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Mechanisms of Sevoflurane-Induced Myocardial Preconditioning In Anesthesiology 2003; 99:27–33 © 2003 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Mechanisms of Sevoflurane-induced Myocardial Preconditioning in Isolated Human Right Atria In Vitro Alexandra Yvon, B.Sc.,* Jean-Luc Hanouz, M.D, Ph.D.,† Benoît Haelewyn, B.Sc.,* Xavier Terrien, B.Sc.,* Massimo Massetti, M.D.,‡ Gérard Babatasi, M.D., Ph.D.,‡ André Khayat, M.D.,§ Pierre Ducouret, Ph.D.,࿣ Henri Bricard, M.D.,# Jean-Louis Gérard, M.D., Ph.D.** Background: The authors examined the role of adenosine postischemic contractile function,5–7 and metabolic triphosphate–sensitive potassium channels and adenosine A 7 1 function. Although the mechanisms involved in anes- receptors in sevoflurane-induced preconditioning on isolated thetic preconditioning remain incompletely understood, human myocardium. Methods: The authors recorded isometric contraction of hu- protein kinase C, adenosine triphosphate–sensitive po- man right atrial trabeculae suspended in oxygenated Tyrode’s tassium (KATP) channels, and adenosine A1 receptors Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/99/1/27/408853/0000542-200307000-00008.pdf by guest on 02 October 2021 solution (34°C; stimulation frequency, 1 Hz). In all groups, a seem to play a key role.1,2,5,6 However, recent studies 30-min hypoxic period was followed by 60 min of reoxygenation. suggest that volatile anesthetic–induced myocardial pre- Seven minutes before hypoxia reoxygenation, muscles were ex- posed to 4 min of hypoxia and 7 min of reoxygenation or 15 min conditioning may be dependent on species and experi- 5,8 of sevoflurane at concentrations of 1, 2, and 3%. In separate mental models. Thus, halothane has been shown to 1 groups, sevoflurane 2% was administered in the presence of 10 ␮M precondition rabbit myocardium but failed to precon- HMR 1098, a sarcolemmal adenosine triphosphate–sensitive po- dition isolated human myocardium.5 Similarly, isoflurane ␮ tassium channel antagonist; 800 M 5-hydroxy-decanoate, a mito- failed to precondition isolated rat heart8 but precondi- chondrial adenosine triphosphate–sensitive potassium channel tioned rabbit,1 dog,2,3 and human myocardium.5,9 Fi- antagonist; and 100 nM 8-cyclopentyl-1,3-dipropylxanthine, an adenosine A1 receptor antagonist. Recovery of force at the end of nally, sevoflurane failed to precondition rabbit myocar- the 60-min reoxygenation period was compared between groups dium in vivo10 but has been shown to precondition dog4 -mean ؎ SD). and guinea pig myocardium.7 Furthermore, it was re) Results: Hypoxic preconditioning (90 ؎ 4% of baseline) and cently suggested that the myocardial effects of volatile ؎ ؎ sevoflurane 1% (82 3% of baseline), 2% (92 5% of baseline), 11 and 3% (85 ؎ 7% of baseline) enhanced the recovery of force anesthetics and the mechanisms involved in ischemic 12 after 60 min of reoxygenation compared with the control preconditioning may be different among species. -groups (52 ؎ 9% of baseline). This effect was abolished in the Sevoflurane has been shown to precondition myocar presence of 5-hydroxy-decanoate (55 ؎ 14% of baseline) and dium in vivo in dogs4 and in isolated guinea pig heart,7 ؎ 8-cyclopentyl-1,3-dipropylxanthine (58 16% of baseline) but but its effects on ischemic–reperfused human myocar- was attenuated in the presence of HMR 1098 (73 ؎ 10% of baseline). dium remain unknown. Although two recent clinical Conclusions: In vitro, sevoflurane preconditions human myo- studies examined this issue in patients undergoing car- cardium against hypoxia through activation of adenosine diopulmonary bypass surgery, they have led to contra- triphosphate–sensitive potassium channels and stimulation of dictory results on postoperative cardiac troponin I peak adenosine A receptors. 