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Canadian Journal of Anesthesia 53:1118-1125 (2006)
© Canadian Anesthesiologists' Society, 2006
Cardiothoracic Anesthesia, Respiration and Airway

Effects of halothane, sevoflurane and desflurane on the force-frequency relation in the dog heart in vivo

[Les effets de l’halothane, du sévoflurane et du desflurane sur la relation force-fréquence des coeurs de chiens in vivo]

Benedikt Preckel, MD DEAA*,{dagger}, Detlef Obal, MD DESA{dagger},{ddagger}, Jost Müllenheim, MD DEAA§, Juliane Hennes, MD, Marc Heiderhoff, MD, Volker Thämer, MD and Wolfgang Schlack, MD DEAA*,{dagger}

* From the Department of Anesthesiology, Academic Medical Center, University of Amsterdam, The Netherlands;
{dagger} Department of Anesthesiology, University Hospital of Duesseldorf, Germany;
{ddagger} Department of Anesthesiology, University of Louisville, Louisville, Kentucky, USA; the
§ South Tyneside District Hospital, South Shields, UK; and the
Institute for Physiology, University of Duesseldorf, Germany.

Address correspondence to: Dr. Benedikt Preckel, Associate Professor, Academic Medical Center, University of Amsterdam, Postbus 22660 H1Z-139, 1100 DD Amsterdam, The Netherlands. Phone: +31-20-5662533; Fax: + 31-20-6979441; E-mail: b.preckel{at}amc.uva.nl


   Abstract
TOP
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Purpose: Frequency potentiation is the increase in force of contraction induced by an increased heart rate (HR). This positive staircase phenomenon has been attributed to changes in Ca2+ entry and loading of intracellular Ca2+ stores. Volatile anesthetics interfere with Ca2+ homeostasis of cardiomyocytes. We hypothesized that frequency potentiation is altered by volatile anesthetics and investigated the influence of halothane (H), sevoflurane (S) and desflurane (D) on the positive staircase phenomenon in dogs in vivo.

Methods: Dogs were chronically instrumented for measurement of left ventricular (LV) pressure and cardiac output. Heart rate was increased by atrial pacing from 120 to 220 beats·min–1 and the LV maximal rate of pressure increase (dP/ dtmax) was determined as an index of myocardial performance. Measurements were performed in conscious dogs and during anesthesia with 1.0 minimal alveolar concentrations of each of the three inhaled anesthetics.

Results: Increasing HR from 120 to 220 beats·min–1 increased dP/dtmax from 3394 ± 786 (mean ± SD) to 3798 ± 810 mmHg sec–1 in conscious dogs. All anesthetics reduced dP/dtmax during baseline (at 120 beats·min–1: H, 1745 ± 340 mmHg·sec–1; S, 1882 ± 418; D, 1928 ± 454, all P < 0.05 vs awake) but did not influence the frequency potentiation of dP/dtmax (at 220 beats·min–1: H, 1981 ± 587 mmHg·sec–1; S, 2187 ± 787; D, 2307 ± 691). The slope of the regression line correlating dP/dtmax and HR was not different between awake and anesthetized dogs. Increasing HR did not influence cardiac output in awake or anesthetized dogs.

Conclusion: These results indicate that volatile anesthetics do not alter the force-frequency relation in dogs in vivo.


   Introduction
TOP
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
THE cardiac force-frequency relation (FFR) was first identified more than a century ago, yet its mechanisms remain incompletely elucidated (for a detailed review, see reference 1).1 In most mammalian species, changes in stimulation frequency induce an increase in contractile force. The FFR plays a major role in adaptation to exercise. Prior studies have shown that the FFR is mainly influenced by Ca2+ handling of both the sarcoplasmic reticulum (SR) and sarcolemma, and as such can be considered a macroscopic measure of excitation-contraction coupling.2 The FFR depends on Ca2+-influx via L-type and SR-Ca2+ channels3 and the frequencydependent force generation is accompanied by an increase in both systolic and diastolic Ca2+ levels.

