Anesth Analg 1999;89:466
© 1999 International Anesthesia Research Society
GENERAL ARTICLES
The Effects of Dantrolene on the Contraction, Relaxation, and Energetics of the Diaphragm Muscle
Olivier Langeron, MD*,
Catherine Coirault, MD, PhD ,
Sylvia Fratea, MD*,
Gilles Orliaguet, MD ,
Pierre Coriat, MD*, and
Bruno Riou, MD, PhD*
*Laboratory of Anesthesiology, Department of Anesthesiology and Critical Care, Groupe Hospitalier Pitié-Salpêtrière, Paris VI University, Paris;
Institut National de la Santé et de la Recherche Médicale U451, LOA-ENSTA-Ecole Polytechnique, Palaiseau; and
Department of Anesthesiology and Critical Care, Hôpital Necker-Enfants Malades, Paris, France
Address correspondence and reprint requests to Oliver Langeron, MD, Département d’Anesthésie-Réanimation, CHU Pitié-Salpêtrière, 47 Blvd. de l’Hôpital, 75651 Paris Cedex 13, France. Address e-mail to olivier.langeron{at}psl.ap-hop-paris.fr
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Abstract
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Dantrolene is used in patients with muscle spasticity and is the only known effective treatment for malignant hyperthermia. However, its effects on muscle relaxation and energetics are unknown and may have important consequences in diaphragmatic function. We studied the effects of dantrolene (10-8 to 10-4 M) on diaphragm muscle strips (n = 12) in the hamster in vitro (Krebs-Henseleit solution, 29°C, 95% oxygen/5% carbon dioxide) in response to tetanic stimulation (50 Hz). We studied contraction and relaxation under isotonic and isometric conditions, as well as energetics. Data are mean ± SD. Dantrolene induced a negative inotropic effect in the hamster diaphragm (active force at 10-4 M: 34% ± 7% of baseline; P < 0.05) but did not significantly modify the curvature of the force-velocity relationship. Dantrolene did not significantly modify isotonic relaxation. Dantrolene, up to 10-5 M, did not significantly impair isometric relaxation. In conclusion, dantrolene induced a marked negative inotropic effect on diaphragm muscle without affecting myothermal efficiency and relaxation.
Implications: Dantrolene induced a significant and concentration-dependent negative inotropic effect on diaphragm muscle but did not modify isotonic relaxation, which suggests no alteration of the calcium reuptake by the sarcoplasmic reticulum; up to 10-5 M dantrolene did not alter isometric relaxation, i.e., myofilament calcium sensitivity. Dantrolene did not modify the energetics of diaphragm muscle.
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Introduction
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Dantrolene, a postsynaptic skeletal muscle relaxant, inhibits calcium release from the sarcoplasmic reticulum (SR) and reduces the myoplasmic free calcium concentration in a dose-dependent manner (1,2). Dantrolene is advocated for the treatment of patients with muscle spasticity from various neuromuscular diseases (3) and is the only known effective treatment for malignant hyperthermia (3,4). Dantrolene acts by either direct or indirect interaction with the skeletal muscle calcium release channel of the SR (i.e., ryanodine receptor) (5). Palnitkar et al. (6) have provided convincing evidence of molecular distinction between the ryanodine and dantrolene receptors.
Dantrolene induces a major negative inotropic effect on normal skeletal and diaphragm muscles. However, the effects of dantrolene on relaxation (lusitropy) and energetics are unknown, whereas alteration in diaphragmatic relaxation may participate in respiratory failure (7). Muscle weakness and impairment of muscle relaxation, promoting diaphragmatic fatigue and respiratory failure, may have important clinical consequences in diaphragm function and/or weaning from mechanical ventilation after dantrolene administration (8). We therefore conducted an in vitro study on the effects of dantrolene on hamster diaphragm muscle. The experimental model we used enabled us to determine the effects of dantrolene not only on contraction, but also on the relaxation and energetics of diaphragm muscle.
