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Canadian Journal of Anesthesia 49:375-379 (2002)
© Canadian Anesthesiologists' Society, 2002
General Anesthesia

Xenon and nitrous oxide do not depress cardiac function in an isolated rat heart model

[Le xénon et le protoxyde d'azote ne diminuent pas la fonction cardiaque d'un coeur de rat isolé]

Harumi Nakayama, MD*, Hiroshi Takahashi, MD{dagger}, Naomitsu Okubo, MD{dagger}, Masayuki Miyabe, MD{dagger} and Hidenori Toyooka, MD{dagger}

* From the Department of Anesthesia, Ushiku Aiwa General Hospital, and
{dagger} the Department of Anesthesiology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

Dr. Harumi Nakayama, Department of Anesthesia, Ushiku Aiwa General Hospital, 896 Shishiko-cho, Ushiku-shi, Ibaraki 300-1296, Japan. Phone: 011-81-298-73-3111; Fax: 011-81-298-74-1031; E-mail: hami{at}sky.zero.ad.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Purpose: To examine the inotropic and chronotropic effects of xenon (Xe) and nitrous oxide (N2O) compared with nitrogen (N2) on isolated rat hearts. The differences between Xe and N2O were also compared.

Methods: The effects of Xe, N2O and N2 on coronary perfusion pressure (CPP), heart rate, left ventricular developed pressure (LVDP) and double product (DP) were examined in isolated rat hearts perfused at constant flow (10 mL•min-1). Following stabilization and baseline measurement with 95% O2 (plus 5% CO2), the heart was exposed to buffer equilibrated with one of three test gases; 50% N2 with 45% O2 (Group N2: n=9), 50% Xe with 45% O2 (Group Xe: n=9), or 50% N2O with 45% O2 (Group N2O: n=9) for 30 min. Measurements were performed in the last minute of exposure to the test gases.

Results: Gas exposure in all three groups decreased O2 delivery (-50%), CPP (-11%), LVDP (-30%) and DP (-44%) compared with baseline values (P <0.001). However, there were no differences among the groups.

Conclusion: Our data suggest that cardiac contractility was decreased by the effects of reduced O2 delivery, but both Xe and N2O did not cause further cardiac depressant effects compared to N2 in this experimental model.


   Introduction
TOP
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
XENON (Xe) has many of the properties of an ideal anesthetic, because it is non-explosive, non-toxic, non-teratogenic, and probably is not metabolized.1–3 Xe also offers rapid induction and recovery from anesthesia4,5 due to its extremely low blood/gas partition coefficient (0.115–0.14).6,7 The minimum alveolar concentration (MAC) of Xe is 71% in humans, indicating that it is a moderately more potent anesthetic than nitrous oxide (N2O) (104%).6,8 In these respects, Xe has been proposed as a replacement for N2O in clinical use.4,9 However, the direct and global effects of Xe on the heart have not been compared with those of N2O. The current investigation examined the action of Xe compared with N2O and nitrogen (N2) in isolated rat hearts using the Langendorff preparation to avoid the mechanical, humoral and autonomic nervous system influences of Xe.

We tested the hypothesis that 50% Xe does not produce inotropic or chronotropic adverse effects compared with the effects of N2O on isolated rat hearts.


   Materials and methods
TOP
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Langendorff heart preparation
The study protocol was approved by the Institutional Animal Care Committee of the University of Tsukuba. Twenty seven male Sprague-Dawley rats (weighing 380–460 g, aged 13–14 weeks) were injected ip with 35 mg (76–92 mg•kg-1) sodium pentobarbitone and 1,000 units heparin. Following thoracotomy, the heart was rapidly excised and perfused via retrograde cannulation of the aorta in a Langendorff apparatus at a constant flow of 10 mL•min-1 (Radnoti Grass®; Monrovia, CA, USA) using modified Krebs-Henseleit (K-H) buffer.10 K-H buffer was composed of (mM) NaCl 118, KCl 4.7, KH2PO 1.2, MgSO4 1.2, CaCl2 2.8, NaHCO3 25, glucose 5.5 and sodium pyruvate 2.0. Constant flow was maintained throughout the experiment. Buffer and bath temperatures were maintained at 37.5 ± 0.3°C throughout the experiment with a thermostatically controlled recirculating water bath (Harvard Thermocirculator®, Kent, UK).

Systolic left ventricular pressure was measured isovolumetrically with a transducer connected to a thin, saline-filled, latex balloon. The balloon was inserted into the left ventricle through the mitral valve via an incision in the left atrium. Balloon volume was adjusted to create an end-diastolic left ventricular pressure of 0 or less than 5 mmHg during the initial baseline period. The volume of the balloon was not modified until the end of the experiment. Spontaneous heart rate (HR) was determined from the left ventricular contraction interval. Left ventricular developed pressure (LVDP) was calculated by subtracting end-diastolic left ventricular pressure from left ventricular peak systolic pressure, which was regarded as an index of contractile function of the isolated heart. Double product (DP) was calculated as follows: HR x LVDP/1000, which is an estimate of myocardial oxygen demand. Coronary perfusion pressure (CPP), which reflects coronary artery resistance, was measured by a pressure transducer (TruWaveTM UK0804SA, Edwards, Inc., CA, USA) connected to the aortic cannula, the tip of which was positioned just above the aortic valve. Isovolumetric left ventricular pressure, spontaneous HR and CPP were measured continuously (M1166A Model 66S, Hewlett Packard Co. Ltd., Boeblingen, Germany). Oxygen delivery (DO2) was calculated from the inflow O2 tension x O2 solubility (0.0031 mL•mmHg-1•100 mL-1) x coronary flow per gram wet heart tissue.11 Oxygen extraction ratio was calculated as follows: (inflow O2 content - outflow O2 content) x 100 / inflow O2 content.

