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Anesth Analg 2002;95:31-38
© 2002 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

The Paradoxical Positive Inotropic Effect of Sevoflurane in Healthy and Cardiomyopathic Hamsters

Benoît Vivien, MD*, Jean-Stéphane David, MD{dagger}, Jean-Luc Hanouz, MD, PhD{ddagger}, Julien Amour, MD*, Yves Lecarpentier, MD, PhD§, Pierre Coriat, MD*, and Bruno Riou, MD, PhD*||

*Laboratory of Experimental Anesthesiology, Department of Anesthesiology, Centre Hospitalier Universitaire (CHU) Pitié-Salpêtrière, Université Paris VI, Paris, France; {dagger}Department of Anesthesiology, CHU Edouard Herriot, Lyon, France; {ddagger}Department of Anesthesiology, CHU Côte de Nacre, Caen, France; §Department of Physiology, CHU de Bicêtre, and Institut National de la Santé et de la Recherche Médicale, Palaiseau, France; and ||Department of Emergency Medicine, CHU Pitié-Salpêtrière, Université Paris VI, Paris, France

Address correspondence and reprint requests to B. Vivien, MD, Département d’Anesthésie-Réanimation, Centre Hospitalier Universitaire Pitié Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Address e-mail to benoit.vivien{at}psl.ap-hop-paris.fr


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We investigated the effects of sevoflurane (0.7 to 3.6 vol%) on inotropy and lusitropy in left ventricular papillary muscles of healthy hamsters and genetically induced cardiomyopathic (strain BIO 14.6) hamsters in vitro (29°C, pH 7.40, Ca2+ 2.5 mM, stimulation frequency three per minute) under low (isotony) and high (isometry) loads. Sevoflurane induced a moderate positive inotropic effect in healthy hamsters (maximum unloaded shortening velocity and isometric active force at 3.6 vol%: 115% ± 12% and 128% ± 21% of baseline values, respectively; P < 0.01) and in cardiomyopathic hamsters (maximum unloaded shortening velocity and isometric active force at 3.6 vol%: 115% ± 20% and 124% ± 31% of baseline values, respectively; P < 0.05). This positive inotropic effect did not differ between healthy and cardiomyopathic hamsters, even when sevoflurane concentrations were corrected for minimum alveolar anesthetic concentration values in each strain, and was unchanged after {alpha}- and ß-adrenoceptor blockade. After calcium-channel blockade, this positive inotropic effect was abolished in healthy hamsters but enhanced in cardiomyopathic hamsters. In both strains, sevoflurane induced a moderate negative lusitropic effect under low and high loads.

IMPLICATIONS: A paradoxical moderate positive inotropic effect of sevoflurane was observed in hamster ventricular muscle. This effect was likely related to calcium channel interaction, because after calcium-channel blockade, it was abolished in healthy hamsters and enhanced in cardiomyopathic hamsters.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Sevoflurane induces a moderate depression of cardiac function, which is reported in vivo as less important than that induced by halothane and similar to that produced by isoflurane (1,2). Several in vitro studies have shown that the negative inotropic effects of sevoflurane were similar to (3–5) or less important than (6–8) those induced by equianesthe-tic concentrations of isoflurane. Electrophysiological studies have demonstrated that the inotropic and lusitropic effects of sevoflurane are at least partly due to decreases in transsarcolemmal calcium influx and myofibrillar calcium sensitivity (8–11). Nevertheless, most previous studies of the cardiovascular effects of sevoflurane were conducted in healthy myocardium (1,2,4,5,8,9,11), and the effects of sevoflurane in diseased myocardium remain debatable (12–15). However, previous studies have reported that the negative inotropic effects of other volatile anesthetics are more pronounced in ischemic myocardium (16), pacing-induced cardiomyopathy (17), and hypertrophic cardiomyopathy (18). Therefore, it is of interest to anesthesiologists to determine the inotropic and lusitropic effects of sevoflurane in diseased myocardium.

