Differential role of calcium/calmodulin-dependent protein kinase II in desflurane-induced preconditioning and cardioprotection by metoprolol: metoprolol blocks desflurane-induced preconditioning.
BACKGROUND
Anesthetic preconditioning is mediated by beta- adrenergic signaling. This study tested the hypotheses that desflurane-induced preconditioning is dose-dependently blocked by metoprolol and mediated by calcium/calmodulin-dependent protein kinase II (CaMK II).


METHODS
Pentobarbital-anesthetized New Zealand White rabbits were instrumented for measurement of systemic hemodynamics and subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion. Rabbits were assigned to receive vehicle (control), 0.2, 1.0, 1.75, or 2.5 mg/kg metoprolol for 30 min, or the CaMK II inhibitor KN-93 in the absence or presence of 1.0 minimum alveolar concentration desflurane. Protein expression of CaMK II, phospholamban, and phospho-phospholamban was measured by Western blotting. Myocardial infarct size and area at risk were measured with triphenyltetrazolium staining and patent blue, respectively.


RESULTS
Baseline hemodynamics were not different among groups. Infarct size was 60 +/- 3% in control and significantly (* P < 0.05) decreased to 33 +/- 2%* by desflurane. The CaMK II inhibitor KN-93 did not affect infarct size (55 +/- 4%) but blocked desflurane-induced preconditioning (57 +/- 3%). Metoprolol at 0.2 and 1.0 mg/kg had no effect on infarct size (55 +/- 3% and 53 +/-3%), whereas metoprolol at 1.75 and 2.5 mg/kg reduced infarct size to 48 +/- 4%* and 39 +/- 5%*, respectively. Desflurane-induced preconditioning was attenuated by metoprolol at 0.2 mg/kg, leading to an infarct size of 46 +/- 5%*, and was completely abolished by metoprolol at 1.0, 1.75, and 2.5 mg/kg, resulting in infarct sizes of 51 +/- 3%, 52 +/- 3%, and 55 +/- 3%, respectively.


CONCLUSIONS
Desflurane-induced preconditioning is dose-dependently blocked by metoprolol and mediated by CaMK II.
Lange
Markus
M
Department of Anesthesiology and Critical Care, Würzburg, Germany.
Smul
Thorsten M
TM
Redel
Andreas
A
Lotz
Christopher
C
Jazbutyte
Virginija
V
Schnupp
Verena
V
Roewer
Norbert
N
Kehl
Franz
F
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000077335:Desflurane; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D007530:Isoflurane / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008790:Metoprolol / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011817:Rabbits
D002316:Cardiotonic Agents; D000077335:Desflurane; D007530:Isoflurane; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D008790:Metoprolol