Protocol
Before the experiment, four cylinders containing 95% O2 + 5% CO2, 50% N2 + 45% O2 + 5% CO2, 50% Xe + 45% O2 + 5% CO2, and 50% N2O + 45% O2 + 5% CO2 were prepared. The concentration of each gas in the cylinders was measured by gas chromatography. After 30 min of perfusion with buffer for equilibration with 95% O2 and 5% CO2, baseline measurements were taken. The hearts were then randomly assigned to one of three groups. In Group N2 (n=9), the hearts were exposed to buffer equilibrated with 50% N2, 45% O2 and 5% CO2. In Group Xe (n=9), the hearts were exposed to buffer equilibrated with 50% Xe, 45% O2 and 5% CO2. In Group N2O (n=9), the hearts were exposed to buffer equilibrated with 50% N2O, 45% O2 and 5% CO2. After a 30-min period of exposure to buffer with test gases, measurements were made.

Statistics
All data are expressed as mean ± SEM. Statistical analysis was performed on a personal computer with the statistical package SPSS® for Windows (available software package SPSS® for Windows 9.0.1 J). Variables were analyzed twice: by paired t test to analyze change from baseline, and by ANOVA to analyze between group differences. P values of less than 0.05 were considered significant.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Inflow pH and carbon dioxide tension (PCO2) were identical in the three groups. Oxygen tension (PO2) and calculated DO2 decreased in the three groups after exposure to buffer equilibrated with test gases. However, there were no statistically significant differences among the three groups (Table IGo).


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  		TABLE I Inflow pH, PCO2, PO2 and calculated DO2
 
CPP, LVDP and DP were decreased by exposure to buffer equilibrated with test gases. However, these variables were not different among the three groups (Table IIGo).


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  		TABLE II Cardiac variables in the three groups
 
Percent changes of CPP, LVDP and DP from baseline decreased in all three groups. However, these changes were not different among the groups (FigureGo).



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  		FIGURE Percent change of cardiac variables from baseline. There were no differences in % change of cardiac variables between groups N2, Xe and N2O. CPP=coronary perfusion pressure; HR=heart rate; LVDP=left ventricular developed pressure; DP=double product. *P <0.05 vs baseline.

 
Oxygen extraction ratio decreased significantly (P <0.001) with exposure to Xe (-28 ± 6%), N2O (-25 ± 2%) and N2 (-27 ± 4%) compared with 95% O2. However, there were no differences between the three groups.


   Discussion
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In the present study, the administration of Xe, as well as N2O, produced cardiodepressant effects in isolated rat hearts; however, these were identical to the effects of N2. This means that the cardiodepressant effects observed with Xe and N2O were due to reduced oxygen delivery, and that Xe or N2O themselves did not have cardiodepressant effects.

Previously, many studies have surmised that Xe causes minimal cardiovascular effects. Xe produced little effects on hemodynamics in pigs,12 and minimal cardiovascular effects were observed in dogs with and without experimental dilated cardiomyopathy during Xe inhalation.13 The latter finding indirectly suggested that Xe may be tolerated in unfavourable conditions, i.e., pre-existing LV dysfunction. Xe has been shown not to alter voltage-gated ion channels in the myocardium,14 nor does it sensitize the myocardium to the dysrhythmogenic effects of epinephrine.15 In humans, Xe was also found to provide stable cardiovascular conditions.2,5,16 Stowe et al. reported that Xe displayed no, or very minimal, physiologically important effects on isolated erythrocyte-perfused guinea pig hearts.17 Our results are consistent with these findings in that, regarding cardiac depressant effects, Xe exhibited no difference relative to N2 in isolated rat hearts.

Several studies have suggested that Xe might cause a decrease in HR,3,16,18,19 despite reports of little effect on hemodynamics in in vivo studies. The current investigation examined the effects of Xe in isolated rat hearts with Langendorff perfusion to avoid mechanical, humoral, and autonomic nervous system influences of the gas. Our results show that isolated hearts maintained a stable spontaneous HR during exposure to Xe. Xe was reported to depress both sympathetic and parasympathetic transmission more than isoflurane at 0.8 MAC, and was suggested to be relatively vagotonic in clinical trials.20 Further, the HR response can vary with autonomic tone and baroreflex activation.21 Therefore, the decrease in HR with Xe in vivo may be mediated via the cardiac autonomic nervous system. Xe is also capable of preventing activation of the adrenal medullary system3 and inhibits adrenal secretion,3,12 which might result in decreased HR in vivo.