The various strains of Syrian hamsters with hereditary cardiomyopathy offer an opportunity to investigate the effects of anesthetics on intrinsic myocardial contractility (18–20). Contractility, cellular biochemistry, molecular biology, and pathophysiology have been studied extensively in this model, the time course of heart failure is well known, and impairment in contractility is primarily due to cardiac muscle cell disease and thus may be more relevant to clinical cardiomyopathies. We therefore conducted an in vitro study to compare the inotropic and lusitropic effects of sevoflurane on left ventricular papillary muscles from healthy hamsters and those with hypertrophic cardiomyopathy.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Twenty-four healthy Syrian hamsters (strain F1B) and 32 cardiomyopathic Syrian hamsters (strain BIO 14.6) were used (Bio Breeders, Fitchburg, MA). In the cardiomyopathic strain, all animals of both genders develop hypertrophic cardiomyopathy from the age of 6 wk. Care of the animals conformed to the recommendations of the Helsinki Declaration, and the study was performed with permission from and in accordance with the regulations of the official edict of the French Ministry of Agriculture. All healthy and cardiomyopathic hamsters were 6 mo old. Body weight (BW) and heart weight (HW) were determined at the moment of killing, and the HW/BW ratio was calculated. The degree of cardiac hypertrophy was determined by dividing the HW/BW value of each cardiomyopathic hamster by the mean HW/BW value in healthy hamsters, as previously reported (18).

Sixty-nine left ventricular papillary muscles from both healthy and cardiomyopathic hamsters (one or two muscles from each animal) were studied. After brief anesthesia with ether, the hearts were quickly removed, and left ventricular papillary muscles were carefully excised and suspended vertically in a 200-mL jacketed reservoir with Krebs-Henseleit bicarbonate buffer solution containing 118 mM NaCl, 4.7 mM KCl, 1.2 mM MgSO4, 1.1 mM KH2PO4, 25 mM NaHCO3, 2.5 mM CaCl2, and 4.5 mM glucose. This solution was prepared daily with highly purified water. The jacketed reservoir was maintained at 29°C with a thermostatic water circulator, with continuous monitoring of the solution temperature. Muscles were field-stimulated at three pulses per minute by two platinum electrodes with rectangular wave pulses of 5 ms duration just above threshold. The bathing solution was bubbled with 95% oxygen/5% carbon dioxide, resulting in a pH of 7.40. After a 90-min stabilization period at the initial muscle length at the apex of the length/active isometric tension curve (Lmax), papillary muscles recovered their optimal mechanical performance, which remained stable for several hours.

We were surprised to observe that sevoflurane induced a positive inotropic effect in both healthy (n = 15) and cardiomyopathic (n = 12) papillary muscles, so we looked for the potential mechanism of this effect. To check the absence of experimental artifact, we performed additional experiments on left ventricular papillary muscles from healthy rats (n = 10) and on right ventricular papillary muscles from healthy rabbits (n = 10). Moreover, because we had previously shown that desflurane induces a positive inotropic effect in rat myocardium that is related to intramyocardial catecholamine release (21), we looked for a similar effect in hamster myocardium with additional experiments. Thus, {alpha}- and ß-adrenoceptors were blocked with phentolamine (1 µM) and propranolol (1 µM) (Sigma-Aldrich Chimie, L’Isle d’Abeau Chesnes, France), which were added to the bathing solution at the end of the stabilization period. Then sevoflurane was studied in separate groups of papillary muscles from healthy (n = 10) and cardiomyopathic (n = 10) hamsters. Moreover, we investigated the effect of calcium-channel blockade on the positive inotropic effect of sevoflurane. Nifedipine (0.1 µM; Sigma-Aldrich Chimie) was added to the bathing solution at the end of the stabilization period. Then sevoflurane was studied in separate groups of papillary muscles from healthy (n = 10) and cardiomyopathic (n = 12) hamsters with nifedipine 0.1 µM.

Sevoflurane was added to the carbon dioxide/oxygen mixture with a calibrated vaporizer (Sevotec 5; Ohmeda, Steeton, UK). The gas mixture continuously bubbled in the bathing solution. To minimize evaporation of volatile anesthetics, the jacketed reservoir was covered with a thin paraffin sheet, as previously reported (22). Anesthetic concentrations in the gas phase were continuously measured with an infrared calibrated analyzer (Artema MM 206SD; Taema, Antony, France). Sevoflurane concentrations used were 0.7, 1.4, 2.2, 2.9, and 3.6 vol%. These concentrations are equivalent to 0.5, 1.0, 1.5, 2.0, and 2.5 minimum alveolar anesthetic concentration (MAC), respectively, in rodents at 29°C (5). A 20-min period equilibration was allowed between each anesthetic concentration and mechanical variable recording.

