We thank Drs. Xia and Irwin for their interest in our study on the role of β-adrenergic signaling in anesthetic postconditioning1and in the accompanying editorial view.2We agree with Drs. Xia and Irwin that, besides their energy-sparing effect, several alternative mechanisms of β blockers might be responsible for their infarct size–reducing capacity. Apart from their effect on the interaction between β receptor activation and reactive oxygen species production3and scavenging,4β blockers can inhibit calcium/calmodulin -dependent protein kinase II5and phospholipase A,6exert membrane stabilizing effects,7and may even have direct effects on mitochondrial electron transport and reactive oxygen species production.8The role of alternative mechanisms is certainly supported by the finding that infarct size reduction by β blockade is independent of heart rate, the main determinant of myocardial oxygen consumption.9It is entirely conceivable that the combination of different cardioprotective principles at different time points during reperfusion might provide additive protective effects. In this context, it is of interest that calcium/calmodulin -dependent protein kinase II is necessary for desflurane-induced postconditioning, whereas prolonged postischemic calcium/calmodulin -dependent protein kinase II blockade might attenuate adverse effects of ischemia/reperfusion injury, including remodeling.10Thus, it might be reasonable to apply anesthetic postconditioning at the onset of reperfusion and to initiate β blockade later during reperfusion. However, further basic research and clinical studies will be necessary to determine an optimized cardioprotective approach and to identify the possible clinical consequences of these experimental findings.

The rabbits used in this study were between 8 and 12 weeks of age and weighed between 2.5 and 3.0 kg. Although cardioprotection by ischemic11and pharmacological12preconditioning can be attenuated or lost in senescent hearts, there is some evidence of preserved ischemic postconditioning in the aged myocardium.13Thus, the impact of aging on the cardioprotective effects of β blockade, anesthetic postconditioning and their interaction with reactive oxygen species needs to be determined in future studies.

*Klinikum der Bayerischen Julius-Maximilians-Universität, Würzburg, Germany. lange_m@klinik.uni-wuerzburg.de

Lange M, Redel A, Lotz C, Smul TM, Blomeyer C, Frank A, Stumpner J, Roewer N, Kehl F: Desflurane-induced postconditioning is mediated by beta-adrenergic signaling: role of beta 1- and beta 2-adrenergic receptors, protein kinase A, and calcium/calmodulin-dependent protein kinase II. Anesthesiology 2009; 110:516–28
Riess ML: The rocky road from bench to bedside: Beta-blockers and anesthetic postconditioning. Anesthesiology 2009; 110:451–2
Moniri NH, Daaka Y: Agonist-stimulated reactive oxygen species formation regulates beta2-adrenergic receptor signal transduction. Biochem Pharmacol 2007; 74:64–73
Srivastava S, Chandrasekar B, Gu Y, Luo J, Hamid T, Hill BG, Prabhu SD: Downregulation of CuZn-superoxide dismutase contributes to beta-adrenergic receptor-mediated oxidative stress in the heart. Cardiovasc Res 2007; 74:445–55
Lange M, Smul TM, Redel A, Lotz C, Jazbutyte V, Schnupp V, Roewer N, Kehl F: Differential role of calcium/calmodulin-dependent protein kinase II in desflurane-induced preconditioning and cardioprotection by metoprolol: Metoprolol blocks desflurane-induced preconditioning. Anesthesiology 2008; 109:72–80
Trotz M, Jellison EJ, Hostetler KY: Propranolol inhibition of the neural phospholipases A of rat heart mitochondria, sarcoplasmatic reticulum and cytosol. Biochem Pharmacol 1987; 36:4251–6
Boucher M, Chapuy E, Duchêne-Marullaz P: Membrane stabilizing activity and β-adrenoceptor antagonist-induced bradycardia in conscious dogs. Eur J Pharmacol 1992; 211:343–9
Kametani R, Miura T, Harada N, Shibuya M, Wang R, Tan H, Fukagawa Y, Kawamura S, Matsuzaki M: Carvedilol inhibits mitochondrial oxygen consumption and superoxide production during calcium overload in isolated heart mitochondria. Circ J 2006; 70:321–6
Warltier DC, Gross GJ, Jesmok GJ, Brooks HL, Hardman HF: Protection of ischemic myocardium: Comparison of effects of propranolol, bevantolol and N-dimethyl propranolol on infarct size following coronary artery occlusion in anesthetized dogs. Cardiology 1980; 66:133–46
Backs J, Backs T, Neef S, Kreusser MM, Lehmann LH, Patrick DM, Grueter CE, Qi X, Richardson JA, Hill JA, Katus HA, Bassel-Duby R, Maier LS, Olson EN: The delta isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload. Proc Natl Acad Sci USA 2009; 106:2342–7
Fenton RA, Dickson EW, Meyer TE, Dobson JG: Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol 2000; 32:1371–5
Sniecinski R, Liu H: Reduced efficacy of volatile anesthetic preconditioning with advanced age in isolated rat myocardium. Anesthesiology 2004; 100:589–97
Lauzier B, Delemasure S, Debin R, Collin B, Sicard P, Acar N, Bretillon L, Joffre C, Bron A, Creuzot-Garcher C, Vergely C, Rochette L: Beneficial effects of myocardial postconditioning are associated with reduced oxidative stress in a senescent mouse model. Transplantation 2008; 85:1802–8