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The Inotropic and Lusitropic Effects of Ketamine in Isolated Human Atrial Myocardium: The Effect of Adrenoceptor Blockade

Hanouz, Jean-Luc MD, PHD; Persehaye, Emmanuel MD; Zhu, Lan MD; Lammens, Stéphane MD; Lepage, Olivier MD; Massetti, Massimo MD; Babatasi, Gérard MD, PHD; Khayat, André MD; Bricard, Henri MD; Gérard, Jean-Louis MD, PHD

doi: 10.1213/01.ANE.0000136466.85913.3C
Anesthetic Pharmacology: Research Report
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We studied the direct myocardial effects of racemic ketamine, in the presence of α- and β-adrenoceptor blockade, on isolated human right atrial myocardium. Isometric force of contraction (FoC), its first derivative with time (+dF/dt), the contraction relaxation coupling parameter R2 = (+dF/dt) / (−dF/dt), and time to half relaxation (T1/2) were recorded before and after addition of 10−6, 10−5 and 10−4 M racemic ketamine alone and in the presence of α-adrenoceptor blockade (phentolamine 10−6 M) and β-adrenoceptor blockade (propranolol at 10−6 M). Ketamine had a moderate positive inotropic effect at 10−5 M (FoC, 104% ± 5% of baseline value; P = 0.03) and 10−4 M (FoC, 107% ± 11% of baseline value; P = 0.09). Racemic ketamine had a negative inotropic effect in the presence of propranolol (FoC, ketamine 10−6 M, 77% ± 11%; ketamine 10−5 M, 63% ± 16%; ketamine 10−4 M, 62% ± 17% of baseline; P < 0.001) but not phentolamine (FoC, ketamine at 10−6 M, 94% ± 6%; ketamine 10−5 M, 96% ± 5%; and ketamine 10−4 M, 98% ± 15% of baseline). Ketamine decreased T1/2 (ketamine 10−5 M, 94% ± 3% of baseline value; P < 0.001 and ketamine 10−4 M, 90% ± 9% of baseline value; P = 0.007) but did not modify R2. In human right atrial myocardium, racemic ketamine induced a moderate positive inotropic effect and hastened isometric relaxation. In the presence of β-adrenoceptor blockade it induced a direct negative inotropic effect.

IMPLICATIONS: In isolated human myocardium, racemic ketamine induced a moderate positive inotropic effect but a profound direct negative inotropic effect in the presence of β-adrenoceptor blockade. Furthermore, ketamine hastened relaxation through stimulation of β-adrenoceptor. This should be interpreted with the known various physiopathologic states and treatments interfering with α- and β-adrenoceptors.

Laboratoire d’Anesthésiologie Expérimentale et de Physiologie Cellulaire, UPRES EA 3212, Département d’Anesthésie-Réanimation, Centre Hospitalier Universitaire (CHU) Côte de Nacre, Caen; France

Supported, in part, by the University of Caen and a grant from the Fondation pour la Recherche Medicale (to Dr. Persehaye).

Accrepted for publication June 2, 2004.

Address correspondence and reprint requests to Jean-Luc Hanouz, MD, PhD, Département d’Anesthésie-Réanimation, CHU de Caen, Avenue Côte de Nacre, 14033 Caen Cedex, France. Address e-mail to hanouz-jl@chu-caen.fr.

Ketamine is used for induction of anesthesia in high-risk patients because it maintains hemodynamic parameters (1). The good cardiovascular profile of ketamine has been related to several mechanisms, including increased sympathomimetic activity by central stimulation of the autonomic nervous system (2) and the inhibition of intra- and extra-neuronal catecholamine uptake (3). However, in critically ill patients (4) and in dogs with a pharmacologically blocked autonomic nervous system (5), ketamine has been shown to have a cardiovascular depressant effect related to the inability of its sympathomimetic action to counterbalance its direct vasodilatory and myocardial depressant effect. Thus, the interaction between ketamine and adrenoceptors is of particular interest to help understand its cardiovascular effects. Furthermore, because various physiopathologic states and treatments may interfere with α- and β-adrenoceptors, it is of particular interest to study the direct myocardial effect of ketamine in the presence of α- or β-adrenoceptor blockade.