The electromagnetic lever system has been previously described (20). Briefly, the load applied to the muscle was determined by means of a servo-mechanism-controlled current through the coil of an electromagnet. Muscular shortening induced a displacement of the lever, which modulated the light intensity of a photoelectric transducer. All analyses were made from digital records of force and length obtained with a computer, as previously described (20).

Conventional mechanical variables at Lmax were calculated from three twitches. The first twitch was isotonic and loaded with the preload corresponding to Lmax. We determined maximum shortening velocity (maxVc) and maximum lengthening velocity (maxVr) from this twitch. The second twitch was abruptly clamped to zero-load just after the electrical stimulus, with a critical damping to slow the first and rapid shortening overshoot resulting from the recoil of series passive elastic components. The maximum unloaded shortening velocity (Vmax) was determined from this twitch. The third twitch was fully isometric at Lmax. We determined the maximum isometric active force normalized per cross-sectional area (AF) and the peak of the positive (+dF · dt-l) and negative (-dF · dt-l) force derivatives normalized per cross-sectional area from this isometric twitch.

Because changes in the contraction phase induce coordinated changes in the relaxation phase, variations in contraction and relaxation must be considered simultaneously to quantify drug-induced changes in lusitropy, and indices of contraction-relaxation coupling have therefore been developed (23). Coefficient R1 = maxVc/maxVr evaluated the lusitropy under low-isotonic conditions (22). Under low-isotonic conditions, the amplitude of sarcomeres shortening is greater than that observed under isometric conditions (24). Because of the decreased sensitivity of myofilaments for calcium when cardiac muscle is markedly shortened under low load, relaxation proceeds more rapidly than contraction, apparently because of the rapid uptake of calcium by the sarcoplasmic reticulum (SR). Thus, R1 would indirectly test SR uptake function. Coefficient R2 = (+dF · dt-l)/(-dF · dt-l) evaluated the lusitropy under high load. When the muscle contracts isometrically, sarcomeres shorten very little (24). Because of the increased sensitivity of myofilaments for calcium in such heavy loading conditions compared with low loading conditions (25), the time course of relaxation is determined by calcium unbinding from troponin C, rather than by calcium sequestration by the SR. Thus, R2 would indirectly reflect myofilament calcium sensitivity. However, one should recognize the limitations that have been attributed to the accuracy of R1 and R2 (22). At the end of the study, the muscle cross-sectional area was calculated from the length and weight of papillary muscle, assuming a muscle density of 1.

Data are expressed as mean ± SD. Comparison of two means was performed with Student’s t-tests. Comparison of several means was performed with repeated-measures analysis of variance and Newman-Keuls tests (concentrations of anesthetics expressed as vol%) or multivariate analysis of variance (concentrations of anesthetics expressed as multiples of MAC). All P values were two tailed, and a P value <0.05 was required to reject the null hypothesis. Statistical analysis was performed on a computer by using NCSS 6.0 software (Statistical Solutions Ltd., Cork, Ireland).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
BW was significantly less in cardiomyopathic hamsters than in healthy hamsters (103 ± 14 g versus 130 ± 15 g; P < 0.001). The HW/BW ratio was significantly larger in cardiomyopathic hamsters (3.9 ± 0.4 mg/g versus 3.1 ± 0.4 mg/g; P < 0.001), indicating cardiac hypertrophy (126% ± 15%; P < 0.001). The intrinsic mechanical performance of papillary muscles from hamsters with cardiomyopathy was significantly lower in both isometric (AF, +dF · dt-l) and isotonic (Vmax, maxVc) conditions (Table 1). R1, which tests the lusitropy under low load, was significantly greater in cardiomyopathic hamsters, whereas R2, which tests the lusitropy under high load, was not significantly different between healthy and cardiomyopathic hamsters (Table 1).