Different volatile anesthetics have unique effects on the Ca2+-homeostasis of cardiomyocytes. Halothane inhibits Na+/Ca2+ exchange,4,5 directly blocks the Ca2+ dependent Ca2+ release channel (ryanodine receptor), 6,7 and might increase Ca2+ uptake of the SR.8 Sevoflurane blocks transmembrane Ca2+ influx,9,10 stimulates Ca2+ uptake into the SR11 and reduces fractional Ca2+ release from the SR,12 leading finally to a reduction of cytoplasmic Ca2+ concentration. Influences of desflurane on cardiac Ca2+ homeostasis have not been established.

With regards to general anesthesia all variables influencing FFR are influenced by volatile anesthetics: heart rate and contractile force of the myocardium are reduced and Ca2+ homeostasis is altered. These changes are similar to alterations in the failing myocardium, in which a positive FFR may be reversed to a negative FFR.13 Importantly, the FFR has been investigated predominantly in isolated muscle preparations, with very few comparable data available in the intact state of in vivo experiments. Limited data are available as to whether volatile anesthetics may alter the FFR. In isolated human ventricular myocardium in non-failing hearts, halothane, sevoflurane and isoflurane did not affect FFR.14 In contrast, halothane restored the positive relation of the FFR in failing myocardium,14 while similar findings for isoflurane or sevoflurane have not been demonstrated.

The present study was designed, first, to confirm the FFR in the intact animal, and to corroborate findings from isolated muscle studies. Secondly, because volatile anesthetics alter Ca2+ handling of cardiomyocytes, we hypothesized that the FFR is altered during general anesthesia with inhaled anesthetics. Therefore, the effects of halothane on FFR were compared with equipotent concentrations of the two newer anesthetics desflurane and sevoflurane.


   Materials and methods
TOP
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
The present study conforms to the Guiding Principles in the Care and Use of Animals, as approved by the Council of the American Physiologic Society, and was approved by the local Bioethical Committee of the District of Düsseldorf.

Mongrel dogs weighing 25–32 kg were trained daily for three weeks to become familiar with the laboratory environment and the investigators. Under general anesthesia, nine dogs were surgically instrumented for long-term physiological monitoring as previously described.15 The instrumentation included an aortic catheter (Tygon R3603; Norton, Akron, OH, USA) to determine aortic pressure (AOP), a Koenigsberg transducer (LP 200, Koenigsberg, Pasadena, CA, USA) for measurement of left ventricular pressure (LVP) and its first derivative, rate of pressure change (dP/dt), and an ultrasonic flowprobe (T 208; Transonic Systems Inc., Ithaca, NY, USA) around the pulmonary artery for measurement of cardiac output (CO). A pair of ultrasonic crystals (Triton Technology Inc., San Diego, CA, USA) was implanted in the subendocardium of the LV anteroapical wall. For cardiac pacing, two electrodes were fixed epicardially at the left atrium. The dogs were allowed to recover for a minimum of two weeks prior to experimentation.

Experimental protocol
Data were collected during steady-state conditions in awake dogs and, in a cross-over design, each animal was anesthetized with 1.0 minimal alveolar concentration (MAC) of the respective anesthetic on different days. The order in which the anesthetics were sequentially administered was randomized. Following insertion of an endotracheal tube (after induction of anesthesia with propofol 3 mg·kg–1 iv), the animals’ lungs were ventilated with 30% O2 in air (tidal volume 10 mL·kg–1, respiratory frequency 14 min–1 to maintain normocarbia) and anesthesia was maintained with 1.0 MAC halothane (end-tidal concentration, Datex Capnomac Ultima, Division of Instrumentarium Corp., Helsinki, Finland), sevoflurane or desflurane (Vapor 19.3, Devapor, Drägerwerke AG, Lübeck, Germany); MAC values in dogs: halothane, 0.9 vol.%, sevoflurane 2.4 vol.%; desflurane 7.2 vol.%.16,17 To measure the FFR, data were collected at increasing heart rates of 120, 140, 160, 180, 200, and 220 beats·min–1 using atrial pacing. After each measurement, heart rate was increased and at least ten minutes were allowed to reach steady state conditions before the next data were collected. To exclude variations of dP/dt caused by mechanical ventilation, measurements were performed during transient periods of applied apnea.

Data recording
Left ventricular pressure, dP/dt, CO, AOP and myocardial segment length (SL) in the anteroapical wall were continuously recorded on an ink-recorder (Recorder 2800; Gould Inc., Cleveland, OH, USA) during all experiments. The data were digitized using an analogue-to-digital converter (Data Translation, Marlboro, MA, USA) at a sampling rate of 500 Hz and later processed on a personal computer.

