Correspondence  |   February 2012
Potential Synergy of Antioxidant N  -Acetylcysteine and Insulin in Restoring Sevoflurane Postconditioning Cardioprotection in Diabetes
Author Affiliations & Notes
  • Zhengyuan Xia, M.D., Ph.D.
  • *Sun Yat-Sen University, Guangzhou, China, and University of Hong Kong, Hong Kong, China.
Article Information
Correspondence   |   February 2012
Potential Synergy of Antioxidant N  -Acetylcysteine and Insulin in Restoring Sevoflurane Postconditioning Cardioprotection in Diabetes
Anesthesiology 2 2012, Vol.116, 488-489. doi:10.1097/ALN.0b013e31823fd063
Anesthesiology 2 2012, Vol.116, 488-489. doi:10.1097/ALN.0b013e31823fd063
To the Editor: 
We read with great interest the article recently published by Drenger et al.  1 The authors demonstrated in their study that in rats with streptozotocin-induced type 1 diabetes, the cardioprotective effects of either ischemic postconditioning or the volatile anesthetic sevoflurane postconditioning were lost and that short duration (48 h) of insulin treatment to “normalize” glucose concentration failed to restore the sensitivity of the hearts from early-stage (4–5 weeks after streptozotocin injection) diabetic rats to postconditioning. Of interest, the author showed that insulin administration before ischemia–reperfusion event in the model of diabetic rats exacerbated postischemic myocardial infarction than without insulin therapy. Accordingly, they suggested that caution should be taken not to add insulin before the planned ischemic period.
However, we cannot completely agree with the authors' suggestion. Hyperglycemia-induced increase in mitochondrial superoxide anion production has been shown to represent a key mechanism of hyperglycemic damage.2 Results of prospective, randomized clinical trails have shown that aggressive control of blood glucose achieved by intensive insulin therapy (target glucose concentration of 80–110 mg/dl) significantly decreased mortality in critically ill patients3 whereas poor or marginal intraoperative blood glucose control was associated with a worse hospital outcome after cardiac surgery in diabetic patients.4 In the study by Drenger et al.  ,1 the blood glucose concentrations in the diabetic insulin-treated rats receiving postconditioning (mean 126 ± 10 mg/dl and 131 ± 9 mg/dl, respectively, in the ischemic and sevoflurane postconditioning groups) were at most marginally controlled. Given the big SDs and small sample size in these groups (n = 6 per group), the glucose concentration in a considerable number of rats in these groups could have been hyperglycemic rather than normoglycemic (defined by the authors as lower than 135 mg/dl). Therefore, it seems reasonable for us to postulate that it was the insufficient acute insulin therapy but not the administration of insulin before ischemia that resulted in the exacerbation of postischemic infarct size seen in the study of Drenger et al.  1 The exact mechanism for this phenomenon is unclear. One possible explanation, in addition to those postulated by the authors, could be that insufficient acute insulin therapy may have abrogated chronic hyperglycemia-induced compensatory increases of myocardial endogenous antioxidant enzymes such as superoxide dismutase enzyme production and activity5 and rendered the diabetic hearts more vulnerable to oxidative damage after ischemia–reperfusion.
We want to congratulate the authors for their in-depth mechanistic explorations, which showed that phosphorylation of the signal transducer and activator of transcription 3 (STAT3), a key mediator in postconditioning-mediated cardioprotection,6 was reduced in various parts of the diabetic myocardium (which may contribute to the diabetes-related loss of ischemic and sevoflurane postconditioning). This is an important finding that suggests that enhancing myocardial p-STAT3 may restore postconditioning cardioprotection in diabetes. Indeed, in a similar model of streptozotocin-induced diabetic rats, we found that myocardial p-STAT3 was significantly reduced in rats 4–5 weeks after streptozotocin injection and that treatment with the antioxidant N  -acetylcysteine enhanced myocardial p-STAT3 and attenuated postischemic myocardial infraction.7 Furthermore, we showed in the same model of diabetic rats that N  -acetylcysteine treatment restored the responsiveness of diabetic hearts to anesthetic preconditioning with remifentanil.8 The findings by Drenger et al.  1 and us7,8 together with the findings of Kehl et al.  , who showed that N  -acetylcysteine can restore isoflurane-induced preconditioning against myocardial infarction during hyperglycemia,9 lead us to postulate that N  -acetylcysteine may restore sevoflurane postconditioning in diabetes, possibly by enhancing myocardial p-STAT3. Given that short duration of N  -acetylcysteine treatment did not reduce plasma glucose concentration in diabetic rats,7 we further postulate that N  -acetylcysteine and insulin may potentially confer synergy in restoring sevoflurane postconditioning cardioprotection in diabetes.
In summary, we agree with the authors that a longer period of insulin therapy might have a different effect on restoring postconditioning in diabetes. However, we propose that prompt insulin administration, in particular sufficient insulin therapy when added before the planned ischemic period, should also confer beneficial effects, especially when it is used in conjunction with other therapy such as antioxidants, although this hypothesis need to be further tested.
Drenger B, Ostrovsky IA, Barak M, Nechemia-Arbely Y, Ziv E, Axelrod JH: Diabetes blockade of sevoflurane postconditioning is not restored by insulin in the rat heart: Phosphorylated signal transducer and activator of transcription 3- and phosphatidylinositol 3-kinase-mediated inhibition. ANESTHESIOLOGY 2011; 114:1364–72
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 2000; 404:787–90
van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R: Intensive insulin therapy in the critically ill patients. N Engl J Med 2001; 345:1359–67
Ouattara A, Lecomte P, Le Manach Y, Landi M, Jacqueminet S, Platonov I, Bonnet N, Riou B, Coriat P: Poor intraoperative blood glucose control is associated with a worsened hospital outcome after cardiac surgery in diabetic patients. ANESTHESIOLOGY 2005; 103:687–94
Xia Z, Guo Z, Nagareddy PR, Yuen V, Yeung E, McNeill JH: Antioxidant N-acetylcysteine restores myocardial Mn-SOD activity and attenuates myocardial dysfunction in diabetic rats. Eur J Pharmacol 2006; 544:118–25
Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R: Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 2008; 102:131–5
Wang T, Qiao S, Lei S, Liu Y, Ng KF, Xu A, Lam KS, Irwin MG, Xia Z: N-acetylcysteine and allopurinol synergistically enhance cardiac adiponectin content and reduce myocardial reperfusion injury in diabetic rats. PLoS ONE 2011; 6:e23967
Xia Z, Qiao S, Liu Y, Wang TT, Mao X, Liu HM, Wong GT, Irwin MG: Antioxidant N-acetylcysteine restores remifentanil preconditioning cardioprotection in rats with streptozotocin-induced diabetes (abstract). Anesth Analg 2011; 112:S-31
Kehl F, Krolikowski JG, Weihrauch D, Pagel PS, Warltier DC, Kersten JR: N-acetylcysteine restores isoflurane-induced preconditioning against myocardial infarction during hyperglycemia. ANESTHESIOLOGY 2003; 98:1384–90