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  		Table 1. Mechanical Variable of Papillary Muscles in Healthy and Cardiomyopathic Hamsters
 
In both healthy and cardiomyopathic hamsters, sevoflurane induced a significant positive inotropic effect under isotonic and isometric conditions, as shown by the increase in Vmax and AF (Fig. 1). This positive inotropic effect was not significantly different between the two strains, either in isotonic or in isometric conditions. Because we have previously shown that the MAC of sevoflurane is 13% less in cardiomyopathic hamsters (26), we also plotted Vmax and AF as functions of MAC values determined in each strain (Fig. 2). Accordingly, the inotropic effects of equipotent anesthetic concentrations of sevoflurane were not significantly different between healthy hamsters and those with cardiomyopathy.



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  		Figure 1. Comparison of the inotropic effects of sevoflurane on (A) maximum unloaded shortening velocity (Vmax) and (B) isometric active force (AF) normalized per cross-sectional area, in papillary muscles from healthy (n = 15) and cardiomyopathic (n = 12) hamsters. Sevoflurane concentrations are reported as vol%. Data are mean ± SD. NS = not significant. *P < 0.05 versus baseline values.

 


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  		Figure 2. Comparison of the inotropic effects of sevoflurane on (A) maximum unloaded shortening velocity (Vmax) and (B) isometric active force (AF) normalized per cross-sectional area, in papillary muscles from healthy (n = 15) and cardiomyopathic (n = 12) hamsters. Sevoflurane concentrations are reported as minimum alveolar anesthetic concentration (MAC) multiples in each strain. Data are mean ± SD. NS = not significant. *P < 0.05 versus baseline values.

 
In both left ventricular papillary muscles from healthy rats and right ventricular papillary muscles from healthy rabbits, sevoflurane induced a concen-tration-dependent negative inotropic effect (Fig. 3). For each strain, this negative inotropic effect was significantly different from the positive inotropic effect observed in papillary muscles from both healthy and cardiomyopathic hamsters (P < 0.05).



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  		Figure 3. Comparison of the inotropic effects of sevoflurane on isometric active force (AF) normalized per cross-sectional area among papillary muscles from healthy hamsters (n = 15), rats (n = 10), and rabbits (n = 10). Sevoflurane concentrations are reported in vol%. Data are mean ± SD. P values refer to between-group differences.

 
In papillary muscles from both healthy and cardiomyopathic hamsters, {alpha}- and ß-adrenoceptor blockade had no effect on baseline inotropic variables (Vmax: 98% ± 6% and 102% ± 5% of baseline value, respectively; AF: 103% ± 6% and 102% ± 8% of baseline value, respectively). In both healthy and cardiomyopathic papillary muscles, the positive inotropic effect of sevoflurane was not significantly modified by adrenoceptor blockade (Fig. 4).



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  		Figure 4. Comparison of the inotropic effects of sevoflurane on isometric active force (AF) normalized per cross-sectional area, in papillary muscles from healthy (A) and cardiomyopathic (B) hamsters in control conditions, after {alpha}- and ß-adrenoceptor blockade (propranolol 1 µM and phentolamine 1 µM), and after calcium-channel blockade (nifedipine 0.1 µM). Sevoflurane concentrations are reported in vol%. Data are mean ± SD. P values refer to between-group differences. NS = not significant.

 
In papillary muscles from healthy hamsters, nifedipine 0.1 µM induced a significant negative inotropic effect, both in isotonic and in isometric conditions (Vmax: 89% ± 8% and AF: 90% ± 9% of baseline values; P < 0.05). In contrast, with papillary muscles from cardiomyopathic hamsters, nifedipine 0.1 µM induced no significant negative inotropic effect (Vmax: 95% ± 7% and AF: 94% ± 11% of baseline values). Nevertheless, the percentage changes induced by nifedipine were not significantly different between healthy and cardiomyopathic muscles, probably because of the small sample size in each group. In healthy hamsters, the positive inotropic effect of sevoflurane was completely abolished with nifedipine 0.1 µM (Fig. 4). In cardiomyopathic hamsters, the positive inotropic effect of sevoflurane was significantly enhanced with nifedipine 0.1 µM (Fig. 4).