Many years of clinical experience with N2O indicate that it possesses mild cardiovascular depressant effects that may be counterbalanced by a simultaneous, reflexly mediated increase in sympathetic tone. These studies demonstrated small increases,22 small decreases,23 or no change24 in indices of contractility. A few in vitro investigations regarding the effects of N2O on myocardial muscle have indicated that N2O depressed contractility similar to, or more than that in controls.25–27 Regarding sympathetic effects, N2O, but not Xe, has been reported to augment its outflow. The sympathetic activation by N2O has been shown by elevated plasma catecholamine concentrations23 and by microneurography.28,29 This sympatho-activating property of N2O can complicate evaluation of its cardiovascular effects and direct effects on cardiac function. In an isolated global heart study, Stowe et al. reported that N2O caused only small but significant depression of indices of cardiac contractility.11 Our findings, however, showed that 50% N2O produced no cardiodepressant effects compared with an identical concentration of N2, which is inconsistent with their report.11 No statistically significant difference between Xe, N2O and N2, could be shown but N2O tended to be cardiodepressant. The number of hearts studied in the current laboratory investigation may not have been sufficient to confirm the cardiodepressant effects of N2O. Meanwhile, Xe did not depress cardiac function more than N2O, at least in the absence of autonomic influence or changes in preload and afterload.

The effect of the restriction of O2 delivery is a limitation of the current investigation. The hearts were solely dependent on the crystalloid solution from which to extract dissolved O2. Exposure to 50% Xe (i.e., exposure to 45% O2) decreased O2 delivery with, possibly, a consequent mild hypoxic condition in isolated hearts11 (Table IGo). Even under such conditions, however, Xe produced identical changes in CPP, LVDP and DP compared with N2.

As mentioned initially, Xe surpasses N2O in several points; lower blood/gas partition coefficient (0.115–0.14),6,7 higher MAC (71% in humans),6,8 and innocuousness to the environment, because Xe is prepared by fractional distillation of atmospheric air. Therefore, the replacement of N2O with Xe may become appropriate when delivery systems (i.e., closed circuit) become available with efficient techniques for recycling the gas to decrease the cost of Xe anesthesia.30

In conclusion, 50% Xe produced cardiac effects identical to those of N2O or N2 in isolated rat hearts under conditions of decreased O2 delivery. Xe itself lacks cardiodepressant effects and may become a useful alternative to N2O.


   Acknowledgments
 
The authors wish to thank Air Water Inc. for their generous donation of Xe. The authors also thank Ms. Yumi Isaka and Mr. Yasuyuki Baba for their technical assistance.


   Footnotes
 
Supported by a Grants-in-Aid for Scientific Research No. 10770740 from the Ministry of Education, Science and Culture, Tokyo Japan.

Revision received September 17, 2001. Accepted for publication August 15, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Lane GA, Nahrwold ML, Tait AR, Taylor-Busch M, Cohen PJ. Anesthetics as teratogens: nitrous oxide is fetotoxic, xenon is not. Science 1980; 210: 899–901.[Abstract/Free Full Text]

2 Lachmann B, Armbruster S, Schairer W, et al. Safety and efficacy of xenon in routine use as an inhalational anaesthetic. Lancet 1990; 335: 1413–5.[Medline]

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6 Steward A, Allott PR, Cowles AL, Mapleson WW. Solubility coefficients for inhaled anaesthetics for water, oil and biological media. Br J Anaesth 1973; 45: 282–93.[Free Full Text]

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11 Stowe DF, Monroe SM, Marijic J, Rooney RT, Bosnjak ZJ, Kampine JP. Effects of nitrous oxide on contractile function and metabolism of the isolated heart. Anesthesiology 1990; 73: 1220–6.[Medline]

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13 Hettrick DA, Pagel PS, Kersten JR, et al. Cardiovascular effects of xenon in isoflurane-anesthetized dogs with dilated cardiomyopathy. Anesthesiology 1998; 89: 1166–73.[Medline]

14 Rehmert GC, Kwok WM, Stadnicka A, Weigt HU, Georgrieff M, Bosnjak ZJ. Xenon does not inhibit cardiac ion channels. Anesthesiology 1998; 89: A594 (abstract).

15 Kamibayashi T, Hayashi Y, Mammoto T, et al. Comparison of myocardial epinephrine sensitization during xenon, halothane and nitrous oxide anesthesia in dogs. Anesthesiology 1998; 89: A614 (abstract).

16 Morita S, Goto T, Niimi Y, Ichinose F, Saito H. Xenon produces minimal cardiac depression in patients under fentanyl-midazolam anesthesia. Anesthesiology 1996; 85 A362 (abstract).

17 Stowe DF, Rehmert GC, Kwok W-M, Weigt HU, Georgieff M, Bosnjak ZJ. Xenon does not alter cardiac function or major cation currents in isolated guinea pig hearts or myocytes. Anesthesiology 2000; 92: 516–22.[Medline]

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