Desflurane-induced Postconditioning Is Mediated by β-Adrenergic SignalingRole of β1- and β2-Adrenergic Receptors, Protein Kinase A, and Calcium/Calmodulin-dependent Protein Kinase II

Background: Anesthetic preconditioning is mediated by adrenergic signaling. This study was designed to elucidate the role of -adrenergic signaling in desflurane-induced postconditioning. Methods: Pentobarbital-anesthetized New Zealand White rabbits were subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion and were randomly assigned to receive vehicle (control), 1.0 minimum alveolar concentration of desflurane, esmolol (30 mg kg 1 h ) for the initial 30 min of reperfusion or throughout reperfusion, the 2-adrenergic receptor blocker ICI 118,551 (0.2 mg/kg), the protein kinase A inhibitor H-89 (250 g/kg), or the calcium/calmodulin-dependent protein kinase II inhibitor KN-93 (300 g/kg) in the presence or absence of desflurane. Protein expression of protein kinase B, calcium/calmodulin-dependent protein kinase II, and phospholamban was measured by Western immunoblotting. Myocardial infarct size was assessed by triphenyltetrazolium staining. Results: Infarct size was 57 5% in control. Desflurane postconditioning reduced infarct size to 36 5%. Esmolol given during the initial 30 min of reperfusion had no effect on infarct size (54 4%) but blocked desflurane-induced postconditioning (58 5%), whereas esmolol administered throughout reperfusion reduced infarct size in the absence or presence of desflurane to 42 6% and 41 7%, respectively. ICI 118,551 and KN-93 did not affect infarct size (62 4% and 62 6%, respectively) but abolished desflurane-induced postconditioning (57 5% and 64 3%, respectively). H-89 decreased infarct size in the absence (36 5%) or presence (33 5%) of desflurane. Conclusions: Desflurane-induced postconditioning is mediated by -adrenergic signaling. However, -adrenergic signaling displays a differential role in cardioprotection during reperfusion. REPERFUSION of the myocardium after sustained ischemia induces myocardial cell necrosis and apoptosis, resulting in increased infarct size despite the restoration of coronary blood flow. Intracellular mechanisms underlying this so-called reperfusion injury presumably include increased levels of reactive oxygen species, Ca overload, rapid restoration of physiologic pH, and inflammatory processes resulting in opening of the mitochondrial permeability transition pore (mPTP). Volatile anesthetics confer marked protection against myocardial reperfusion injury when administered during early reperfusion. This phenomenon was termed anesthetic-induced postconditioning and might broaden the perspective for the treatment of patients with perioperative myocardial ischemia and infarction. The mechanisms underlying the cardioprotective effects of anestheticinduced postconditioning have not completely been clarified. However, there is substantial evidence that anesthetic-induced preconditioning and postconditioning share similar signal transduction pathways and that prevention of intracellular Ca accumulation might be a primary target of volatile anesthetics in the prevention of the sequelae of myocardial reperfusion injury. Among other G protein–coupled receptors, -adrenergic receptors play a pivotal role in anesthetic-induced preconditioning. However, the role of the -adrenergic pathway in anesthetic-induced postconditioning is unclear. The current study was designed to elucidate the role of -adrenergic signaling in desflurane-induced postconditioning. Therefore, the hypothesis was tested that selective blockade of 1and 2-adrenergic receptors and of the intracellular -adrenergic pathway components protein kinase A (PKA) and Ca /calmodulin-dependent protein kinase II (CaMK II) abolishes desflurane-induced postconditioning. Furthermore, we tested the hypothesis that the prolonged blockade of 1-adrenergic receptors throughout the complete reperfusion period after experimental ischemia reduces myocardial infarct size.