Sevoflurane induced slight but significant negative lusitropic effects under isotonic and isometric conditions in both healthy and cardiomyopathic hamsters (Fig. 5). In both strains, these effects were unchanged after {alpha}- and ß-adrenoceptor blockade. After calcium-channel blockade, R1 remained unchanged in both healthy and cardiomyopathic hamsters (112% ± 6% and 107% ± 11% of baseline value, respectively, at sevoflurane 3.6 vol%), whereas R2 was significantly decreased in muscles from healthy hamsters (98% ± 9% of baseline value at sevoflurane 3.6 vol%; P < 0.05) and was unchanged in muscles from cardiomyopathic hamsters (110% ± 14% of baseline value at sevoflurane 3.6 vol%; not significant).



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  		Figure 5. Comparison of the lusitropic effects of sevoflurane under (A) low load (R1 = maxVc/maxVr) and (B) high load [R2 = (+dF · dt-l)/(-dF · dt-1)] in papillary muscles from healthy (n = 15) and cardiomyopathic (n = 12) hamsters. Sevoflurane concentrations are reported in vol%. Data are mean ± SD. NS = not significant; +dF · dt-l = peak of the positive force derivative normalized per cross-sectional area; -dF · dt-1 = peak of the negative force derivative normalized per cross-sectional area. *P < 0.05 versus baseline values.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, we showed that 1) in both healthy and cardiomyopathic hamsters, sevoflurane induced a moderate positive inotropic effect, which was probably due to species difference, because it was not observed in rat and rabbit myocardium; 2) the positive inotropic effect of sevoflurane in both hamster strains was unchanged after {alpha}- and ß-adrenoceptor blockade; 3) calcium-channel blockade with nifedipine 0.1 µM abolished the positive inotropic effect of sevoflurane in healthy hamsters but enhanced it in those with cardiomyopathy; and 4) sevoflurane had a moderate negative lusitropic effect in both hamster strains.

The cardiovascular effects of sevoflurane have been studied extensively in humans and animals, in vivo and in vitro (1–15). However, one should emphasize the differing effects among volatile anesthetics and, conversely, the differences in their biochemical, molecular, and electrophysiological actions. Halothane is the most cardiodepressant volatile anesthetic, being a potent opener of the SR calcium-release channel, which leads to a loss of SR stores of calcium into the cytoplasm and, therefore, to a depletion of calcium available for the excitation-contraction process (27). However, effects on postrest potentiation, which is a useful tool for examining complex regulatory cellular processes, such as SR calcium release, are different depending on the volatile anesthetic. Indeed, postrest potentiation is abolished by halothane, unchanged by isoflurane, and enhanced by sevoflurane in rat myocardium (5). Moreover, effects of volatile anesthetics could be different in pathophysiological conditions. Indeed, halothane and isoflurane induce many more negative inotropic effects in diseased myocardium than in healthy myocardium (18). Therefore, it was particularly interesting to investigate the inotropic and lusitropic effects of sevoflurane in papillary muscles from healthy and genetically induced cardiomyopathic hamsters.

In this study, we observed a paradoxical moderate positive inotropic effect of sevoflurane in both healthy and cardiomyopathic muscles (Fig. 1). These results are in disagreement with those from previous in vivo and in vitro studies, which showed a slightly negative inotropic effect of sevoflurane in healthy myocardium, similar (3–5) or less important (6–8) than that of isoflurane. On the contrary, in rat and rabbit myocardium, we observed a concentration-dependent negative inotropic effect of sevoflurane, comparable to that observed by Azuma et al. (10) in guinea-pig papillary muscles. Indeed, the paradoxical positive inotropic effect of sevoflurane in both hamster strains that we reported in this study seems to be very specific, because we previously observed with the exact same experimental model a negative inotropic effect of halothane and isoflurane in healthy and cardiomyopathic hamster papillary muscles (18) and a negative inotropic effect of sevoflurane in rat papillary muscles (5). Nevertheless, some recent experimental findings may help to interpret our results.

