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Anesth Analg 2005;100:707-712 © 2005 International Anesthesia Research Society doi: 10.1213/01.ANE.0000146511.79069.01
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Abstract |
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The main concern with the use of the long-acting local anesthetics bupivacaine and ropivacaine is inadvertent IV injection, which exposes the heart to toxic drug concentrations. We tested the hypothesis that these chiral anesthetics exert enantioselective actions on coronary vascular tone, the regulation of which does not involve voltage-gated Na+ channels. Coronary perfusion pressure (CPP) was continuously measured in isolated hearts perfused via the aorta at a constant flow rate. This method provides a sensitive assay of coronary vascular resistance in the intact heart. In parallel experiments, we examined the effects of bupivacaine and ropivacaine on intracellular [Ca2+] in coronary endothelial cells. In addition, the effect of bupivacaine on mitochondrial membrane potential was assessed using isolated ventricular myocytes. Racemic bupivacaine and R(+)-bupivacaine produced similar dose-dependent decreases in CPP. However, S(-)-bupivacaine, S(-)-ropivacaine and R(+)-ropivacaine increased CPP. In contrast to adenosine triphosphate, neither racemic bupivacaine nor S(-)-ropivacaine changed endothelial intracellular [Ca2+], suggesting that these clinically used drugs do not modulate endothelial nitric oxide synthase. We also showed that the putative uncoupler bupivacaine did not depolarize mitochondria in intact ventricular myocytes. In conclusion, the long-acting local anesthetics have enantioselective actions on coronary resistance vessels. Racemic bupivacaine and R(+)-bupivacaine are coronary vasodilators, whereas S(-)-bupivacaine, S(-)-ropivacaine and, to a lesser extent, R(+)-ropivacaine all induce coronary vasoconstriction.
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Introduction |
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When local anesthetics are deposited locally in large concentration, the voltage-gated ion channels of axons are their primary targets. At the site of deposition, local anesthetics also exert direct vascular effects. With the exception of cocaine, these drugs are generally thought to produce vasodilation (1), and, therefore, epinephrine is often added to local anesthetics such as bupivacaine, lidocaine, and prilocaine to induce local vasoconstriction, thereby decreasing the rate of drug absorption and prolonging the duration of block. However, ropivacaine, the pure S(-)-enantiomer of 1-propyl-2',6'-pipecoloxylidide, was shown to produce local skin blanching (2), suggesting that it acted as a vasoconstrictor of cutaneous blood vessels, as demonstrated by Kopacz et al. (3) using laser Doppler.
The introduction of ropivacaine to clinical practice has promoted interest in chiral local anesthetics, especially because this pure enantiomer and S(-)-bupivacaine have been reported to be less cardiotoxic than their respective R(+)-enantiomers (4). Iida et al. (5) demonstrated that the S(-)-enantiomers of ropivacaine and bupivacaine, as well as R(+)-ropivacaine, exerted opposite vascular effects to R(+)-bupivacaine and racemic bupivacaine. To gain a better understanding of the direct vascular actions of these chiral local anesthetics, we tested the hypothesis that ropivacaine and bupivacaine exert enantiospecific actions on coronary arteries. The results of this study may shed light on mechanisms of local anesthetic cardiovascular toxicity, which include cardiovascular collapse, after inadvertent IV injection.
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Methods |
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Experiments were approved by our local animal ethics committee and performed in accordance with the animal welfare guidelines at the Regierungspräsidium, Giessen. Coronary vascular resistance was monitored using a modification of the methods described previously (6,7). In brief, guinea pigs weighing 300–350 g were anesthetized with 6%–8% sevoflurane in oxygen and decapitated. The heart was excised and the aorta was attached to a perfusion cannula. The standard perfusate contained (in mM) 105 NaCl, 15 KCl, 0.8 MgCl2, 1 NaH2PO4, 24 NaHCO3, 1 CaCl2, 2 Na pyruvate, and 10 glucose. Solutions were gassed with 95% O2/5% CO2 (pH, 7.4). Although the addition of 15 mM KCl prevents spontaneous contractile activity, it has the disadvantage that it causes a small increase in coronary vascular resistance.
The quiescent heart was perfused using a four-channel peristaltic pump (Perimax 16, Spetec GmbH, Germany). Two alternately pulsating channels of the pump were combined to provide flow that was minimally pulsatile. Aortic perfusion pressure (coronary perfusion pressure), which is proportional to coronary vascular resistance, was measured with a piezoresistive pressure transducer (NT 143E; PMT, Ettringen Germany). Data were acquired and displayed online by a computer via an analog-to-digital converter (Digidata 1200; Axon Instruments, Inc., Union City, CA). Drug-induced changes in coronary resistance were indexed by computing the change (expressed as percentage) in coronary perfusion pressure (CPP) before and after drug application.
