Obligatory role of inducible nitric oxide synthase in ischemic preconditioning.
Sublethal insults can induce a transient tolerance toward subsequent lethal ischemia, a phenomenon termed ischemic preconditioning (IPC). In the myocardium, nitric oxide derived from 'inducible' nitric oxide synthase (iNOS or NOS II) plays a critical role in the expression of IPC produced by sublethal ischemia. Here, we investigated whether iNOS is involved in IPC in brain. Ischemic preconditioning was produced in mice by three episodes of 1-min bilateral common carotid artery (BCCA) occlusion, each followed by 5 mins of reperfusion. After 24 h, mice underwent middle cerebral artery (MCA) occlusion for 20 mins. Intraischemic cerebral blood flow was monitored during both in BCCA and MCA occlusion (MCAO) by laser-Doppler flowmetry. Mice were killed 3 days after MCAO, and infarct volume was determined in thionine-stained sections. Infarct volume was significantly reduced 24 h after IPC (70%; P<0.05). Treatment with the iNOS inhibitor aminoguanidine (400 mg/kg), abolished the IPC-induced protection. Furthermore, IPC failed to induce ischemic tolerance in iNOS-null mice. In wild-type mice, IPC increased the resistance to Ca(2+)-mediated depolarization in isolated brain mitochondria. However, in iNOS-null mice IPC failed to induce such resistance. We conclude that iNOS is required for the full expression of IPC and that such effect is coupled to an increased resistance of mitochondria to injury. Thus, iNOS-derived nitric oxide, in addition to its deleterious effects on the late stages of ischemic brain damage, can also be beneficial by promoting ischemic tolerance through signaling, ultimately resulting in mitochondrial protection.
Cho
Sunghee
S
Division of Neurobiology, Department of Neurology and Neuroscience, Weill Cornell Medical College, New York, New York 10021, USA.
Park
Eun-Mi
EM
Zhou
Ping
P
Frys
Kelly
K
Ross
M Elizabeth
ME
Iadecola
Costantino
C
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology; D002118:Calcium / Q000494:pharmacology; D016893:Carotid Stenosis / Q000503:physiopathology; D006146:Guanidines / Q000494:pharmacology; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D019194:Ischemic Preconditioning; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II
D006146:Guanidines; D008070:Lipopolysaccharides; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C004479:pimagedine; D002118:Calcium