The direct myocardial effect of ketamine has been widely studied in vitro, resulting either in a positive (6,7) or a negative inotropic effect (8,9). The differences between experimental conditions and species may explain at least in part these discrepancies. Actually, species differences remain a major issue in experimental studies concerning the myocardial effects of anesthetics, especially if autonomic nervous system and α- and β-adrenoceptors are involved. In isolated human myocardium, ketamine, at clinically relevant concentrations, has been reported to induce no inotropic effect (9,10) or a positive inotropic effect (11). In human myocardium, the direct myocardial effect of ketamine in the presence of α- or β-adrenoceptor blockade remains unknown. The goal of our experimental study was to determine the direct inotropic effect of ketamine on isolated human atrial myocardium in the presence of α- and β-adrenoceptors blockade.

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Methods

After approval of the local medical ethics committee and informed consent, 66 human right atrial trabeculae were obtained from 66 patients scheduled for routine coronary artery bypass surgery or aortic valve replacement. Patient characteristics, preoperative drug treatment, and preoperative left ventricular ejection fraction are shown in Table 1. All patients received anesthesia with midazolam, sufentanil, etomidate, pancuronium, and isoflurane. Patients with chronic atrial dysrhythmia were excluded from the study. The right atrial appendage was obtained during cannulation for cardiopulmonary bypass.

Table 1

Table 1

Long, thin, and rectilinear trabeculae were dissected and suspended vertically between an isometric force transducer (MLT202; AD Instruments, Sydney, Australia) and a stationary stainless clip in a 200 mL jacketed reservoir filled with daily prepared Tyrode’s modified solution containing (mM) 120 NaCl, 3.5 KCl, 1.1 MgCl2, 1.8 NaH2PO4, 25.7 NaHCO3, 2.0 CaCl2, and 5.5 glucose. The bath was maintained at 34°C using a thermostatic water circulator (Polystat micropros; Bioblock, Illkirch, France). The bathing solution was bubbled with carbogen (95% O2-5% CO2), resulting in a pH of 7.40 and a partial pressure of oxygen of 600 mm Hg. Isolated muscles were field-stimulated at 1 Hz by 2 platinum electrodes with rectangular wave pulses of 5 ms duration 20% above threshold (CMS 95107, Bionic Instrument, Paris, France).

Trabeculae were equilibrated for 60 to 90 min to allow stabilization of their optimal mechanical performance at the apex of the length-active isometric tension curve (Lmax) and randomly assigned to one experimental group. At the end of each experiment, the length and the weight of the muscle were measured. To avoid core hypoxia, trabeculae included in the study had to have a cross-sectional area <1.0 mm2, an active Force of Contraction normalized per cross-sectional area (FoC) > 5.0 mN/mm2 and a ratio of resting force/total force (RF/TF) <0.45.

The force developed by the muscle and its positive derivative were measured continuously, digitized online at a sampling frequency of 200 Hz (PowerLab 4/sp; AD Instruments), and stored on the hard disk of a microcomputer for analysis with a specific software (Chart v5.0.1; AD Instruments).

Total force (TF) and resting force (RF) were measured. The inotropic state in isometric conditions was tested by FoC, and the peak of the positive force derivative was normalized per cross-sectional area (+dF/dt).

The relaxation phase of the isometric twitch was tested by the time-to-half relaxation (t1/2), a good index of isometric relaxation in mammalian myocardium (12). This parameter is insensitive to increase in contractility induced by increasing extracellular calcium concentration. Because changes in the contraction phase induce coordinated changes in the relaxation phase, the peak of the negative force derivative normalized per cross-sectional area (−dF/dt) could not assess isometric relaxation independently of the contraction phase. Therefore, indices of contraction-relaxation coupling have been used to take simultaneous variations in contraction and relaxation into account and to quantify drug-induced changes in myocardial lusitropy (12,13).

The coefficient R2 = (+dF/dt)/(−dF/dt) tests the coupling between contraction and relaxation under high load and, thus, the lusitropic state under high load in a manner that is less dependent on inotropic changes. The parameter R2 (contraction-relaxation coupling under high load) indirectly reflects myofilament calcium sensitivity (14) and has been validated as an index of myocardial lusitropy (15).

