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© 2002 International Anesthesia Research Society
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Abstract |
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Isoflurane protects myocardium during ischemia-reperfusion via a mechanism involving the adenosine triphosphate-sensitive potassium channels. We tested the hypothesis that an inhibition of the neutrophil-endothelium interactions by isoflurane contributes to this effect. Polymorphonuclear neutrophils and coronary artery segments were obtained from 35 healthy dogs. Superoxide production by neutrophils, stimulated with platelet-activating factor (PAF; 1.0 µM), was measured spectrophotometrically. Adherence of PAF-activated neutrophils to the endothelium of coronary segments was assessed by direct counting of neutrophils labeled with fluorescent dye. Coronary artery rings were exposed to PAF-activated neutrophils, and, after washing and preconstriction with U46619, they were evaluated for vasorelaxation responses to acetylcholine (endothelium dependent) and sodium nitroprusside (endothelium independent). Measurements were performed in the absence and presence of isoflurane (1 and 2 minimum alveolar anesthetic concentration) both with and without glibenclamide (10 µM). Isoflurane inhibited superoxide production and adherence by neutrophils and abolished neutrophil-induced reductions in coronary vascular relaxation responses to acetylcholine. Glibenclamide did not alter the effects of isoflurane on neutrophils or coronary artery endothelium. In conclusion, isoflurane had an inhibitory action on neutrophil-endothelium interactions and neutrophil-mediated coronary endothelial dysfunction—effects that may be involved in its cardioprotective action in vivo. These inhibitory actions of isoflurane were not mediated by adenosine triphosphate-sensitive potassium channels.
IMPLICATIONS: Isoflurane inhibited neutrophil-endothelium interactions and the inflammatory response in vitrovia a pathway independent of the adenosine triphosphate-sensitive potassium channels. This action could be involved in the cardioprotection by isoflurane observed in vivo.
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Introduction |
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Over the past 15 yr, evidence has accumulated suggesting that neutrophil-endothelium interactions and the inflammatory response play a significant role in the pathophysiology of myocardial reperfusion injury (1). Adherence of neutrophils to the endothelium, via the adhesion molecules P selectin and intercellular adhesion molecule-1 (ICAM-1), is believed to represent a critical step in the process of neutrophil transmigration and influx into injured myocardium. Stimulated neutrophils release oxygen free radicals and proteolytic enzymes, which cause injury to the myocardium and its components cells, including the myocytes and endothelium. Endothelial cell damage increases vascular permeability and exacerbates adherence of neutrophils, and it diminishes the release of factors, e.g., nitric oxide.
Previous studies in both animal models and human subjects have demonstrated that isoflurane may reduce cardiac dysfunction and myocardial infarct size after ischemia and reperfusion (2–5). This effect has been attributed to the ability of isoflurane to open the adenosine triphosphate-sensitive potassium (KATP) channels (2,3). The possibility that an inhibitory action on neutrophil-endothelium interactions may contribute to the cardioprotective effects of isoflurane has been largely ignored.
This study was conducted to test the hypothesis that isoflurane reduces superoxide by activated neutrophils, neutrophil-induced coronary endothelial dysfunction, and neutrophil adherence to the coronary vascular endothelium. After first determining that isoflurane inhibited all these features of the neutrophil-endothelium interaction, we sought to evaluate the role of the KATP channels in these effects by using the KATP channel inhibitor glibenclamide. For comparative purposes, analogous studies were conducted with the specific KATP channel opener pinacidil in the absence and presence of glibenclamide.
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Methods |
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The study was conducted after approval from the institutional animal research committee. Experiments were performed on 35 healthy, heartworm-free mongrel dogs of either sex (weight, 18.5–25.8 kg). The dogs were anesthetized with IV bolus injections of 30 mg/kg sodium pentobarbital and mechanically ventilated (Air Shields, Inc., Hatboro, PA) with oxygen-enriched room air. The right carotid artery was cannulated to collect 400–600 mL of blood. Neutrophils were isolated from this blood by use of standard methods (6). The final neutrophil suspensions contained >98% neutrophils, and cell viability was >95% as evaluated by trypan blue exclusion.