1 serum concentration.13,14 Consequently, we performed an experimental study to examine the effect of sevoflu- THE beneficial effects of volatile anesthetic–induced pre- rane on isolated human myocardium challenged with 1–4 conditioning have been shown on infarct volume, simulated ischemia–reperfusion. In addition, because the mechanisms involved in sevoflurane-induced pre- conditioning have received less attention than those of This article is featured in “This Month in Anesthesiology.” other volatile anesthetics, the role of sarcolemmal KATP ᭛ Please see this issue of ANESTHESIOLOGY, page 5A. (sarcKATP) and mitochondrial KATP (mitKATP) channels and adenosine A1 receptors were assessed by use of selective antagonists. * Research fellow, Laboratory of Experimental Anesthesiology and Cellular Physiology, † Assistant Professor, Department of Anesthesiology, ‡ Assistant Pro- fessor, Department of Cardiac and Thoracic Surgery, § Professor of Cardiotho- racic Surgery, Department of Cardiac and Thoracic Surgery, ࿣Staff Scientist, Laboratory of Experimental Anesthesiology and Cellular Physiology, # Professor of Anesthesiology, Department of Anesthesiology, ** Professor of Anesthesiology, Materials and Methods Chairman, Director of the Laboratory of Experimental Anesthesiology and Cel- lular Physiology, Department of Anesthesiology. Experimental Conditions Received from the Laboratoire d’ Anesthésiologie Expérimentale et de Physi- After the approval of the local medical ethics commit- ologie Cellulaire, Equipe d’ Accueil (EA) 3212, Département d’ Anesthésie-Réani- tee and written informed consent had been obtained, mation Chirurgicale, Centre Hospitalier Universitaire Côte de Nacre, Caen, France. Submitted for publication July 25, 2002. Accepted for publication Feb- human right atrial trabeculae were obtained from pa- ruary 12, 2003. Supported in part by a grant from the Fondation pour la tients scheduled for routine coronary artery bypass sur- Recherche Médicale, Paris, France, and by the University of Caen, Caen, France. Address reprint requests to Dr. Hanouz: Département d’ Anesthésie-Réanima- gery or aortic valve replacement. All patients received tion, Centre Hospitalier Universitaire de Caen, Avenue Côte de Nacre, 14033 midazolam or propofol, sufentanil, etomidate, pancuro- Caen Cedex, France. Address electronic mail to: [email protected]. Individ- ual article reprints may be purchased through the Journal Web site, nium, and isoflurane. Patients with atrial dysrhythmia www.anesthesiology.org. and those taking oral hypoglycemic medications were Anesthesiology, V 99, No 1, Jul 2003 27 28 YVON ET AL. Table 1. Patient Demographic Data, Preoperative Drug Treatments, and Preoperative Left Ventricular Ejection Fraction Groups and Heart Disease Age, yr Preoperative Drug Treatments Ejection Fraction, % Control 64 Ϯ 10 ␤AB (5), ACE (2), ATZ (1), AMI (2), FUR (2), MOL (1), TNT (4) 62 Ϯ 7 AVR (n ϭ 4); CABG (n ϭ 7) PC 67 Ϯ 6 ␤AB (3), ACE (5), BZD (3), CA (3), KϩA (2), MOL (2), TNT (3) 70 Ϯ 9 AVR (n ϭ 3); CABG (n ϭ 3) Sevoflurane 1% 63 Ϯ 16 ␤AB (2), ACE (2), AMI (2), BZD (3), FUR (2), STA (4), TNT (3) 71 Ϯ 8 AVR (n ϭ 3); CABG (n ϭ 3) Sevoflurane 2% 67 Ϯ 6 ␤AB (4), ACE (4), BZD (2), MOL (3), STA (6) 67 Ϯ 11 AVR (n ϭ 3); CABG (n ϭ 5) Ϯ ␤ ␤ Ϯ Sevoflurane 3% 70 9 AB (6), 2A (2), ACE (5), BZD (2), STA (3), TNT (1) 71 10 AVR (n ϭ 4); CABG (n ϭ 3) ϩ Ϯ ␤ ␤ Ϯ Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/99/1/27/408853/0000542-200307000-00008.pdf by guest on 02 October 2021 Sevoflurane 2% 5-HD 61 15 AB (0), 2A (1), ACE (4), AMI (1), BZD (2), FUR (2), MOL (2), STA (2) 75 7 AVR (n ϭ 3); CABG (n ϭ 3) ϩ Ϯ ␤ ␤ Ϯ Sevoflurane 2% HMR 71 8 AB (6), 2A (2), ACE (3), AMI (2), ATZ (2), MOL (3), STA (4), TNT (4) 66 5 AVR (n ϭ 4); CABG (n ϭ 3) ϩ Ϯ ␤ ␤ Ϯ Sevoflurane 2% DPX 69 5 AB (0), 2A (2), ACE (3), AMI (1), ATZ (2), FUR (2), MOL (3), STA (3) 61 8 AVR (n ϭ 6); CABG (n ϭ 0) Control 5-HD 77 Ϯ 5 ␤AB (0), ACE (1), AMI (1), ATZ (2), BZD (1), FUR (2), MOL (2), STA (1) 73 Ϯ 12 AVR (n ϭ 2); CABG (n ϭ 2) Ϯ ␤ ␤ Ϯ Control HMR 67 9 AB (0), 2A (2), ACE (3), BZD (2), FUR (2) 73 3 AVR (n ϭ 2); CABG (n ϭ 2) Control DPX 66 Ϯ 14 ␤AB (1), ACE (3), BZD (1), FUR (1), STA (3), TNT (2) 70 Ϯ 7 AVR (n ϭ 2); CABG (n ϭ 2) Age and ejection fraction are expressed as mean Ϯ SD. The numbers in brackets after heart disease and drug abbreviations indicate the number of patients. Among the 69 trabeculae, 20 were obtained from 10 patients. When two trabeculae were obtained from one patient, they were never included in the same experimental group. ϭ ϭ ϭ ϭ ␤ ϭ ␤ ␤ ϭ ␤ ACE angiotensin-converting enzyme inhibitors; AMI amiodarone; ATZ acetazolamide; AVR aortic valve replacement; 2A 2-agonists; AB -adrenergic blocking drugs; BZD ϭ benzodiazepine; CA ϭ calcium channel antagonist; CABG ϭ coronary artery bypass graft; DPX ϭ 8-cyclopentyl-1,3-dipropylxanthine; EF ϭ left ventricular ejection fraction; FUR ϭ furosemide; KϩA ϭ potassium channel agonist; 5-HD ϭ 5-hydroxydecanoate; HMR ϭ HMR 1098; MOL ϭ molsidomine; PC ϭ hypoxic preconditioning; STA ϭ statin. excluded from the study. Patients’ demographic data, stored on a Writable Compact Disc for analysis (MacLab, preoperative drug treatment, and preoperative left ven- AD Instrument, Sydney, Australia). tricular ejection fraction are reported in table 1. The At the end of each experiment, the length and weight right atrial appendage was obtained during cannulation of the muscle were measured. The muscle cross-sec- for cardiopulmonary bypass as described previously.6 tional area was calculated from its weight and length Trabeculae were suspended vertically between an iso- assuming a cylindrical shape and a density of 1. To avoid metric force transducer (UC3, Gould, Cleveland, OH) and a core hypoxia, trabeculae included in the study should stationary stainless steel clip in a 200-ml jacketed reservoir have a cross-sectional area less than 1.0 mm2, a force of filled with Tyrode’s modified solution, prepared daily, con- contraction normalized per cross-sectional area (FoC) 2 taining (mM) 120 NaCl, 3.5 KCl, 1.1 MgCl2, 1.8 NaH2PO4, greater than 5.0 mN/mm , and a ratio of resting force to 25.7 NaHCO3, 2.0 CaCl2, and 5.5 glucose.
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