After a 60-min equilibration period, racemic ketamine at concentrations of 10−6 M (n = 6), 10−5 M (n = 10), and 10−4 M (n = 10) was added in the bathing solution and mechanical parameters were measured after 10 min. These concentrations were chosen because they encompass the free plasmatic concentrations of ketamine measured in clinical anesthesia after induction of anesthesia with ketamine at 2 mg/kg (16). We did not test ketamine in a cumulative manner because we thought that it could have an indirect myocardial effect through intramyocardial catecholamine release. Thus we chose to examine the net effect of each concentration of ketamine independently of the effect of a previous one.

In additional experiments, α- and β-adrenoceptors were blocked by 10−6 M phentolamine and 10−6 M propranolol, respectively. After 15 min equilibration, ketamine 10−6 (n = 6), 10−5 (n = 6), and 10−4 M (n = 6) was added in the propranolol and phentolamine treated trabeculae.

Propranolol and phentolamine were purchased from ICN Pharmaceuticals (Orsay, France), and racemic ketamine was purchased from SigmaAldrich (Sigma Aldrich Chimie, St Quentin Fallavier, France).

Data are expressed as mean ± sd. Baseline values between groups were compared by analysis of variance. Comparison of several means was performed using a repeated-measures analysis of variance and Newman-Keuls post hoc analysis. All P values were two-tailed, and a P value of <0.05 was required to reject the null hypothesis. Statistical analysis was performed using StatView 5 software (Deltasoft, Meylan, France).

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Results

Sixty-six human right atrial trabeculae were studied. The main baseline parameters of trabeculae in each group are reported in Table 2.

Table 2

Table 2

Racemic ketamine at 10−6 M (97% ± 5% of baseline value; P = 0.07) and 10−4 M (107% ± 11% of baseline value; P = 0.09) did not modify FoC (Fig. 1). In contrast, racemic ketamine at 10−5 M (104% ± 5% of baseline value; P = 0.03) significantly increased FoC (Fig. 1). As shown in Figure 1, +dF/dt was significantly increased by ketamine at 10−5 M (105% ± 5% of baseline value; P = 0.007) and 10−4 M (114% ± 15% of baseline value; P = 0.01) but not at 10−6 M (99% ± 8% of baseline value; P = 0.25)

Figure 1

Figure 1

As shown in Figure 1, T1/2 was significantly decreased by racemic ketamine at 10−5 M (94% ± 3% of baseline value; P < 0.001) and 10−4 M (90% ± 9% of baseline value; P = 0.007) but not at 10−6 M (98% ± 6% of baseline value; P = 0.12). Racemic ketamine did not modify R2 (Fig. 1).

As shown in Figure 2, after 15 min equilibration, phentolamine at 10−6 M did not modify FoC (ketamine 10−6 M group: 97% ± 3%; ketamine 10−5 M group: 98% ± 3%; and ketamine 10−4 M group: 99% ± 1% of baseline; P = 0.07 for phentolamine effect; no difference between groups) and +dF/dt (ketamine 10−6 M group: 95% ± 7%; ketamine 10−5 M group: 97% ± 4%, and ketamine 10−4 M group: 98% ± 10% of baseline P = 0.11 for phentolamine effect; no difference between groups). In contrast, propranolol significantly decreased FoC (ketamine 10−6 M group: 87% ± 5%; ketamine 10−5 M group: 92% ± 13%; and ketamine 10−4 M group: 90% ± 8% of baseline; P < 0.001 for propranolol effect; no difference between groups) and +dF/dt (ketamine 10−6 M group: 89% ± 6%; ketamine 10−5 M group: 82% ± 12%; and ketamine 10−4 M group: 88% ± 9% of baseline; P < 0.001 for propranolol effect; no difference between groups).

Figure 2

Figure 2

Pretreatment with phentolamine 10−6 M did not modify the direct inotropic effect of ketamine at 10−6 M (FoC, 94% ± 6%; +dF/dt, 95% ± 5% of baseline; P = 0.15), 10−5 M (FoC, 96% ± 5%; +dF/dt, 95% ± 8% of baseline; P = 0.19), and 10−4 M (FoC, 98% ± 15%; +dF/dt, 104 ± 13% of baseline). In contrast, in the presence of propranolol, ketamine 10−6 M (FoC, 77% ± 11%; +dF/dt, 8% ± 10% of baseline; P = 0.003), 10−5 M (FoC, 63% ± 16%; +dF/dt, 70 ± 14% of baseline; P = 0.009), and 10−4 M (FoC, 62% ± 17%; +dF/dt, 62% ± 15% of baseline; P = 0.006) induced a significant negative inotropic effect.