It has been observed that halothane and isoflurane, but not sevoflurane, could induce a transient increase in contractions in isolated rat ventricular myocytes and that ryanodine could abolish the transient positive inotropic effect obtained after exposure to halothane (7). Because this effect was similar to that seen on exposure of rat ventricular myocytes to caffeine, these authors suggested that the positive inotropic effect of halothane was related either to a sensitization of the calcium-induced calcium-release mechanism of the SR or to a rapid and substantial leak of calcium from the SR (27). In rat myocardium, Hanouz et al. (5) showed that sevoflurane enhances postrest potentiation, a process that is highly dependent on SR calcium release. However, in skinned muscle fiber preparations of mice, Kunst et al. (28) noted that sevoflurane can induce a release of calcium from the SR. Obviously, experimental conditions were different from those used in our study, but the observation that sevoflurane appears to be able to induce a release of calcium from the SR is important. Elsewhere, Kudoh and Matsuki (29) showed that sevoflurane stimulates inositol 1,4,5-triphosphate formation in rat skeletal muscles, leading to an increase in calcium release from the SR. Conversely, Bartunek and Housmans (8) suggested that the faster isotonic relaxation observed with sevoflurane may reflect a mild stimulation of calcium uptake by the SR. Finally, in voltage-clamped guinea-pig ventricular cardiomyocytes, sevoflurane may transiently activate the L-type calcium current (30), a process that does not seem to involve the SR. Occurrence of one or several of the previously described mechanisms could therefore explain the positive inotropic effect of sevoflurane that we observed in papillary muscles from both healthy and cardiomyopathic hamsters. Hamster myocardium is somewhat different from other mammalian hearts, because it has a remarkable capacity for intracellular calcium homeostasis, even in pathological conditions that usually lead to calcium overload in other mammalian species (31); therefore, "calcium response" to sevoflurane in hamster myocardium might be different from that in other mammalian myocardium.

In both healthy and cardiomyopathic hamster papillary muscles, the positive inotropic effect of sevoflurane was unchanged after {alpha}- and ß-adrenoceptor blockade (Fig. 4). This indicates that this positive inotropic effect was not related to intramyocardial catecholamine release, in contrast to that observed with desflurane in rat myocardium (21).

In papillary muscles from healthy hamsters, nifedipine 0.1 µM induced a significant negative inotropic effect. This is in agreement with the negative inotropic effect of calcium antagonists, mainly because of a decrease in transsarcolemmal calcium influx (32). On the contrary, in papillary muscles from cardiomyopathic hamsters, nifedipine induced no significant negative inotropic effect. Although the small sample size in each group did not allow demonstration of a difference in the absolute percentage changes between healthy and cardiomyopathic muscles, the absence of a negative inotropic effect of nifedipine in cardiomyopathic hamsters could probably be related to the reduced density of L-type calcium channels (33) or the increased density of dihydropyridine-insensitive T-type calcium channels (34,35) reported in this strain. However, because hamster cardiomyopathy is characterized by intracellular calcium overload, the negative inotropic effect caused by a decrease in transsarcolemmal calcium influx could be counterbalanced by the benefit of reducing intracellular calcium overload. Indeed, Finkel et al. (36) have shown that verapamil, another calcium antagonist, can induce a paradoxical positive inotropic effect in papillary muscles from cardiomyopathic hamsters.

In healthy papillary muscles, the positive inotropic effect of sevoflurane was completely abolished by nifedipine (Fig. 4). Because calcium antagonists mainly block transsarcolemmal calcium influx through an inhibition of voltage-gated L-type calcium channels, we suggest that the positive inotropic effect of sevoflurane is related to an activation of these channels, therefore increasing cytoplasm calcium available through the calcium-induced calcium-release process. Conversely, in papillary muscles from cardiomyopathic hamsters, the positive inotropic effect of sevoflurane was significantly enhanced by nifedipine (Fig. 4). Indeed, reduction of intracellular calcium overload by nifedipine may have improved intracellular calcium homeostasis and, consequently, contractility; thereafter, the positive inotropic effect of sevoflurane related to the calcium-induced calcium release might be enhanced in cardiomyopathic myocardium. Cardiomyopathic hamsters also present paradoxical responses to various other nonanesthetic drugs, such as verapamil (36) and isoprenaline (37), that interact with calcium homeostasis.