Superoxide production by neutrophils in suspension was determined by measuring the superoxide dismutase (SOD) inhibitable reduction of ferricytochrome c to ferrocytochrome c (6). Neutrophils (5 x 106 cells per milliliter) were prewarmed in a shaking incubator at 37°C with 160 µM cytochrome c and 5 µg/mL cytochalasin B in the absence (control) or presence of the test agents for 5 min and then stimulated with platelet-activating factor (PAF; 1.0 µM) (6). The final reaction volume was 0.5 mL. For each assay, duplicate samples were run. Half of the tubes were provided with an excess of SOD (100 µg/mL) as a control for nonspecific activity or color generation. Five minutes after PAF was added, cytochrome c reduction was measured spectrophotometrically by determining the optical density of the supernatant at 550 nm, by using a Vmax kinetic microtiter plate reader (Molecular Devices, Palo Alto, CA). Superoxide production was calculated by using an extinction coefficient of 21 mM-1cm-1 for cytochrome c. Results are expressed as nanomolar amounts of SOD-inhibitable superoxide produced by a suspension of 5 x 106 neutrophils per milliliter.
Our initial studies evaluated the effect of isoflurane (millimolar equivalents of 1.0 and 2.0 minimum alveolar anesthetic concentration; MAC) on superoxide production. After observing inhibitory effects, the role of the KATP channels in these effects was evaluated. This was accomplished by using glibenclamide in a concentration of 10 µM, in accordance with our preliminary studies, previous reports (6), and our studies with pinacidil (see below).
Dogs were killed with an overdose of IV pentobarbital sodium (80 mg/kg), and the heart was rapidly excised and immediately placed into cold (4°C), oxygenated Krebs solution with the following composition (mM): 118 NaCl, 4.75 KCl, 1.19 MgSO4, 1.12 KH2PO4, 2.54 CaCl2, 12.5 NaHCO3, and 10 glucose. Left anterior descending and circumflex coronary arteries were carefully dissected, cleaned of connective and adipose tissue without disturbing the endothelium, and cut into rings 2–3 mm in length. The rings were mounted on stainless-steel hooks, placed into organ baths containing 10 mL of Krebs solution aerated with a gas mixture of 95% oxygen and 5% CO2 at 37°C, and connected to isometric force transducers (model TR 001; Radnoti, Monrovia, CA). Changes in isometric force were digitized at 3 Hz by using an analog-to-digital converter and analyzed with a videographics program (SPECTRUM®; Triton Technology, San Diego, CA).
The coronary artery rings were first tested for functionality and the optimal preconstrictor dose of U46619, a thromboxane A2 mimetic agent. The rings were initially stretched to yield a preload of 1.0 g of tension. After equilibration for 20 min, the constrictor responses to KCl (30 mM) were determined for each 1.0-g increment until the optimal response to KCl was obtained. This prestretch tension was used for the subsequent acetylcholine (ACh) and sodium nitroprusside (SNP) trials (see below). A concentration-response curve for U46619 was then generated for each ring with concentrations over the range of 2.5 to 5.0 nM. The concentration for U46619 that caused the maximal constrictor effect was used for the ACh and SNP trials. After a thorough washing, the rings were allowed to stabilize at baseline tension for 20 min and then were carefully removed from the chamber. The rings were then placed in capped glass test tubes containing Krebs solution saturated with oxygen within a heated (37°C) shaking bath. Neutrophils (1 x 107 cells per milliliter) and PAF (1 µM), when appropriate, were added to the tubes alone or together with isoflurane and incubated for 25 min. In our initial studies, the rings were randomly assigned to one of four experimental conditions: 1) control (no neutrophils, PAF, or drugs); 2) neutrophils alone; 3) PAF and neutrophils; and 4) PAF, neutrophils, and isoflurane (1 and 2 MAC). After we observed an ability of isoflurane to reduce neutrophil-mediated vascular dysfunction, we performed additional studies with glibenclamide (10 µM) in the presence of PAF and neutrophils, with and without isoflurane.
After the incubation period, the rings were removed from the test tubes and washed three times with Krebs solution to remove neutrophils as well as drugs. They were then remounted in the chambers and allowed to stabilize at the appropriate pre-tension for 40 min. Indomethacin (10 µM) was added to the chambers to prevent vascular responses to prostaglandins. Once a stable contraction to U46619 was obtained, endothelial function was assessed with the endothelium-dependent dilator ACh. Cumulative concentration-response curves to ACh (10-9 to 10-6 M) were generated. After the rings were washed and allowed to stabilize, vascular smooth muscle function was assessed with the endothelium-independent smooth muscle dilator SNP (10-9 to 10-6 M). Additional similar studies were conducted to determine whether prior exposure to isoflurane (1 MAC) alone affects coronary vascular relaxation responses to ACh and SNP.
