title: Hyperglycemia inhibits anesthetic-induced postconditioning in the rabbit heart via modulation of phosphatidylinositol-3-kinase/Akt and endothelial nitric oxide synthase signaling.
abstract: Hyperglycemia is known to inhibit ischemic and anesthetic preconditioning. We tested whether hyperglycemia inhibits anesthetic postconditioning with isoflurane and whether this effect is mediated via phosphatidylinositol-3-kinase/Akt and nitric oxide signaling. New Zealand white rabbits subjected to 40 minutes of myocardial ischemia, followed by 3 hours of reperfusion were assigned to the following groups: ischemia and reperfusion (I/R), isoflurane (1 minimal alveolar concentration) postconditioning, and isoflurane postconditioning with hyperglycemia (15% dextrose in water infusion). A control group of hyperglycemia + I/R was also included. Levels of MB fraction of creatine kinase (CK-MB) were assessed as an indicator of myocardial damage, and infarct size was evaluated. Akt, iNOS, and endothelial nitric oxide synthase (eNOS) expression was assessed by immunoblotting. Determination of nitrite and nitrate levels in the myocardium was also performed. Isoflurane postconditioning reduced infarct size compared with the I/R group: 25% +/- 4% versus 49% +/- 5% (P < 0.01). CK-MB concentrations in the postconditioned animals (124% +/- 14% above baseline levels) were lower than those in the I/R group (236% +/- 9% above baseline levels; P < 0.01). Hyperglycemia inhibited the cardioprotective effect of isoflurane: myocardial infarction size was 46% +/- 4% and CK-MB increased to 241% +/- 11% above baseline. Phosphorylated Akt and eNOS protein expression increased after isoflurane postconditioning compared with the I/R group. These effects were also inhibited by hyperglycemia. iNOS expression, however, did not change significantly within the various experimental groups. There were increased tissue levels of nitrite and nitrate (NO(x)) in the postconditioning group. This was also blocked by hyperglycemia. Our results suggest that hyperglycemia inhibits cardioprotection provided by isoflurane postconditioning. This effect seems to be mediated via modulation Akt and eNOS.
authors.affiliation: Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, USA. jr5ef@virginia.edu
authors.forename: Jacob
authors.initials: J
authors.lastname: Raphael
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Gozal
authors.forename: Nachum
authors.initials: N
authors.lastname: Navot
authors.forename: Zhiyi
authors.initials: Z
authors.lastname: Zuo
mesh_terms: D000777:Anesthetics / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000502:physiology; D052279:Creatine Kinase, MB Form / Q000097:blood; D005947:Glucose / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006943:Hyperglycemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D007530:Isoflurane / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009566:Nitrates / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000777:Anesthetics; D001786:Blood Glucose; D009566:Nitrates; D009573:Nitrites; D007530:Isoflurane; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D052279:Creatine Kinase, MB Form; D005947:Glucose