Coefficient R1 tests the lusitropic state under low load and reflects the rapid uptake of calcium by the SR (24). In both healthy and cardiomyopathic hamsters, sevoflurane induced a slight but significant negative lusitropic effect under low load, as shown by an increase in R1 (Fig. 5). This result may appear inconsistent with the generally admitted weak interference of sevoflurane with the SR in rodent myocardium (38). However, because Kunst et al. (28) proved that sevoflurane could induce a release of calcium from the SR, a substantial release of calcium from the SR in hamster myocardium could explain both the positive inotropic and the negative lusitropic effects of sevoflurane that we observed in our study. Nevertheless, the negative lusitropic effect of sevoflurane remained very moderate in both healthy and cardiomyopathic hamsters (Fig. 5).

R2 tests the lusitropic state under high load and thus reflects myofilament calcium sensitivity (5,24). Our study showed that sevoflurane significantly increased R2 in healthy and in cardiomyopathic hamsters, which indicates a negative lusitropic effect under high load (Fig. 5). These results were in opposition to those of Bartunek and Housmans (8,11), who suggested that sevoflurane decreases myofibrillar calcium sensitivity in ferret ventricular myocardium. However, we have previously demonstrated that a change in AF per se may induce a moderate change in the same direction in R2 (22). Therefore, the increase in coefficient R2 could be explained by the increase in AF in both strains. Indeed, {alpha}- and ß-adrenoceptor blockade had no effect on the positive inotropic effect of sevoflurane or on its negative lusitropic effect under high load. In papillary muscles from healthy hamsters, after nifedipine, sevoflurane induced no significant inotropic effect and did not modify R2. On the contrary, in papillary muscles from cardiomyopathic hamsters, nifedipine enhanced both the positive inotropic and the negative lusitropic effects of sevoflurane under high load. This phenomenon is in agreement with the cooperativity concept, whereby the myofilament calcium sensitivity is modified by calcium itself. Our results suggest that the lusitropic effect of sevoflurane under high load is indirect and is probably not related to significant changes in myofilament calcium sensitivity.

The following points must be considered in the assessment of the clinical relevance of our results. First, because this study was conducted in vitro, it assessed only intrinsic myocardial contractility. Observed changes in cardiac function after anesthetic drug administration also depend on modifications in heart rate, venous return, afterload, and sympathetic nervous system activity. This point should be of special importance in patients with cardiomyopathy, whose cardiac function does not depend only on intrinsic contractility, but also on preload, afterload, and sympathetic activity. Second, this study was conducted at 29°C at a low-stimulation frequency. Papillary muscles must be studied at this temperature because the stability of mechanical variables is not sufficient at 37°C and at a low frequency because high-stimulation frequency induces core hypoxia (39). Third, hamster myocardium differs somewhat in its cardiac behavior from other species, including humans, especially regarding intracellular calcium homeostasis (31). Our results suggests that this strain may not be appropriate for all drugs, especially sevoflurane, and that species differences occur in the myocardial effects of volatile anesthetics—a concept widely observed with IV anesthetics, such as ketamine (40) and propofol (41,42), but not previously described with volatile anesthetics. Fourth, the results obtained in this experimental model of genetically induced cardiomyopathy cannot be generalized to all types of cardiac failure. Although cardiomyopathic hamsters have been considered as a suitable model of human cardiomyopathy with progressive heart failure over a prolonged period, as it is observed either in dilated or hypertrophic cardiomyopathies, our study suggests that the BIO 14.6 cardiomyopathic strain may not be appropriate for studying all drugs, especially sevoflurane. Consequently, sevoflurane may act differently, depending on the calcium homeostasis impairment. Because many myocardial diseases are associated with some degree of calcium homeostasis abnormalities, it would be useful to perform clinical investigations for characterization of the myocardial effects of sevoflurane in patients with cardiac diseases.

In conclusion, in both healthy and cardiomyopathic hamsters, sevoflurane induced a moderate positive inotropic effect; in contrast to desflurane, this effect was not related to an induced intramyocardial catecholamine release. This paradoxical positive inotropic effect of sevoflurane occurred only in the hamster species and was probably related to calcium channel interactions, because calcium-channel blockade abolished the response in healthy hamsters but enhanced it in cardiomyopathic hamsters.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication February 28, 2002.




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T. Barbry, M. Le Guen, V. De Castro, P. Coriat, B. Riou, and B. Vivien
Minimum alveolar concentration of halogenated volatile anaesthetics in left ventricular hypertrophy and congestive heart failure in rats
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