Hypoxia induces late preconditioning in the rat heart in vivo.
BACKGROUND
Although hypoxic late preconditioning (LPC) limits ischemia-reperfusion injury in vitro, its cardioprotective effect is not established in vivo.


METHODS
In part 1, rats were exposed to 4 h of hypoxia (16%, 12%, 8% oxygen) before 24 h of reoxygenation. In part 2, normoxic rats received early preconditioning with sevoflurane (1 minimum alveolar concentration [MAC] for 3 × 5 min), continuous administration of 1 MAC sevoflurane, or 11 mg · kg · h propofol. Thereafter, all rats underwent 25 min of regional myocardial ischemia and 120 min of reperfusion. After reperfusion, hearts were excised for infarct staining. The expression of protein kinase C (PKC)α and PKCε was assessed by Western blot analysis and the expression of heme oxygenase-1 and vascular endothelial growth factor by reverse transcriptase polymerase chain reaction.


RESULTS
In normoxic control rats, infarct size was 62 ± 6% of the area at risk. Hypoxic LPC reduced infarct size (LPC16: 36 ± 11%, LPC12: 38 ± 10%, LPC8: 39 ± 11%; each P < 0.001) to approximately the same magnitude as sevoflurane-preconditioning (40 ± 8%; P < 0.001). Combined LPC16 and sevoflurane preconditioning was not superior to either substance alone. Continuous sevoflurane or propofol was not protective. The PKC inhibitor calphostin C abolished the cardioprotective effects of LPC16. PKCε, but not PKCα, expression was increased 6 and 28 h after hypoxic LPC. Heme oxygenase-1 and vascular endothelial growth factor were transiently up-regulated after 6 h.


CONCLUSIONS
Hypoxic LPC at 8%, 12%, and 16% oxygen reduces infarct size in the rat heart in vivo. This effect is as powerful as sevoflurane-preconditioning. PKCε is a key player in mediating hypoxic LPC.
Department of Anesthesiology, University Hospital of Heidelberg, Heidelberg, Germany.
Marc M
MM
Berger
Ragnar
R
Huhn
Gezina T
GT
Oei
André
A
Heinen
Andreas
A
Winzer
Inge
I
Bauer
Benedikt
B
Preckel
Nina C
NC
Weber
Wolfgang
W
Schlack
Markus W
MW
Hollmann
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000502:physiology; D000860:Hypoxia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology; D019157:Ischemic Preconditioning, Myocardial; D008738:Methyl Ethers / Q000494:pharmacology; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D009281:Naphthalenes / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077149:Sevoflurane; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology
D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008738:Methyl Ethers; D009281:Naphthalenes; D042461:Vascular Endothelial Growth Factor A; D000077149:Sevoflurane; D006419:Heme Oxygenase (Decyclizing); D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; C058819:calphostin C; D010100:Oxygen