Global systolic function was measured in terms of LVP and the maximal rate of pressure increase (dP/ dtmax). Left ventricular dP/dtmin was used as an index of global LV diastolic function. The rate pressure product was calculated from the product of systolic pressure and heart rate. Regional myocardial systolic function was assessed in the anteroapical wall and was evaluated as mean systolic SL shortening velocity as well as percent systolic SL shortening (SLes%), calculated as:

SLes% = (SLed-SLes/SLed) =100, where SLed represents end-diastolic SL and SLes represents endsystolic SL.

Statistical analysis
Measured values are presented as means ±SD. For comparison of the FFR between experimental groups, a Tukey-Kramer test was calculated for the hemodynamic variables at each individual heart rate. Control measurements of three experiments in each dog were summarized and used as one data point. To assess the FFR within experimental groups (awake, respective anesthetics), regression analysis was performed for dP/dtmax. Differences between regression lines were analyzed by an F-test. Other hemodynamic variables were analyzed within each group using Dunnett’s test with 120 beats·min–1 as reference value. Changes were considered statistically significant when P <0.05.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Nine dogs were instrumented and studied on different days. In two dogs, atrial pacing was not always possible. Therefore, data are presented from seven experiments with each anesthetic and the respective control recordings in seven dogs.

The hemodynamic data of experiments in awake dogs are summarized in Table IGo. In chronically instrumented awake dogs, increasing heart rate from 120 to 220 augmented dP/dtmax from 3394 ±786 to 3798 ±810 mmHg sec–1 (FigureGo), confirming the existence of FFR in vivo. The slope of the regression line was 3.8 ±0.9 mmHg sec-–1·beats–1 and significantly different from zero (P < 0.05, r = 0.91).


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  		TABLE I Hemodynamic response to increasing heart rates in awake dogs
 

Figure 1
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  		FIGURE Force-frequency relation in conscious dogs and during anesthesia with 1-minimal alveolar concentrations of halothane, sevoflurane or desflurane. The slope of the regression lines were different from zero but were not altered during anesthesia. Equations of regression lines: Awake: y = 3.8 ± 0.9 x + 2891 ± 150; Halothane: y = 3.0 ± 0.6 x + 1371 ± 107; Sevoflurane: y = 2.8 ± 1.0 x + 1540 ± 170; Desflurane: y = 3.6 ± 0.3 x + 1536 ± 56. All values during anesthesia are significantly different from the respective values in awake dogs (P < 0.05).

 
All anesthetics produced a marked negative inotropic effect, reducing LVP, mean aortic pressure, systemic vascular resistance, and dP/dt in comparison to the awake state (Tables IIGo–IVGoGo, FigureGo). The variable of contractile function, dP/dtmax, was reduced during baseline from 3394 ±786 mmHg·sec–1 in awake dogs to 1745 ±340 mmHg·sec–1 (halothane), 1882 ±418 mmHg·sec–1 (sevoflurane) and 1928 ±454 mmHg·sec–1 (desflurane) at 120 beats·min–1, respectively (all P < 0.05 vs awake). However, the FFR was not influenced by volatile anesthetics, and dP/dtmax increased to 1981 ±587 mmHg·sec–1 (halothane), 2187 ±787 mmHg·sec–1 (sevoflurane) and 2307 ±691 mmHg·sec–1 (desflurane) at 220 beats·min–1, respectively (in each group, P < 0.05 vs 120 beats·min–1). Although reduction of dP/dtmax was numerically greater during halothane anesthesia, no significant differences were observed between the three inhalational agents. The slopes of the regression lines (halothane: 3.0 ±0.6 mmHg·sec–1·beats–1; sevoflurane: 2.8 ±1.0 mmHg·sec–1·beats–1; desflurane: 3.6 ±0.3 mmHg·sec–1 ·beats–1) were significantly different from zero but not significantly different from the experiments in awake dogs (3.8 ±0.9 mmHg·sec–1·beats–1). Increasing heart rate had no significant effect on mean aortic pressure, CO or systemic vascular resistance during general anesthesia. However, regional myocardial function assessed as systolic SL shortening was slightly impaired at least at higher heart rates.


