School of Biomedical Sciences and 1 Academic Unit of Anaesthesia, University of Leeds, Leeds LS2 9JT, UK
Corresponding author. E-mail: s.m.harrison@leeds.ac.uk
Accepted for publication: December 9, 2002
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Abstract |
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Methods. Myocytes were isolated from the sub-endocardium and sub-epicardium of the left ventricle of spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Action potentials were recorded before, during, and after a 1-min exposure to 0.6 mM halothane and APD measured from the peak of the action potential to repolarization at 50 mV (APD50 mV). Data are presented as mean (SEM).
Results. In WKY myocytes, halothane reduced APD50 mV from 21 (2) to 18 (2) ms (P<0.001, n=15) in sub-epicardial myocytes but abbreviated APD50 mV to a greater extent in sub-endocardial myocytes (37 (4) to 28 (3) ms; P<0.001, n=14). In SHR myocytes, APD50 mV values were prolonged compared with WKY and APD50 mV was reduced by halothane from 36 (6) to 27 (4) ms (P<0.016) and from 77 (10) to 38 (4) ms (P<0.001) in sub-epicardial and sub-endocardial myocytes, respectively.
Conclusions. In the SHR, hypertrophic remodelling was not homogeneous; APD50 mV was prolonged to a greater extent in sub-endocardial than sub-epicardial cells. Halothane reduced APD to a greater extent in sub-endocardium than sub-epicardium in both WKY and SHR but this effect was larger proportionately in SHR myocytes. The transmural gradient of repolarization was reduced in WKY and effectively abolished in SHR by halothane, which might disturb normal ventricular repolarization.
Br J Anaesth 2003; 90: 5013
Keywords: anaesthetics volatile, halothane; nerve, transmission
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Introduction |
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Exposure to halothane leads to a reduction in ventricular action potential duration4 5 secondary to inhibition of both inward and outward membrane currents (e.g. ICa6 and Ito7). Recently, it has been reported8 that halothane abbreviates action potential duration (APD) to a greater extent in left ventricular sub-endocardial than sub-epicardial myocytes and it was proposed that the transmural gradient in expression of Ito9 contributed to this effect. As several halothane-sensitive currents are affected during hypertrophic remodelling (e.g. Ito), our aim was to investigate whether halothane affected the action potential differentially in hypertensive and normotensive ventricle.
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Methods and results |
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SHR myocytes were significantly longer (145 (4) µm, n=27) than WKY myocytes (128 (4) µm, n=28; P=0.005, t-test); however, the degree of hypertrophy was regional; myocyte length was greater in sub-endocardial (SHR, 148 (4) µm vs WKY, 123 (6) µm; P<0.05) than sub-epicardial myocytes (SHR, 141 (7) µm vs WKY, 134 (4) µm; P>0.05).
In WKY, APD50 mV was shorter (P=0.003) in sub-epicardial myocytes (21 (2) ms, n=15) than sub-endocardial myocytes (37 (4) ms, n=14; Fig. 1). Halothane reduced APD50 mV to 18 (2) ms (P<0.001) in sub-epicardial myocytes and to 28 (3) ms (P<0.001) in sub-endocardial myocytes. In SHR myocytes, APD50 mV values were prolonged compared with WKY and APD50 mV was reduced from 36 (6) to 27 (4) ms (P<0.016), and from 77 (10) to 38 (4) ms (P<0.001) by halothane in sub-epicardial and sub-endocardial myocytes, respectively. Halothane did not affect the resting membrane potential in either WKY or SHR myocytes although action potential amplitude was depressed significantly by halothane in all cells (P<0.05).
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Comments |
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The second main point of this study is that exposure to a clinically relevant concentration of halothane (approximately twice the minimum alveolar concentration) had a greater proportionate inhibitory effect on APD in hypertrophied than in normotensive myocytes, especially in sub-endocardial cells (Fig. 1). As such, the transmural gradient of repolarization in SHR was reduced to 27% of its control value by halothane, and APD50 mV was no longer significantly different between the sub-endocardium and sub-epicardium in the presence of halothane. This effect was greater than observed in WKY myocytes where the transmural gradient of APD was reduced to 63% of its control value by halothane.
In summary, the data show that halothane reduces APD, which could potentially reduce the incidence of re-entrant arrhythmias in the hypertrophied ventricle by reducing the increased transmural dispersion of repolarization/refractoriness. However, as sub-endocardial APD was reduced dramatically by halothane, the transmural gradient in APD50 mV was essentially abolished in the SHR and this may also impact on repolarization in hypertrophied ventricle.
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References |
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2 Yan GX, Rials SJ, Wu Y, et al. Ventricular hypertrophy amplifies transmural repolarization dispersion and induces early afterdepolarization. Am J Physiol 2001; 281: H196875
3 Wickenden AD, Kaprielian R, Kassiri Z, et al. The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure. Cardiovasc Res 1998; 37: 31223[CrossRef][ISI][Medline]
4 Harrison SM, Robinson M, Davies LA, Hopkins PM, Boyett MR. Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes. Br J Anaesth 1999; 82: 60921
5 Polic S, Bosnjak ZJ, Marijic J, Hoffmann RG, Kampine JP, Turner LA. Actions of halothane, isoflurane and enflurane on the regional action potential characteristics of canine Purkinje fibers. Anesth Analg 1991; 73: 60311[Abstract]
6 Pancrazio JJ. Halothane and isoflurane preferentially depress a slow inactivating component of Ca2+ channel current in guinea-pig myocytes. J Physiol 1996; 494: 94103
7 Davies LA, Hopkins PM, Boyett MR, Harrison SM. Effects of halothane on the transient outward K+ current in rat ventricular myocytes. Br J Pharmacolol 2000; 131: 22330
8 Rithalia A, Gibson CN, Hopkins PM, Harrison SM. Halothane inhibits contraction and action potential duration to a greater extent in subendocardial than subepicardial myocytes from the rat left ventricle. Anesthesiology 2001; 95: 12139[CrossRef][ISI][Medline]
9 Liu D-W, Gintant GA, Antzelevitch C. Ionic bases for electrophysiological distinctions among epicardial, midmyocardial and endocardial myocytes from the free wall of the canine left ventricle. Circ Res 1993; 72: 67187[Abstract]
10 Yin FC. Ventricular wall stress. Circ Res 1981; 49: 82942[ISI][Medline]