Nitric oxide triggers delayed anesthetic preconditioning-induced cardiac protection via activation of nuclear factor-kappaB and upregulation of inducible nitric oxide synthase.
Nitric oxide (NO) plays a pivotal role both in triggering and mediating delayed protection against myocardial I/R injury during anesthetic-induced preconditioning (APC). However, the signaling mechanisms that underlie this phenomenon remain unclear. Using isoflurane as a representative anesthetic, the present study tested the hypothesis that NO released after anesthetic-induced preconditioning initiates delayed cardioprotection via activation of nuclear transcription factor-kappaB (NF-kappaB), leading to myocardial adaptation by upregulation of iNOS and increase in production of NO. Sprague-Dawley rats that received open-chest surgery under pentobarbital anesthesia were subject to 30 min of left coronary artery occlusion, followed by 120 min of reperfusion. Exposure to 60 min of 2.1% isoflurane inhalation with oxygen 24 h before ischemia significantly reduced I/R-induced myocardial infarct size that was associated with overexpression of iNOS protein and increased NO content in the heart. These protective effects were abolished by pretreatment with a NOS inhibitor, N-nitro-L-arginine methyl ester, an NF-kappaB blocker, diethyldithiocarbamate, before isoflurane, or a selective iNOS inhibitor, S-methylisothiourea, before left coronary artery occlusion. Isoflurane exposure also evoked a robust increase in myocardial NO content, followed by nucleus-bound translocation of p65 or p50 subunit of NF-kappaB and increase in NF-kappaB DNA-binding activity in heart tissues. These molecular events after isoflurane exposure were blocked by pretreatment with N-nitro-L-arginine methyl ester. We conclude that NO generated immediately after isoflurane exposure triggers downstream activation of NF-kappaB, resulting in subsequent upregulation of iNOS expression and NO synthesis that mediate APC-induced delayed cardioprotection.
Chen
Chen Hsiu
CH
Department of Anesthesiology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China.
Chuang
Jiin Haur
JH
Liu
Kang
K
Chan
Julie Y H
JY
D018685:Anesthetics, Inhalation / Q000494:pharmacology; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D006321:Heart / Q000187:drug effects*; D019157:Ischemic Preconditioning, Myocardial; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis*; D011486:Protein C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury; D015854:Up-Regulation
D018685:Anesthetics, Inhalation; D016328:NF-kappa B; D011486:Protein C; D007530:Isoflurane; D052247:Nitric Oxide Synthase Type II