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Methods
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Care of the animals conformed to the recommendations of the Helsinski Declaration, and the study was performed in accordance with the regulations of the official edict of the French Ministry of Agriculture. Experiments were conducted in 6-mo-old Syrian hamsters.
After a brief anesthesia with ether, a muscle strip from the ventral costal diaphragm was carefully dissected from the muscle in situ (9–12). This diaphragm strip was immediately vertically suspended in a 200-mL jacketed reservoir with Krebs-Henseleit bicarbonate buffer solution containing (in mM): NaCl 118, KCl 4.7, MgSO4 1.2, KH2PO4 1.1, NaHCO3 25, CaC12 2.5, and glucose 4.5 and prepared daily with highly purified water. The jacketed reservoir was maintained at 29°C with a thermostatic water circulator and continuous monitoring of the solution temperature with a temperature probe. The bathing solution was bubbled with 95% oxygen/5% carbon dioxide, resulting in a pH of 7.40.
Preparations were field-stimulated (30 V) by using two platinum electrodes with rectangular-wave pulses of 1 ms duration at 10 pulses/min in the twitch mode. After a 30-min stabilization period in twitch mode, at the initial muscle length at the apex of the length-active isometric force curve (Lmax), diaphragm muscle strips recovered their optimal mechanical performance (9–11). Experiments were conducted in the tetanus mode with stimuli delivered at 50 Hz for a duration of 300 ms, performed with 1-ms rectangular pulses, and this sequence was repeated every 6 s (10 trains/min). At the end of the study, the cross-sectional area was calculated from the ratio of muscle weight to muscle length, assuming a muscle density of 1.
Because dantrolene is poorly soluble in aqueous media, we used dimethylsulfoxide (DMSO) as a solvent. Therapeutic concentrations of dantrolene range from 0.3 to 10 µg/mL (1–30 x 10-6 M) (3,13). Therefore, five concentrations of dantrolene (10-8, 10-7, 10-6, 10-5, and 10-4 M ) were tested in a cumulative manner, with a 15-min period between each concentration. In a preliminary study, we observed that the effects of the highest concentration of dantrolene remained stable between 15 and 60 min and that DMSO alone had no significant effect on cardiac muscle, as previously reported (14). Moreover, we verified the stability of the preparation over the time duration of our experiment (i.e., 90 min) in a separate group of diaphragmatic strips (n = 8). Active isometric force remained stable (96% ± 10% of baseline) up to 60 min, and a slight but significant decrease in active isometric force (87% ± 8% of baseline; P < 0.05) was observed after 90 min. Twelve diaphragm muscle strips were studied with dantrolene. All drugs were purchased from Sigma-Aldrich Chimie (L’Isle d’Abeau Chesnes, France).
The electromagnetic lever system has been previously described (9–11,15). Briefly, the load applied to the muscle was determined by using a servomechanism-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. The initial preload (resting force [RF]), which determined Lmax, the length at which active force development is maximal, was automatically maintained constant throughout the experiment. All analyses were made from digital records of force and length obtained by using a computer (9–12,14,15).
Variables characterizing contraction were the shortening velocity (Vc), extent of shortening ( L), peak of the positive force derivative normalized per cross-sectional area (dF/dt), and active force normalized per cross-sectional area (AF). Variables characterizing relaxation were the lengthening velocity (Vr) and peak of the negative force derivative normalized per cross-sectional area (-dF/dt) (Fig. 1).
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Figure 1. Mechanical variables of contraction and relaxation. Top, Muscle shortening length plotted versus time. Bottom, Force plotted versus time. Tetanus 1 was isotonic, and tetanus 2 was fully isometric. Shortening (Vc) and lengthening (Vr) velocities, extent of shortening (L), peaks of positive (dF/dt) and negative force derivative (-dF/dt), and active force (AF) were determined from these typical isotonic and isometric tetanus.