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  		TABLE II Hemodynamic response to increasing heart rate in halothane anesthetized dogs
 

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  		TABLE III Hemodynamic response to increasing heart rate in sevoflurane anesthetized dogs
 

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  		TABLE IV Hemodynamic response to increasing heart rate in desflurane anesthetized
 

   Discussion
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The results of the present study confirm the positive FFR in awake dogs in vivo. In addition, we demonstrated that the FFR is not altered during general anesthesia with 1 MAC concentrations of halothane, sevoflurane or desflurane.

In most mammalian species, changes in stimulation frequency induce an increase in contractile force. This phenomenon (the "treppe" or positive staircase) was described more than a century ago by Bowditch. In certain species including rats, the staircase is negative. 1,18,19 This difference may be caused by different origins of calcium available for contraction (i.e., transsarcolemmic movements, SR release, or both).20 On a molecular level, the FFR is related to a net gain of circulation of Ca2+ in the cell and increased calcium- induced calcium release, by either increased Ca2+-influx via L-type and SR-Ca2+ channels,3 or a reduction in Na+/ Ca2+ exchanger activity during diastole. The frequency-dependent force generation is accompanied by an increase in both systolic and diastolic Ca2+ levels.3 In the intact animal, Ca2+ handling by the SR is a primary determinant of mechanical performance.21 Ryanodine induced augmentation of the force-frequency response indicates a central role for Ca2+ influx in producing frequency potentiation.21 Endogenous nitric oxide might also influence the FFR, showing an enhancement or a reduction of FFR depending on the experimental setup.22

Mostly previous investigations examining the FFR have been conducted in isolated heart preparations, where experimental conditions might have a substantial influence, and might even change a positive to a negative FFR.23 Very few studies have shown a positive staircase in situ,22,24–26 and from most of these investigations it is apparent that the relevance of FFR is overestimated in vitro, since changes in contraction are smaller in vivo than in vitro.24 The smaller changes in vivo might be attributable to changes in loading conditions during the controlled increase in heart rate.26 Our data confirm previous findings, showing an increase of dP/dtmax by 17 ± 7% over a nearly twofold increase in heart rate from 120 to 220 beats·min–1. The frequency-dependent force generation is accompanied by an increase in both systolic and diastolic Ca2+ levels. Thus, especially at high stimulation frequencies, the Ca2+ lowering mechanism may become crucial and may be responsible for the blunted force-frequency relation in failing human myocardium.3 In contrast to force potentiation, when the interval between successive beats is too short, the force of the following contraction may be attenuated due to an incomplete recovery process. In accordance with previous studies,24,26 a reversal of the positive into a negative staircase was not observed in the frequency range between 120 and 220 beats·min–1.

The sarcoplasmic reticulum plays a central role in cardiac contraction and relaxation by regulating intracellular Ca2+ concentration. Ca2+ uptake by the SR is mediated by an adenosine triphosphate (ATP)- dependent Ca2+ pump, the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA).27 An increase in SERCA expression increases the ability of the SR to store Ca2+. Thus, more calcium is available to be released during each heartbeat at higher stimulation rates.28 The interaction of the SERCA2a with its inhibitory protein phospholamban might be involved in the control of the FFR.1,29 The ratio of phospholamban to SERCA2a is an important component in the control of the FFR30 and the level of phospholamban is a critical negative determinant of myocardial contractility in vivo.31

Different volatile anesthetics have different effects on the Ca2+ homeostasis of cardiomyocytes. Halothane reduces intracellular Ca2+ concentration by inhibiting Na+/Ca2+ exchange 4,5 and blocking the Ca2+ dependent Ca2+ release channel (ryanodine receptor).6,7 By the latter mechanism, halothane reduces Ca2+ oscillations during reoxygenation of previous anoxic cardiomyocytes. 32 In addition, halothane might increase Ca2+ uptake of the SR.8 Sevoflurane blocks transmembrane Ca2+ influx,9,10 stimulates Ca2+ uptake into the SR11 and reduces fractional Ca2+ release from the SR,12 leading finally to a reduction of cytoplasmic Ca2+ concentration. Influences of desflurane on cardiac Ca2+ homeostasis have yet to be investigated. Most studies on the effects of volatile anesthetics on myocardial Ca2+ handling were performed under artificial experimental conditions in isolated hearts or isolated cardiomyocytes. Studying the effect of the anesthetics in the dog heart in vivo shows that the FFR is maintained, suggesting that besides changes in Ca2+ handling, other mechanisms may be involved in the staircase phenomenon.