After a 5-min recovery period, the heart was routinely perfused with 1 µM cromakalim, which, in addition to producing a large and reversible vasodilation, facilitated the establishment of a stable baseline. After washout of cromakalim, the baseline CPP was set to approximately 60 mm Hg by adjusting the flow rate between 4 and 9 mL/min. Thereafter, the flow remained constant and the baseline CPP was remarkably stable: 60 ± 5 mm Hg over 1–2 h. Data were excluded when the baseline CPP drifted more than 10 mm Hg during an experiment. Anesthetics were tested in an ascending order of concentration, and, after each application, the drug was washed out. The next concentration was tested when the CPP had returned to the baseline value. The "apparent" steady-state values (attained after exposure for up to 30 min), rather than the peak values, were used to construct dose-response relations. In any given heart, a maximum of five concentrations was tested. All experiments with the perfused heart were performed at 37°C.
Myocytes were isolated essentially as previously described (8). The initial coronary perfusate contained (in mM) 115 NaCl, 5.4 KCl, 1.5 MgCl2, 0.5 NaH2PO4, 5 HEPES, 16 taurine, 5 sodium pyruvate, 15 NaHCO3, 1 CaCl2, and 5 glucose (pH, 7.4). After 5 min, the heart was perfused for 4–5 min with nominally Ca2+-free solution, followed by a solution containing collagenase type I (Sigma, St. Louis, MO), 0.1% bovine serum albumin, and 40–60 µM Ca2+. After enzymatic digestion (5–7 min), ventricular myocytes were placed in a solution containing (in mM) 45 KCl, 70 K glutamate, 3 MgSO4, 15 KH2PO4, 16 taurine, 10 HEPES, 0.5 EGTA, and 10 glucose (pH, 7.4) and dissociated by trituration with a wide-bore pipette. After 60 min, myocytes were resuspended in Dulbecco’s Modified Eagle Medium (Gibco, Grand Island, NY).
The isolation of coronary endothelial cells from rat heart has been previously described (9). After collagenase treatment the endothelial cell fraction was purified and plated on glass coverslips. Cells were cultured in Medium 199 with Earle’s salts and after 2–3 days, when they had grown to confluence, were used for experiments.
Myocytes or coronary endothelial cells were placed in a Perspex bath (volume 100 µL) located on the stage of an inverted microscope (Diaphot 300; Nikon, Japan) and superfused at a rate of 1 mL/min via gravity flow. Cells were imaged via a x40 oil objective (numerical aperture, 1.3) and experiments were performed using a Deltascan 4000 fluorescence system equipped with two monochromators (Photon Technology International; Photomed, Seefeld, Germany).
Coronary endothelial cells were loaded with fluo-3 (Molecular Probes, Leiden, The Netherlands) by incubation with 10 µM fluo-3/am (dissolved with anhydrous dimethylsulfoxide, DMSO; Aldrich, St. Louis, MO) in physiological salt solution (final DMSO concentration, 0.1%) at room temperature for 15 min. To reduce the rate of fluo-3 extrusion from the cell, experiments were performed at room temperature and the perfusate contained 400 µM probenecid (10). A single endothelial cell was selected and excited at 488 nm via a monochromator while fluorescence was detected at 530 ± 15 nm. Only one cell per cover slip was used for experiments. The fluo-3 fluorescence signal was normalized with respect to the resting fluorescence intensity (F0) and expressed as F/F0.
Ventricular myocytes were loaded with JC-1 or tetramethylrhodamine ethyl ester (TMRE) as described by Ray et al. (11). Myocytes were incubated for 10 min with a solution containing 10 µg/mL JC-1. Cells were excited at 490 nm and J-aggregate related fluorescence was measured at >590 nm. Alternatively, myocytes were loaded with TMRE by superfusion with a solution containing 1.2 µM TMRE for 10–15 min. TMRE was excited at 555 nm and fluorescence was detected at >590 nm. The uncoupler 2,4-dinitrophenol was used to dissipate the mitochondrial membrane potential and scale the JC-1 and TMRE signals. Experiments were performed at 21°C–23°C.
Pure enantiomers of bupivacaine and ropivacaine were kindly provided by AstraZeneca (Södertälje, Sweden). For clarity, clinically used "ropivacaine" is referred to as S(-)-ropivacaine. It should be noted that ropivacaine and bupivacaine are members of the 1-R-2',6'-pipecoloxylidide class of local anesthetics, where R is either a propyl (ropivacaine) or butyl (bupivacaine) group (Fig. 1). Anesthetic drugs were dissolved directly into salt solutions. Glibenclamide was dissolved in DMSO. All chemicals were obtained from Sigma unless stated otherwise.
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Differences among means were tested for statistical significance using two-way analysis of variance. Multiple comparisons were made, where appropriate, using the Tukey test at the 95% confidence level. Data are expressed as mean ± se; the number of preparations is indicated as n.
