Cardioprotection via activation of protein kinase C-delta depends on modulation of the reverse mode of the Na+/Ca2+ exchanger.
BACKGROUND
Pretreatment with the volatile anesthetic sevoflurane protects cardiomyocytes against subsequent ischemic episodes caused by a protein kinase C (PKC)-delta mediated preconditioning effect. Sevoflurane directly modulates cardiac Ca2+ handling, and because Ca2+ also serves as a mediator in other cardioprotective signaling pathways, possible involvement of the Na+/Ca2+ exchanger (NCX) in relation with PKC-delta in sevoflurane-induced cardioprotection was investigated.


RESULTS
Isolated right ventricular rat trabeculae were subjected to simulated ischemia and reperfusion (SI/R), consisting of superfusion with hypoxic glucose-free buffer for 40 minutes after rigor development, followed by reperfusion with normoxic glucose containing buffer. Preconditioning with sevoflurane before SI/R improved isometric force development during contractile recovery at 60 minutes after the end of hypoxic superfusion (83+/-7% [sevo] versus 57+/-2% [SI/R];n=8; P<0.01). Inhibition of the reverse mode of the NCX by KB-R7943 (10 micromol/L) or SEA0400 (1 micromol/L) during preconditioning attenuated the protective effect of sevoflurane. KB-R7943 and SEA0400 did not have intrinsic effects on the contractile recovery. Furthermore, inhibition of the NCX in trabeculae exposed to sevoflurane reduced sevoflurane-induced PKC-delta translocation toward the sarcolemma, as demonstrated by digital imaging fluorescent microscopy. The degree of PKC-delta phosphorylation at serine643 as determined by western blot analysis was not affected by sevoflurane.


CONCLUSIONS
Sevoflurane-induced cardioprotection depends on the NCX preceding PKC-delta translocation presumably via increased NCX-mediated Ca2+ influx. This may suggest that increased myocardial Ca2+ load triggers the cardioprotective signaling cascade elicited by volatile anesthetic agents similar to other modes of preconditioning.
Bouwman
R Arthur
RA
Department of Anesthesiology, VU University Medical Center, de Boelelaan 1118, PO Box 7057, 1007 MB Amsterdam, Netherlands. a.bouwman@vumc.nl
Salic
Kanita
K
Padding
F Gieneke
FG
Eringa
Etto C
EC
van Beek-Harmsen
Brechje J
BJ
Matsuda
Toshio
T
Baba
Akemichi
A
Musters
René J P
RJ
Paulus
Walter J
WJ
de Lange
Jaap J
JJ
Boer
Christa
C
D018685:Anesthetics, Inhalation / Q000494:pharmacology / Q000627:therapeutic use*; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004789:Enzyme Activation; D005947:Glucose / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D008297:Male; D008738:Methyl Ethers / Q000494:pharmacology / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000517:prevention & control*; D010647:Phenyl Ethers / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000032:analysis; D051745:Protein Kinase C-delta / Q000502:physiology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012508:Sarcolemma / Q000201:enzymology; D000077149:Sevoflurane; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000502:physiology*; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D018685:Anesthetics, Inhalation; D000814:Aniline Compounds; D002316:Cardiotonic Agents; D008738:Methyl Ethers; D010647:Phenyl Ethers; C430918:SEA 0400; D019831:Sodium-Calcium Exchanger; D010768:Phosphoserine; D000077149:Sevoflurane; D051745:Protein Kinase C-delta; D013890:Thiourea; D005947:Glucose