Isoflurane Produces Delayed Preconditioning Against Myocardial Ischemia And Reperfusion Injury-Role Of Inducible Nitric Oxide Synthase

Objective Volatile anesthetics preconditioning have been show to produce early phase protection against myocardial ischemia and reperfusion injury. Whether volatile anesthetics produce delayed preconditioning remains unclear. Compared with early phase protection, delayed preconditioning not only limit the myocardial infarct size, but also mitigates myocardial stunning and against arrhythmia. To investigate whether isoflurane causes delayed preconditioning against myocardial infarction and, further, inducible nitric oxide synthase (iNOS) mediates this beneficial effect were examined in the current study.Methods Thirty-six conscious rabbits undergoing 30min of left anterior descending coronary artery (LAD) occlusion followed by 3h of reperfusion were randomly assigned to five groups. (1) The control group: the rabbits received 0.9% intravenous saline 2ml·kg^-1 24h before LAD occlusion and reperfusion; (2) the isoflurane preconditioning group: the rabbits received isoflurane (1.0 minimum alveolar concentration, MAC) continuously 2h and underwent LAD occlusion and reperfusion after 24h; (3) the 1400Wa group: the rabbits received the selective iNOS inhibitor 1400W 0.5mg·kg^-1 24h before LAD occlusion and reperfusion; (4) the 1400Wb group: the rabbits received 1400W 0.5mg·kg^-1 30min before LAD occlusion and reperfusion; (5) the isoflurane + 1400W group: the rabbits received 1.0 MAC isoflurane, and 24h latter, received 1400W 0.5mg·kg-1 30min before LAD occlusion and reperfusion. Rabbits were then instrumented for measurement of hemodynamics during LAD occlusion and reperfusion. Tissue samples were acquired at the end of reperfusion. Myocardial infarct size was measured using triphenyltetrazolium (TTC) staining. RT-PCR and Immunohistochemistry to examine iNOS expression were performed in the control group and isoflurane group rabbit hearts.Results Coronary artery occlusion and reperfusion produced similar decreases in mean arterial pressure (MAP) and rate-pressure product (RPP) in each group. No differences in hemodynamics were observed between groups (P>0.05). No differences in the rabbit weight, left ventricular weight, and left ventricular ischemia size were observed between groups (P>0.05). Isoflurane produced a significant reduction in infarct size (23.98±2.65% ) as compared with control (42.14±3.06%,P <0.01). No differences in myocardial infarct size were observed in the control group, the 1400Wa group (43.68±4.39%), the 1400Wb group (43.01±3.69%), and the isoflurane + 1400W group (42.12±2.60%, P>0.05). Isoflurane produced a significant reduction in infarct size as compared with isoflurane + 1400W group (P <0.01). RT-PCR and immunohistochemistry manifest that isoflurane significantly increased iNOS expression as compared with control.Conclusions The results indicate that the volatile anesthetic isflurane produces a delayed preconditioning against myocardial ischemia and reperfusion injury. Furthermore, iNOS maybe an important mediator of isoflurane-induced delayed preconditioning.