Neutrophil adherence to the endothelial surface of the coronary artery segments was assessed with neutrophils labeled with a vital fluorescent dye, as described previously (6). Briefly, 1 mL of a 4 µM solution of PKH26 dye was added to 1 mL of a neutrophil suspension (2 x 107 cells per milliliter). After the sample was gently mixed, it was incubated at room temperature for 5 min; the labeling reaction was stopped by adding 2 mL of plasma and incubating for 1 min. The plasma-stopped sample was diluted with 4 mL of Hanks balanced salt solution (HBSS) and then centrifuged at 400g for 10 min at 4°C. The resultant cell pellet was transferred to a new tube for additional duplicate washings, and the cells were resuspended. This labeling procedure yields neutrophils possessing normal viability and function (6).
Coronary artery rings were carefully opened without damaging the endothelium and placed in the tube containing 3 mL of HBSS with Ca2+ at 37°C. Labeled neutrophils were added to each tube to achieve a final concentration of 5 x 106 neutrophils per milliliter. The coronary vascular segments were incubated with the labeled neutrophils for 20 min, either alone or with the various drugs described below, including isoflurane. PAF (1 µM) was used to stimulate neutrophil adherence. After the incubation period, the vascular segments were removed and flushed gently with HBSS. Adherence was determined by counting the number of neutrophils adhering to the endothelial surface in six separate microscopic fields under epifluorescent microscopy (490-nm excitation, 504-nm emission) (Fryer Company, Inc., Huntley, IL) and expressed per square millimeter of endothelium.
The following conditions were evaluated in our initial studies: 1) neutrophils alone (control); 2) neutrophils and PAF; and 3) neutrophils, PAF, and 1.0 or 2.0 MAC isoflurane. After observing a reduction in neutrophil adherence by isoflurane, additional studies were performed to assess the effect of glibenclamide alone and combined with 1.0 or 2.0 MAC isoflurane on PAF-induced neutrophil adherence.
Additional studies were conducted to assess the effect of the KATP channel opener pinacidil (50 µM) on neutrophil superoxide production, neutrophil adherence, and neutrophil-mediated endothelial dysfunction in the absence and presence of glibenclamide. The procedures were similar to those described previously for the isoflurane studies.
The following chemicals and reagents were obtained from Sigma Chemical (St. Louis, MO): ACh chloride, SNP, Ficoll-Pacque, SOD, cytochrome c, cytochalasin B, PKH26 dye, indomethacin, pinacidil, glibenclamide, and dimethyl sulfoxide. PAF and HBSS without Mg2+ and Ca2+ were purchased from Avanti Polar Lipids (Alabaster, AL) and Meditech, Inc. (Salt Lake City, UT), respectively. All solutions were prepared freshly on the day of the study.
Millimolar concentrations for isoflurane were calculated with an isoflurane MAC value of 1.4 vol% for the dog (7) and a buffer/gas partition coefficient of 0.55 at 37°C and 1 atm (8). The values were 0.30 and 0.60 mM for 1 and 2 MAC, respectively. A stable level of isoflurane during the experimental protocols was confirmed by gas chromatography (9).
Concentration responses for vascular relaxation were calculated as a percentage of the decrease of U46619-induced isometric force. The drug concentration required to elicit 50% of the maximal relaxation response (EC50) was calculated by linear regression analysis and expressed as the negative logarithm of the drug concentration (-log [M]). The maximal relaxant response was also determined. A maximal relaxant response value equal to 100% indicates complete reversal of U46619-induced contraction. One-way analysis of variance, in combination with the Student-Newman-Keuls test, was used to evaluate treatment effects on superoxide production, neutrophil adherence, and coronary vascular relaxation responses (10). A value of P < 0.05 was considered significant throughout the study.
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Results |
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Figure 1 presents the effects of PAF alone and in the presence of isoflurane (with and without glibenclamide) on superoxide production by neutrophils. PAF alone caused a ninefold increase in superoxide production, which was diminished in a concentration-dependent fashion by isoflurane. Glibenclamide did not alter the isoflurane-induced decreases in superoxide production.
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Figures 2 and 3 demonstrate that PAF caused a pronounced increase in the number of neutrophils adhering to the endothelial surface of the coronary rings and that this effect was prevented by both 1.0 and 2.0 MAC isoflurane. Glibenclamide did not alter the isoflurane-induced inhibition of neutrophil adherence (Fig. 3).