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Mechanical variables were calculated from 10 consecutive tetanic contractions preloaded at Lmax with increasing afterload from zero load to fully isometric contraction (Fig. 2). The first contraction was abruptly clamped to zero load just after the electrical stimulus, with critical damping to slow the first and rapid shortening overshoot resulting from the recoil of a series of passive elastic components (10), enabling us to determine the maximal unloaded shortening velocity (Vcmax). The second (or third) contraction was isotonic and loaded with preload only. The maximal extent of shortening (Lmax) and the maximal lengthening velocity (Vrmax) were determined from this contraction. The last contraction was fully isometric at Lmax. The maximal active force (AFmax) and the peak of the positive (dF/dtmax) and negative (-dF/dtmax) force derivatives were determined from this fully isometric contraction.
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Figure 2. Typical diaphragmatic muscle recording obtained in the hamster. Top, Muscle shortening length plotted versus time. Bottom, Force plotted versus time. Mechanical variables were calculated from 10 consecutive tetanic contractions preloaded at Lmax with increasing afterload from zero load (first contraction) to preload (second or third contraction), then to a fully isometric contraction (fourth to tenth contraction).
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Vcmax and AFmax tested the contraction phase (inotropy). Vrmax and -dF/dtmax tested the relaxation phase. Nevertheless, because changes in the contraction phase induce coordinated changes in the relaxation phase, relaxation variables alone cannot adequately assess lusitropy; therefore, variations in contraction and relaxation must be considered simultaneously to quantify drug-induced changes in lusitropy (10,11). Thus, we calculated the ratios Vrmax/Lmax and -dF/dtmax/AFmax, which assessed lusitropy in isotonic and isometric conditions, respectively. Moreover, relaxation is highly dependent on the load level and thus must also be studied over the entire load continuum (from preload to fully isometric contraction) (10,11). To characterize the isotonic relaxation process, the relationship between Vr and L was determined over the load continuum, as previously reported (10). Indeed, L is the main determinant of Vr; the relationship between L and Vr is grossly linear up to 80%–90% of L max; Vr then increases to a lesser degree as L increases up to L max. To characterize the isometric relaxation process, the relationship between -dF/dt and AF was determined over the load continuum (from 10% to 100% of AFmax) (11). Indeed, AF is the main determinant of -dF/dt; in muscle isometrically relaxing at initial muscle length, the relationship between -dF/dt and AF is grossly linear up to 80% of AFmax; -dF/dt then decreases as AF increases from 80% to 100% of AFmax (11).
Muscle energetics was determined from Huxley’s equations as previously described (12,15). The force-velocity curve was derived from the Vc of various afterloaded contractions, from zero load to fully isometric contraction, plotted against the total force (TF; = RF + AF) normalized per cross-sectional area (12,15). Experimental total force velocity (TF - Vc) curve data were fitted according to Hill’s equation: (TF + a) (Vc + b) = (TFmax + a) b where -a and -b are the asymptotes of the hyperbola and TFmax is the calculated maximal isometric total force for Vc = 0. The following energetic variables were derived from Hill’s hyperbola equation (12,15,16): the curvature of the hyperbola (G) and the non-normalized maximal power output (Emax). G = Vcmax x b-1 = TFmax x a-1. G is linked to myothermal efficiency and cross-bridge kinetics; the more curved Hill’s hyperbola (i.e., the higher value of G), the higher the muscle efficiency (16). M is the positive root of the quadratic equation: GM2 + 2M - 1 = 0, where M2 is the normalized maximal power output (16). Emax is equal to M2 x Vcmax x TFmax (16).
Data are expressed as means ± SD. Comparisons of control values between groups were performed using Student’s t-tests. Several means were compared by using repeated-measure analysis of variance and the Newman-Keuls test. The energetic variables were derived from Hill’s equation using multilinear regression and the least-squares method. All P values were two-tailed, and P < 0.05 was considered significant. Statistical analysis was performed using NCSS 6.0 software (Statistical Solutions Ltd., Cork, Ireland).
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Results
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Mean cross-sectional area was 1.19 ± 0.24 mm2, and mean Lmax 9.6 ± 1.7 mm. Dantrolene induced a significant and concentration-dependent negative inotropic effect in diaphragmatic muscle under low (Vcmax) and high (AFmax) loads (Table 1). Dantrolene did not induce any contracture, regardless of the concentration.