Propranolol and phentolamine did not modify T1/2 and R2 (Fig. 3). Racemic ketamine in the presence of phentolamine (ketamine 10−6 M, 95% ± 3%; ketamine 10−5 M, 92% ± 5%; and ketamine 10−4 M, 90% ± 9% of baseline) but not propranolol (ketamine 10−6 M, 103% ± 10%; ketamine 10−5 M, 95% ± 11%; and ketamine 10−4 M, 98% ± 6% of baseline) significantly decreased T1/2.

Figure 3

Figure 3

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Discussion

This study showed that 1) racemic ketamine induced a moderate positive inotropic effect on human right atrial myocardium; 2) racemic ketamine, in the presence of β-adrenoceptor blockade, induced a negative inotropic effect; and 3) racemic ketamine hastened relaxation through indirect β-adrenoceptors stimulation but did not modify the contraction-relaxation coupling parameter under high load.

Our study shows that racemic ketamine, at clinically relevant concentrations, induces a moderate positive inotropic effect on isolated human atrial myocardium (Fig. 1). This is in accordance with previous results showing that ketamine, especially its isomer S(+), induced a moderate positive inotropic effect in isolated human myocardium (9,11). It could be assumed that this effect should have no clinical relevance. Although Sprung et al. (10) reported a concentration-dependant negative inotropic effect of ketamine in human myocardium, important differences in bath temperature, frequency of stimulation, and patients’ characteristics may have influenced these results. Furthemore, Sprung et al. (10) did not detail the morphological parameters of atrial trabeculae although these are important because it has been shown that a large cross-sectional area might compromise core oxygenation of the isolated preparations and thus the inotropic response to drugs.

Several mechanisms may be involved in the direct myocardial positive inotropic effect of ketamine, such as an increase in intracellular Ca2+ available for myofilaments (6), prolongation of action potential duration (16), and inhibition of catecholamine uptake (3). In isolated guinea pig myocytes, ketamine decreased the inward Ca2+ current, but this effect was less pronounced in ventricular rat myocytes (17). In rat papillary muscles it has been indirectly suggested that ketamine decreased the sarcoplasmic reticular Ca2+ uptake (6). Nevertheless, these results were observed at supraclinical concentrations of ketamine in various species or experimental conditions and cannot be extrapolated to human myocardium. In isolated human myocardium Kunst et al. (11) showed that supraclinical concentrations of ketamine decreased intracellular Ca2+ transient but did not determine its mechanisms. Inhibition of the neuronal and extraneuronal catecholamines uptake has been shown indirectly in isolated rat heart and isolated ferret papillary muscles (3,7).

Although both ketamine isomers can inhibit neuronal and extraneuronal catecholamines uptake, the S(+) isomer has been shown to be more potent (18). However, the relative importance of this effect may vary among species. Thus, in isolated rat myocardium, Riou et al. (6) have shown that the positive inotropic effect induced by ketamine was not modified by pretreatment with α- or β-adrenoceptors blockers. However, Cook et al. (7) have shown that β-adrenoceptors blockade and catecholamine depletion by reserpine abolished the positive inotropic effect of ketamine on isolated ferret myocardium. Finally, it has been shown that reserpine, propranolol, and phenoxybenzamine potentiated the negative inotropic effect of ketamine in isolated guinea pig heart (19). Our study confirms, in human myocardium, that racemic ketamine induced a negative inotropic effect in the presence of propranolol, but not phentolamine. This may be related to the well known preeminent role of β- rather than α-adrenoceptors in the inotropic response of normal human myocardium.

