischemic heart function than the R(-)-isomer.
Some aspects of this study are preliminary. For example, we applied only one protocol of ischemia, and additional influences of other blood components (platelets, plasma, erythrocytes) were not tested. Detailed measurements of myocardial contractile performance before and after ischemia have not been evaluated. Furthermore, the exact site of action of S(+)-ketamine (endothelium versus PMN) has not been resolved, nor has the mechanism of action.
The ketamine enantiomers may have specific, opposing effects on adhesion molecules or endothelial receptors. Ketamine stereoisomers possess different affinity and activity on several types of receptors, such as the N-methyl-D-aspartate receptor (1). In clinical and experimental studies, the superiority of S(+)-ketamine has been described with regard to anesthetic potency, the extent of analgesia, and perioperative effects and side effects, especially psychological dysfunction (18,19). Several studies report a neuroprotective effect after transient cerebral ischemia (20,21). Our study indicates that S(+)-ketamine may act protectively against cardiac reperfusion injury, given that endothelial adhesion of PMN is a major mediator of this injury. However, R(-)-ketamine may worsen endothelial dysfunction, causing increased vascular leak and, thus, edema formation. These disparate effects could reflect a protective action of S(+)-ketamine in vivo and may explain why no such cardiac benefit has been reported for the racemate.
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Acknowledgments |
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This study was supported by the Friedrich-Baur-Foundation of the University of Munich.
We thank Professor Ulrich Welsch (Department of Anatomy, University of Munich) for kindly performing the electron microscopic examination of the hearts.
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Footnotes |
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AS is the recipient of a research fellowship of the European Academy of Anaesthesiology.
Presented in part at the 1998 annual meeting of the European Association of Cardiothoracic Anaesthesiologists, Bergen, Norway.
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