Dantrolene induced no significant changes in the ratio Vrmax/Lmax (Table 1). Because L is the main mechanical determinant of Vr, we also studied the Vr/L relationship over the continuum of load. Dantrolene did not significantly modify the initial linear part of the Vr/L relationship (Fig. 3). Dantrolene induced no significant changes in the ratio -dF/dtmax/AFmax, except at the highest concentration (10-4 M) (Table 1). Because AF is the main mechanical determinant of -dF/dt, we also studied the -dF/dt/AF relationship over the continuum of load. Under baseline conditions, an increase in load accelerated -dF/dt in a linear manner of up to approximately 80% of AFmax. However, under heavy loading conditions, -dF/dt decreased as AF increased. Dantrolene did not significantly modify the initial linear part of the -dF/dt/AF relationship (Fig. 4).
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Figure 4. Effects of dantrolene on the relationship between the peak negative derivative force (-dF/dt) and active force (AF) in diaphragmatic muscles (n = 12). AF is the main determinant of -dF/dt, and the initial part of -dF/dt/AF relationship is grossly linear up to 80%–90% of AFmax; -dF/dt then decreases as AF increases up to AFmax. Despite its marked negative inotropic effect, dantrolene did not significantly modify the initial linear part of the -dF/dt/AF relationship. Data are means, and AF is expressed as a fraction of AFmax under control conditions.
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The force-velocity curves were correctly depicted by Hill’s hyperbola, as shown by the high values of the correlation coefficient (0.97 ± 0.02). Under baseline conditions, Emax was 71 ± 27 Lmax · mN · mm-2 · s-1. Dantrolene 10-5 M induced a marked decrease in Emax (25 ± 32% of baseline; P < 0.05) (Fig. 5, left). Despite this marked negative inotropic effect, dantrolene 10-5 M did not significantly modify the G of the force-velocity curve (3.86 ± 1.07 vs 3.27 ± 0.57). The absence of a dantrolene effect on G is depicted by the absence of any significant modification in the normalized force-velocity curves (Fig. 5, right).
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Figure 5. Effects of dantrolene (10-5 M) on the total force (TF)-velocity (Vc) curve in diaphragmatic muscles (n = 12). Left, Non-normalized TF-Vc curves showing the significant decrease in non-normalized maximum power output induced by dantrolene. Right, Normalized TF-Vc curves showing the absence of a significant effect of dantrolene on the curvature of the hyperbola. NS = not significant.
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Discussion
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Dantrolene induced a significant and concentration-dependent negative inotropic effect in the hamster (Table 1), as previously described in other species in various skeletal muscles, including the diaphragm (3,17). The maximal decrease in AF was similar to the maximal decrease in adductor pollicis muscle force after dantrolene administration in humans in vivo (13). These results suggest that our experimental model was relevant. The negative inotropic effect of dantrolene on skeletal muscle is thought to be related to its effect on calcium release from the SR by either direct or indirect interaction with the ryanodine receptor (5), or with the low-affinity site that reduces the channel open-state probability (18). Proteins associated with the ryanodine receptor participate in the function and modulation of calcium release (19). A study has suggested that the binding sites for dantrolene and ryanodine are pharmacologically distinct and may reside on separate molecules (6).
In striated muscle, sarcomere length modulates myofilament calcium sensitivity and, thus, relaxation. Under isotonic conditions, which correspond to an important sarcomere shortening, the sensitivity of troponin C to calcium is low, and relaxation proceeds more rapidly than contraction, apparently due to rapid calcium uptake by the SR (10). Under isometric conditions, which correspond to greater sarcomere length, the affinity of troponin C to calcium is higher, and relaxation is primarily determined by dissociation of calcium from troponin C, rather than calcium uptake into the SR (11). It has been suggested that impaired isotonic relaxation is related to an impairment in calcium uptake by the SR (9). Dantrolene did not modify isotonic relaxation (Table 1, Fig. 3), which suggests that it did not modify the calcium reuptake by the SR. This result agrees with those previously reported in cardiac muscle, in which dantrolene does not modify calcium uptake by the SR (14).