Although our study does not determine the precise origin of adrenoceptor stimulation (i.e., catecholamine release or inhibition of extraneuronal catecholamine uptake) these experimental data strongly suggest that ketamine indirectly stimulates adrenoceptors through a net increase in catecholamines available in the extracellular space and that it is involved in the net inotropic effect of racemic ketamine. Our result must be interpreted with the known deleterious hemodynamic effect of ketamine in patients with attenuated sympathetic tone or response, such as severely ill patients (4,20), patients under general anesthesia with halothane and enflurane (21), or during epidural anesthesia (22). Our results also suggest that ketamine may exert a direct negative inotropic effect in patients treated with β-adrenoceptor blockers. Nevertheless, further clinical studies are required to determine the precise cardiovascular effects of ketamine in patients treated with β-adrenoceptor blockers.

Our study shows that ketamine decreases the time to half relaxation, which is a good index of myocardial relaxation phase (13). The increase in relaxation rate induced by ketamine may be related, at least in part, to β-adrenoceptor stimulation. Thus β-adrenoceptor blockade, but not α-adrenoceptor blockade, abolished the decrease in time to half relaxation measured in the presence of ketamine. This is in accordance with the potent positive relaxant effect of β-adrenoceptor stimulation in isometric twitch (14).

Ketamine alone or in the presence of α- and β-adrenoceptor blockade did not modify the contraction relaxation coupling parameter R2. This may mean that ketamine has no lusitropic effect under high load and indirectly suggests that it does not modify myofilament Ca2+ sensitivity. This has also been suggested in isolated rat myocardium (6). Finally, simultaneous measurement of rat ventricular myocyte shortening and intracellular Ca2+ concentration have confirmed that ketamine does not modify myofilament Ca2+ sensitivity (23). Nevertheless, further studies are required to examine the effects of ketamine on the complex interactions resulting in force decline during an isometric twitch (i.e., the decrease in intracellular Ca2+ concentration by sarcoplasmic reticular Ca2+ uptake and sarcolemmal Na+-Ca2+ exchange, the changes in affinity of troponin C for Ca2+, and the dynamic of myosin crossbridges detachment from actin after Ca2+ is lost from troponin C).

Our results should be interpreted cautiously because R2 has not been validated in isolated human atrial myocardium, because we solely studied isometric relaxation, and because physiologic relaxation is auxotonic (12). However, these results may have some clinical importance because diastolic function is difficult to assess precisely in clinical studies, as it significantly influences overall cardiac performance and because diastolic dysfunction may precede, or substantially contribute to, abnormalities of systolic function in various pathologic conditions.

The following points must be considered in the assessment of the clinical relevance of our results. First, because this study was conducted in vitro at 34°C, it dealt only with intrinsic myocardial contractility and did not take vascular effects of ketamine or its influences on sympathetic nervous system tone in vivo into account. Observed changes in cardiac function after anesthetic administration also depend on modifications in heart rate, venous return, afterload, sympathetic nervous system activity, and compensatory mechanisms. Second, we studied only isometric conditions, whereas, in vivo, the myocardium contracts against various levels of afterload in auxotonic conditions. Further studies are needed to assess the effect of ketamine on inotropy and lusitropy in various loading conditions. Third, it was performed on atrial myocardium, which differs from ventricular myocardium. In atrial myocardium, isometric twitch is shorter and force generation is less than in ventricular myocardium, at least in part attributable to a smaller releasable amount of Ca2+ and a faster uptake rate by sarcoplasmic reticulum (24). Fourth, as there is no protein in Tyrode’s solution, the concentrations of ketamine tested in our study were free concentrations. However, considering the 20% protein binding of ketamine, the range of concentrations tested included the free plasmatic concentrations of ketamine encountered in clinical anesthesia (16). Fifth, although experiments performed in human myocardium have the benefit of more relevant clinical extrapolations, effects of anesthetics, diseases, or treatments received by the patients cannot be excluded. We have previously reported that treatments received preoperatively, especially those interfering with adrenoceptors, could not blunt the effect of β-adrenoceptor stimulation on the same experimental model (25). Finally, the patients included in this study are representative of those who may receive ketamine. In clinical situations the preoperative disease or treatments would be present.

In conclusion, in isolated human right atrial myocardium, racemic ketamine induced a moderate positive inotropic effect but a direct negative inotropic effect in the presence of β-adrenoceptor blockade. Furthermore, ketamine hastened relaxation through stimulation of β-adrenoceptor.

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