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Results |
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Figure 2A shows the dose-response curve, obtained from six hearts, for changes in CPP as a function of racemic bupivacaine concentration. Typical for local anesthetics (1), a dose-dependent decrease in vascular resistance was observed. However, we noted that the vascular response to bupivacaine was biphasic (Fig. 2B), that is, the initial decrease in CPP was followed by a small increase. This vasoconstrictive component was more prominent at racemic bupivacaine concentrations less than 50 µM. We also noted that during washout of the drug, CPP transiently increased above resting level. Such an overshoot was not observed after the washout of the potent vasodilators cromakalim (Fig. 2C) or ATP (Fig. 2D) or after the reversal of hypoxia (not shown), which reduced CPP to 36.6 ± 1.2% (n = 25), 26.6 ± 2.2% (n = 5), and 31 ± 2% (n = 7), respectively.
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One possible explanation for the biphasic vascular response elicited by bupivacaine could be that the different enantiomers of the drug exert different actions on coronary vascular tone, that is, one enantiomer could be a vasoconstrictor while the other acts as a vasodilator. We therefore investigated this possibility using pure R(+)- and S(-)-enantiomers of bupivacaine.
The pure R(+)-enantiomer of bupivacaine produced vasodilation whereas the S(-)-enantiomer produced vasoconstriction, except at the largest concentration (100 µM) tested (Fig. 3). Typical responses of coronary arteries to 25 µM R(+)-bupivacaine and 25 µM S(-)-bupivacaine are shown in Figure 3A. Note that the time course of vasodilation induced by R(+)-bupivacaine was much faster than the time course of vasoconstriction induced by S(-)-bupivacaine. Dose-response curves for the steady-state effects of S(-)-bupivacaine and R(+)-bupivacaine are shown in Figures 3B and 3C, respectively.
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Whereas the bupivacaine enantiomers exerted opposite effects on coronary vascular tone, both enantiomers of ropivacaine were predominantly vasoconstrictive (Fig. 4). Similar to S(-)-bupivacaine, S(-)-ropivacaine induced vasoconstriction, albeit more potently (Fig. 3B and Fig. 4A). Moreover, whereas S(-)-bupivacaine produced vasodilation at the largest dose tested (100 µM), this was not the case for S(-)-ropivacaine. In contrast to R(+)-bupivacaine, R(+)-ropivacaine was a weak vasoconstrictor, giving way to vasodilation at larger concentrations.
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To shed light on the mechanisms and sites of action of bupivacaine, we compared this drug with the potent vasodilators cromakalim and adenosine triphosphate (ATP). Figures 5A and B show that application of 10 µM ATP induced an increase in endothelial [Ca2+] (F/F0, 5.4 ± 0.3; n = 8) that was rapidly reversed. A second application of 10 µM ATP produced a smaller Ca2+ response (68.7 ± 1.6%; n = 8), presumably as a result of desensitization of the P2Y receptors. In contrast to ATP, application of 100 µM racemic bupivacaine had no effect on intracellular [Ca2+] (n = 5), (Figure 5A). Similarly, S(-)-ropivacaine (100 µM) had no effect on endothelial [Ca2+] (n = 4) (Figure 5B). Hence, the local anesthetics bupivacaine and ropivacaine probably do not modulate coronary vascular tone via endothelial nitric oxide synthase (eNOS).
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The potent KATP channel opener cromakalim also had no effect on endothelial [Ca2+] (n = 3), suggesting that KATP channels were not expressed in the cultured endothelial cells. However, we cannot exclude that KATP channels may be expressed in the coronary vasculature of the intact heart (12). In the whole heart, we used the KATP channel blocker glibenclamide to test whether the vasodilatory action of racemic bupivacaine involved KATP channels. In control experiments, the vasodilatory action of cromakalim was fully reversed with glibenclamide (not shown). Glibenclamide, though, had no effect on the vascular response to racemic bupivacaine (n = 3; not shown). However, we found that the constrictor S(-)-bupivacaine (25 µM) reversed by 63.4% ± 4.9% the vasodilation induced by cromakalim (n = 3) (Fig. 6), indicating that this enantiomer may inhibit KATP channels or exerts some other opposing action.