Dantrolene did not significantly modify isometric relaxation, except at the highest concentration (Table 1, Fig. 4). This result agrees with previous results in skeletal muscles (20). Isometric relaxation is a complex process that involves different regulatory mechanisms over the load continuum. Up to 80% of AFmax, isometric relaxation rate seems to be mainly determined by passive mechanisms (11). Under fully isometric conditions, the calcium myofilament sensitivity remains high and seems to play a major role by counterbalancing the accelerating effects of increased force on the cross-bridges (21). Therefore, our results suggest that dantrolene up to 10-5 M did not alter myofilament calcium sensitivity and passive mechanisms, which determine isometric relaxation. At 10-4 M, dantrolene induced a significant decrease in the ratio -dF/dtmax/AFmax,, which indicates a negative lusitropic effect with an impairment of isometric relaxation and suggests an increase in myofilament calcium sensitivity.
Dantrolene significantly decreased the maximal power output, whereas it did not significantly modify the curvature (G) of the force-velocity curve (Fig. 5). G is linked to myothermal economy and cross-bridge kinetics (15,16); the more curved the hyperbola (i.e., the higher the value of G), the higher the muscle efficiency. In our study, the G value observed in the hamsters was lower than that previously observed (12). This discrepancy could be explained by strain differences, difference in temperature (22°C vs 29°C), and/or degree of damping. In any case, our results show that dantrolene did not significantly modify the energetics of diaphragm muscle, as previously observed in cardiac muscle (14).
These effects of dantrolene on diaphragm may have consequences. The side effects of dantrolene, including muscle weakness, are frequent (3,22). Objective signs of muscle weakness contributed to prolonged postoperative tracheal intubation in a patient after dantrolene administration (8). Dantrolene may also affect the breathing pattern in decreasing tidal volume (23,24), whereas minute ventilation is maintained by increasing respiratory rate (23,25). In patients suffering from respiratory muscle weakness, delayed relaxation may lead to incomplete relaxation, especially at high respiratory rates, such as in sepsis and congestive heart failure. Increased resting tension and/or decreased muscle length at the onset of diaphragm inspiratory contraction may further reduce ventilatory muscle force by shifting the diaphragm along its length-tension curve with a decreased transdiaphragmatic pressure and an increasing lung volume, progressively placing the diaphragm at mechanical disadvantages (7,26). Because diaphragmatic blood flow is impeded at a high transmural pressure, delayed and/or incomplete relaxation may facilitate diaphragmatic ischemia and, thus, acute respiratory failure. Consequently, impairment of diaphragm relaxation may increase the cost of breathing and promote diaphragmatic fatigue and respiratory failure. In our study, we demonstrated that dantrolene did not significantly alter diaphragmatic relaxation.
The following points must be considered in the assessment of the relevance of our results. First, this study was conducted at 29°C, because stability is not sufficient at 37°C. Very low temperatures (18–20°C) can markedly modify the negative inotropic effect of dantrolene (3,20). However, the inotropic effect of dantrolene we observed was comparable to that observed in vivo in humans at 37°C (13). Second, our study did not enable us to detect the small increase in resting tension that has been reported to occur with low concentrations of dantrolene (18). Nevertheless, this phenomenon is thought to involve high-affinity binding sites and thus to occur at very low concentrations (10-9 M) of dantrolene, and it is associated with a positive inotropic effect (18), which we did not observe, even at the lowest concentration (10-8 M).
In conclusion, in this study conducted on isolated diaphragm muscle, dantrolene induced a marked negative inotropic effect without affecting myothermal efficiency and relaxation. These results may have important consequences regarding the effects of dantrolene on diaphragmatic function, with an impaired contractility that may be responsible for respiratory failure and/or unsuccessful weaning from mechanical ventilation.
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Acknowledgments
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This work was supported by a research grant from Société Française d’Anesthésie et de Réanimation.
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References
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Accepted for publication April 16, 1999.
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Abstract
Introduction