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ACh caused concentration-dependent relaxation responses in the control coronary rings (Figs. 4A and 5A). Preincubation and subsequent washout of unactivated neutrophils had no effect on these responses. Activating the neutrophils with PAF reduced the relaxation responses of the coronary rings to ACh, which caused a rightward shift in the concentration-response curve, and it reduced the maximal response (Figs. 4A and 5A, Table 1). The EC50 for ACh responses in rings exposed to PAF-activated neutrophils was greater than that for control rings (Table 1). Combining the PAF-activated neutrophils with isoflurane reversed the impairment to ACh-induced coronary relaxation caused by the PAF-activated neutrophils alone, and it returned EC50 and the maximal response to control values. The findings for 1.0 and 2.0 MAC isoflurane were similar. Thus, only those for 1.0 MAC are presented in Figures 4 and 5 and Table 1. Glibenclamide did not alter the ability of isoflurane to inhibit the neutrophil-mediated decreases in ACh responses. The concentration-related vascular relaxation responses to SNP were not affected by neutrophils (with or without PAF) either in the absence or presence of isoflurane (Figs. 4B and 5B, Table 1). Prior exposure to isoflurane alone did not alter the concentration-related relaxation responses to either ACh or SNP (Fig. 6).
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Pinacidil caused decreases in superoxide production and adherence by neutrophils (Fig. 7A and B), and it prevented the neutrophil-induced rightward shift in the concentration-response curve to ACh ( Fig. 8A). Responses to SNP were unaffected (Fig. 8B). Glibenclamide reversed the effects of pinacidil. Glibenclamide alone had no effect on the ability of PAF to enhance superoxide production by neutrophils and neutrophil adherence to the vascular endothelium or to cause vascular endothelial dysfunction (data not shown).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our main findings were that 1) isoflurane inhibited superoxide production by neutrophils, neutrophil adherence to the endothelial surface of coronary artery segments, and neutrophil-induced coronary endothelial dysfunction and that 2) these inhibitory effects of isoflurane on neutrophil function and the neutrophil-endothelium interactions were independent of the KATP channels.
Isoflurane, in clinically relevant concentrations, caused pronounced, concentration-dependent reductions in superoxide production by the PAF-stimulated neutrophils. Direct stimulation of neutrophil suspensions by PAF bypasses the normal adherence-dependent, selectin-initiated activation and resultant production of superoxide. PAF binds to a specific receptor on the neutrophil membrane, and this is the first event in the signal transduction sequence. Ultimately, the production of superoxide by neutrophils results from activation and assembly of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which is a transmembrane electron transport chain that reduces oxygen to superoxide. Superoxide production is accompanied by an increase in cytosolic Ca2+ caused by release from intracellular stores and influx through the plasma membrane (11). The ability of isoflurane to inhibit superoxide production could be caused by a direct inhibitory effect on NADPH oxidase or to an inhibitory effect at some site in the signal transduction pathway regulating NADPH oxidase.
Several lines of evidence suggest that neutrophils possess KATP channels, which modulate their activity. First, our findings and those of Zhao et al. (6) demonstrate the ability of the KATP channel opener pinacidil to attenuate superoxide production of PAF-stimulated canine neutrophils. Second, Pieper and Gross (12) showed that the KATP channel opener bimakalim inhibited both superoxide production and luminal-enhanced chemiluminescence in opsonized zymosan-activated canine neutrophils. Third, Krause and Welsh (13) observed potassium currents in human neutrophils by using patch-clamp techniques. Finally, IV bimakalim before reperfusion reduced myeloperoxidase activity, a marker of neutrophil accumulation in myocardium, in the ischemic area (14). Presumably the opening of the KATP channels in the neutrophils hyperpolarizes its membrane, which reduces Ca2+ influx (and the increase in intracellular Ca2+), thus inhibiting superoxide production.
Because of the apparent involvement of the KATP channels in the cardioprotective effects of isoflurane in vivo (2,3) and because of studies indicating that isoflurane can open the KATP channels in various cell types, including coronary vascular smooth muscle cells (15) and cardiomyocytes (16), we performed studies with the KATP channel blocker glibenclamide to assess the role of these channels in the inhibitory effect of isoflurane on superoxide production by neutrophils. Our findings indicated that glibenclamide did not impair the ability of isoflurane to inhibit neutrophil superoxide production, suggesting that the KATP channels did not play an essential role. This could be because isoflurane does not activate the KATP channels in neutrophils or that it does so but, in addition, reduces Ca2+ influx via effects downstream, which would mask antagonism of these channels.