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The above data suggest that racemic bupivacaine does not induce vasodilation via either eNOS or KATP channels. In light of the report that bupivacaine exerts a protonophoric uncoupling action in isolated mitochondria (13), we assessed whether bupivacaine produced a change in the mitochondrial membrane potential of intact cardiomyocytes using the fluorescent indicators JC-1 and TMRE (Fig. 7). Uncoupling could produce vasodilation indirectly by impairing energy supply from mitochondria, which would lead to the liberation of vasoactive agonists (such as adenosine) from the myocytes. Bupivacaine had no effect on J-aggregate fluorescence (JC-1 fluorescence at 590 nm) whereas the classic uncoupler dinitrophenol produced a reversible decrease (n = 3) (Fig. 7A). The steady decrease in JC-1 fluorescence was attributable to photobleaching (11). In accord with the JC-1 experiments, bupivacaine did not increase TMRE fluorescence (n = 4) (Fig. 7B). The small decrease in TMRE fluorescence induced by bupivacaine (seen in all experiments) may reflect direct interaction of the lipophilic drug bupivacaine with the fluorescent dye TMRE (11). The consistent results obtained with the fluorescent indicators JC-1 and TMRE suggest that bupivacaine produced no uncoupling.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the search for safer drugs, there has been an increasing interest in the enantioselective actions of anesthetic drugs (14). In the present study we found that the long-acting local anesthetic bupivacaine, clinically used as a racemic mixture, exerted a biphasic effect on CPP, suggesting that its R(+)- and S(-)-enantiomers could be exerting opposing actions. Indeed, we found that the reportedly less toxic S(-)-enantiomer (4,15,16) was predominantly vasoconstrictive, whereas the R(+)-enantiomer was solely vasodilatory. The faster action of R(+)-bupivacaine would explain why the initial response to infusion of racemic bupivacaine is vasodilation, followed by a vasoconstrictive component (Fig. 2B). The overshoot observed after washout of racemic bupivacaine (Fig. 2B) may be attributable to a faster washout of the vasodilatory component. When compared to bupivacaine, the enantiomers of ropivacaine exhibited less extreme differences in that they both predominantly produced vasoconstriction; S(-)-ropivacaine (used clinically) was more potent.
Consistent with our findings, Iida et al. (5) reported that S(-)-ropivacaine, R(+)-ropivacaine and S(-)-bupivacaine constricted cerebral pial arterioles whereas R(+)-bupivacaine and racemic bupivacaine produced vasodilation. Hence, the pattern of enantioselective actions that we observed in the heart may be common to various vascular beds, with notable exceptions such as uterine arteries, where racemic bupivacaine was reported to induce vasoconstriction (17). The vasoconstrictive actions of the S(-)-enantiomers may prevent cardiovascular collapse, which would contribute to their lower cardiovascular toxicity. Vasoconstriction of critical vessels such as coronary or cerebral arterioles could, however, be potentially deleterious to vital organ function.
In further work, we found that glibenclamide did not reverse the coronary vasodilatory action of racemic bupivacaine, suggesting that bupivacaine does not activate vascular KATP channels. Interestingly, however, we found that S(-)-bupivacaine, at a vasoconstrictive dose, partly reversed vasodilation induced by the KATP channel opener cromakalim. Cromakalim is a potent vasodilator that is thought to induce vasodilation via the activation of KATP channels (causing membrane hyperpolarization) in arterial smooth muscle cells and possibly also endothelial cells (12,18). The simplest explanation for this effect is that S(-)-bupivacaine inhibits "vascular" smooth muscle KATP channels, which are probably composed of Kir6.1 and SUR2B (19). In support of this notion, Olschewski et al. (20) reported that bupivacaine blocked the KATP channel of cardiac ventricular myocytes, the molecular correlate of which is Kir6.2/SUR2A (21). In addition, inhibition of two-pore domain K+ channels in vascular smooth muscle cells by S(-)-bupivacaine (22,23) may have contributed to the reversal of the effects of the KATP channel opener cromakalim. However, it cannot be excluded that S(-)-bupivacaine exerted some action unrelated to changes in the membrane potential of vascular smooth muscle cells.
To further elucidate the mechanisms of action of bupivacaine, we examined the effects of racemic bupivacaine on intracellular [Ca2+] in isolated coronary endothelial cells. The potent vasodilator ATP, which activates G protein-coupled P2Y receptors (24), induced a reversible increase in intracellular [Ca2+], whereas racemic bupivacaine had no effect, indicating that racemic bupivacaine does not decrease coronary vascular tone via eNOS. S(-)-ropivacaine also had no effect on endothelial intracellular [Ca2+] which would be expected since it acted as a vasoconstrictor.
Theoretically, bupivacaine could induce vasodilation indirectly by uncoupling mitochondria, as recently suggested. However, using intact myocytes, we found that racemic bupivacaine did not decrease mitochondrial membrane potential, monitored using either JC-1 or TMRE. Hence, bupivacaine-induced uncoupling, observed in isolated mitochondria, probably does not readily manifest in the intact cell. On balance, we infer that bupivacaine and ropivacaine modulate coronary vascular tone via direct enantioselective actions on smooth muscle cells. We speculate that racemic bupivacaine and R(+)-bupivacaine are general vasodilators whereas S(-)-bupivacaine, S(-)-ropivacaine and R(+)-ropivacaine are largely vasoconstrictors.
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