Halothane reduces myocardial contractility in a dose-dependent manner.33 Sevoflurane and desflurane also have negative inotropic properties,33–35 although desflurane might exert positive inotropic actions by direct catecholamine release from cardiac nerve endings.36 The negative inotropic effects were also observed in the present investigation, with no significant differences between anesthetics. However, the negative inotropy did not alter FFR in vivo.

Halothane inhibited the SERCA2a, an effect that was reduced by phospholamban.37 However, this anesthetic had no effect on FFR in dogs in vivo. Effects of sevoflurane or desflurane on SERCA or phospholamban are not known. Hydroxyl radicals induce an impairment of contraction and relaxation and an attenuation of the FFR in human myocardium accompanied by an inhibition of SERCA.38 Inhalational anesthetics inhibited generation and cytotoxic effects of free hydroxyl radicals39 and might thereby change SERCA activity and maintain FFR.

There are several potential limitations with the experimental model used in this study. First, a pacing induced tachycardia was used to investigate the FFR in dogs in vivo. Whether this effect mirrors the hemodynamic response to sinus tachycardia is not known. Importantly, however, atrial pacing avoids the ventricular wall motion abnormalities and changes in ventricular preload associated with ventricular pacing. In addition, mechanical respiration might have introduced a subtle confounding influence on the measured hemodynamic variables. To take this possibility into consideration, we sampled the data over ten to 12 successive heart beats to minimize influences of intrathoracic pressure changes, and recorded measurements during apnea. The normal resting heart rate of this canine species averages 82 beats·min–1,40 and a maximal heart rate of 220 beats·min–1 was chosen because higher pacing rates frequently result in severe arrhythmias. Therefore, a decline in the FFR at heart rates above 220 beats·min–1 might have been anticipated. Heart rates were increased in a stepwise manner during each experiment, while allowing sufficient time for hemodynamic variables to equilibrate after each step increase. However, possible carry-over effects from one step change in heart rate to the next cannot be excluded. Furthermore, the changes in contractile force were relatively small, and might therefore not lead to alterations of a well regulated hemodynamic variable - CO. Higher heart rates led to a reduced SLes%, showing reduced regional myocardial function. This might be explained by reduced left ventricular filling at higher heart rates, as evidenced by a reduced diastolic SL and a reduction in stroke work per cardiac cycle. Finally, we examined the cardiac response at only one concentration of each anesthetic, and conclusions about higher or lower concentrations cannot be drawn. Because only a single injection of propofol was used and sufficient time was allowed to reach steady state conditions, an effect of propofol on dP/dtmax is unlikely.

In conclusion, the present study confirms the existence of a positive FFR in vivo and demonstrates for the first time that general anesthesia with 1-MAC concentrations of halothane, sevoflurane or desflurane does not alter FFR.


   Acknowledgments
 
We thank E. Hauschildt, BTA and A. Moloschavij, MD for their technical assistance with the experiments.


   Footnotes
 
Supported by a grant of the German Research Foundation to Wolfgang Schlack (SCHL 448/2-1).

Assessed June 7, 2006. Revision accepted August 17, 2006. Final revision accepted August 28, 2006.


   References
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Endoh M. Force-frequency relationship in intact mammalian ventricular myocardium: physiological and pathophysiological relevance. Eur J Pharmacol 2004; 500: 73–86.[Medline]

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3 Reuter H, Zobel C, Brixius K, Bolck B, Schwinger RH. The force-frequency relationship is dependent on Ca2+-influx via L-type and SR-Ca2+-channels in human heart. Basic Res Cardiol 1999; 94: 159–70.[Medline]

4 Haworth RA, Goknur AB. Inhibition of sodium/calcium exchange and calcium channels of heart cells by volatile anesthetics. Anesthesiology 1995; 82: 1255– 65.[Medline]

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6 Komai H, Rusy BF. Direct effect of halothane and isoflurane on the function of the sarcoplasmic reticulum in intact rabbit atria. Anesthesiology 1990; 72: 694–8.[Medline]

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