Other potential targets for isoflurane’s inhibitory effect on superoxide production by neutrophils include the following: 1) the PAF receptor on the neutrophil membrane; 2) the guanosine triphosphate-binding proteins (G proteins) which are involved in transduction of agonist signals (11); 3) phospholipase C, which generates two second messengers—inositol 1,4,5-triphosphate and diacylglycerol—leading to an increase in cytosolic free Ca2+; and 4) protein kinase C and protein phosphorylation, which are involved in the neutrophil respiratory burst (17).
Another possible explanation for our findings was that isoflurane did not inhibit superoxide production, but that it was a scavenger of superoxide. However, the finding that volatile anesthetics, albeit in supratherapeutic concentrations, did not blunt the increase in superoxide levels produced by a xanthine-xanthine oxidase system (18) would argue against this possibility.
We observed that isoflurane completely inhibited the PAF-induced adherence of neutrophils to the endothelial surface of the coronary artery segments. This finding is consistent with studies that evaluated the effects of volatile anesthetics on postischemic adherence of neutrophils in isolated guinea pig hearts (19) and on N-formyl-Leu-Phe-induced adherence of neutrophils to human umbilical vein endothelial cells (20).
A potential mechanism for inhibition of neutrophil adherence by isoflurane involves modulation of adhesion molecule-mediated interactions between the neutrophil and endothelial cell. The initial "rolling" step of neutrophil adherence in vivo occurs via upregulation of the endothelial adhesion molecule P selectin, whereas the later firm adherence occurs via upregulation of the endothelial adhesion molecule ICAM-1 (1). In the PAF-stimulated in vitrosystem used in this study, adherence was ICAM-1 dependent (21). Thus, these findings are consistent with suppression of ICAM-1 (and/or its coligand CD11b/CD18) by isoflurane (20).
KATP channels have been identified in both vascular smooth muscle and endothelial cells (22). Because endothelial cells lack voltage-dependent Ca2+ channels, hyperpolarization increases the electrochemical gradient, which facilitates Ca2+ entry, thus enhancing nitric oxide release (23). Nitric oxide can cause vascular relaxation and, in theory, protect the endothelium by reducing neutrophil-derived superoxide generation and neutrophil adherence (24). Previous studies have suggested a role for the KATP channels in endothelial protection from reperfusion dysfunction (25). Our findings with pinacidil provide additional support for this pathway. However, the inability of glibenclamide to reverse inhibition of neutrophil adherence and neutrophil-mediated endothelial dysfunction by isoflurane suggests that these effects were not dependent on activation of the KATP channels.
Regardless of the molecular mechanism, isoflurane attenuated the dysfunction to the coronary artery endothelium caused by activated neutrophils. This dysfunction is the consequence of endothelial damage, which is caused, in part, by superoxide produced by activated neutrophils (1). Endothelial damage can result from adherence-independent and adherence-dependent pathways for superoxide production (21). Our data showing inhibition of superoxide production by neutrophils and reduced adherence of neutrophils suggest that isoflurane may inhibit both these pathways.
We showed in additional studies that prior exposure of coronary vascular rings to isoflurane alone did not alter relaxation responses to ACh. This finding eliminates the possibility that isoflurane’s beneficial effect on ACh-induced coronary relaxation in the studies involving activated neutrophils was caused by an enhancement of baseline endothelial function and was not related to protection against neutrophil-induced endothelial damage.
In summary, this study demonstrated that isoflurane can inhibit the neutrophil-endothelium interactions in the heart. In light of the well established correlation between decreased neutrophil adherence and accumulation and decreased myocardial infarct size (1), this action of isoflurane may have contributed to its cardioprotective effects in vivo (2–5). An activation of the KATP channels in neutrophils or coronary vascular endothelium played no apparent role in the inhibitory actions of isoflurane on the neutrophil-endothelium interactions. This finding, when combined with those obtained in vivo (2,3), suggests that isoflurane protects the heart via both KATP channel-independent and KATP channel-dependent pathways.
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Acknowledgments |
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Supported by funding from the Department of Anesthesiology, Advocate Illinois Masonic Medical Center.
The authors thank Derrick L. Harris, BS, for technical assistance.
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Footnotes |
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Presented in part at the annual meeting of the American Society of Anesthesiologists, San Francisco, CA, October 14–18, 2000.
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