(Stroke. 1996;27:1373-1380.)
© 1996 American Heart Association, Inc.
Articles |
Inducible Nitric Oxide Synthase Gene Expression in Vascular Cells After Transient Focal Cerebral Ischemia
the Laboratory of Cerebrovascular Biology and Stroke, Department of Neurology, and the Division of Neuropathology, Departments of Neurology and Laboratory Medicine and Pathology (H.B.C.), University of Minnesota Medical School (Minneapolis).
Correspondence to C. Iadecola, MD, Department of Neurology, University of Minnesota Medical School, Box 295 UMHC, 420 Delaware St SE, Minneapolis, MN 55455. E-mail iadec001@maroon.tc.umn.edu.
Background and Purpose We investigated whether inducible nitric oxide synthase (iNOS) is expressed after transient cerebral ischemia and, if so, we sought to define the temporal profile and cellular localization of the expression and the role of iNOS in the mechanism of ischemic brain injury.
Methods The middle cerebral artery in rats was occluded for 2 hours by an intraluminal filament. The occurrence of transient ischemia and reperfusion was confirmed by laser-Doppler flowmetry (n=5). iNOS message in the ischemic neocortex was determined by reverse-transcription polymerase chain reaction. iNOS enzymatic activity was assessed by citrulline assay. The cellular localization of iNOS expression was determined by immunohistochemistry.
Results iNOS mRNA was maximally expressed in postischemic brain at 12 hours and was not present at 4 days (n=3 per time point). iNOS mRNA was not observed in the contralateral cerebral cortex. iNOS enzymatic activity developed in the postischemic brain between 12 and 24 hours (P<.05) and subsided at 4 days (n=4 to 8 per time point). iNOS immunoreactivity in the ischemic region was restricted to the wall of capillaries and of larger blood vessels at 12 to 24 hours. In regions of early necrosis, inflammatory cells were iNOS positive. Treatment with the iNOS inhibitor aminoguanidine (n=5; 100 mg/kg IP, BID for 4 days), starting 6 hours after ischemia, reduced infarct size in neocortex by 36±7% in comparison with vehicle-treated controls (n=5) (P<.05).
Conclusions Transient focal ischemia leads to iNOS expression in postischemic brain. However, the spatial and temporal patterns of expression differ from those occurring in permanent ischemia: iNOS is induced earlier and predominantly in vascular cells rather than in neutrophils. Thus, the temporal profile and localization of postischemic iNOS expression depend on the nature of the ischemic insult. The finding that aminoguanidine reduces infarct size adds further support to the hypothesis that postischemic iNOS expression contributes to ischemic brain damage.
Editorial Comment
Division of Cardiology, Medical College of Virginia, Richmond Va
This article has been cited by other articles:
 |
|
 |
|
  P. Pacher, J. S. Beckman, and L. Liaudet Nitric Oxide and Peroxynitrite in Health and Disease Physiol Rev, January 1, 2007; 87(1): 315 - 424. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Anttila, H. Christou, I. Hagino, Y. Iwata, B. A. Mettler, A. Fernandez-Gonzalez, D. Zurakowski, and R. A. Jonas Cerebral Endothelial Nitric Oxide Synthase Expression is Reduced After Very Low Flow Bypass Ann. Thorac. Surg., June 1, 2006; 81(6): 2202 - 2206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. L. Ma, X. Zhu, P. M. Rivera, O. Toien, B. M. Barnes, J. C. LaManna, M. A. Smith, and K. L. Drew Absence of cellular stress in brain after hypoxia induced by arousal from hibernation in Arctic ground squirrels Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1297 - R1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Lazovic, A. Basu, H.-W. Lin, R. P. Rothstein, J. K. Krady, M. B. Smith, and S. W. Levison Neuroinflammation and Both Cytotoxic and Vasogenic Edema Are Reduced in Interleukin-1 Type 1 Receptor-Deficient Mice Conferring Neuroprotection Stroke, October 1, 2005; 36(10): 2226 - 2231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.A. Gunnett, D.D. Lund, A.K. McDowell, F.M. Faraci, and D.D. Heistad Mechanisms of Inducible Nitric Oxide Synthase-Mediated Vascular Dysfunction Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1617 - 1622. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Goyagi, T. J.K. Toung, J. R. Kirsch, R. J. Traystman, R. C. Koehler, P. D. Hurn, and A. Bhardwaj Neuroprotective {kappa}-Opioid Receptor Agonist BRL 52537 Attenuates Ischemia-Evoked Nitric Oxide Production In Vivo in Rats Stroke, June 1, 2003; 34(6): 1533 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Eguchi, L. V. d'Uscio, C. Wambi, D. Weiler, I. Kovesdi, T. O'Brien, and Z. S. Katusic Inhibitory effect of recombinant iNOS gene expression on vasomotor function of canine basilar artery Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2560 - H2566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Veltkamp, N. Rajapakse, G. Robins, M. Puskar, K. Shimizu, and D. Busija Transient Focal Ischemia Increases Endothelial Nitric Oxide Synthase in Cerebral Blood Vessels Stroke, November 1, 2002; 33(11): 2704 - 2710. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.A. Gunnett, D.D. Lund, M.A. Howard III, Y. Chu, F.M. Faraci, and D.D. Heistad Gene Transfer of Inducible Nitric Oxide Synthase Impairs Relaxation in Human and Rabbit Cerebral Arteries Stroke, September 1, 2002; 33(9): 2292 - 2296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. FLOYD, K. HENSLEY, M. J. FORSTER, J. A. KELLEHER-ANDERSON, and P. L. WOOD Nitrones as Neuroprotectants and Antiaging Drugs Ann. N.Y. Acad. Sci., April 1, 2002; 959(1): 321 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Gunnett, D. D. Lund, Y. Chu, R. M. Brooks II, F. M. Faraci, and D. D. Heistad NO-Dependent Vasorelaxation Is Impaired After Gene Transfer of Inducible NO-Synthase Arterioscler. Thromb. Vasc. Biol., August 1, 2001; 21(8): 1281 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Stella, A. Vercelli, M. Repici, A. Follenzi, and P. M. Comoglio Macrophage Stimulating Protein Is a Novel Neurotrophic Factor Mol. Biol. Cell, May 1, 2001; 12(5): 1341 - 1352. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Iadecola, K. Niwa, S. Nogawa, X. Zhao, M. Nagayama, E. Araki, S. Morham, and M. E. Ross Reduced susceptibility to ischemic brain injury and N-methyl-D-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice PNAS, January 30, 2001; 98(3): 1294 - 1299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Takano, X.-L. Tang, E. Kodani, and R. Bolli Late preconditioning enhances recovery of myocardial function after infarction in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2372 - H2381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Xu, L. He, S. H. Ahmed, S.-W. Chen, M. P. Goldberg, J. S. Beckman, C. Y. Hsu, and C. Iadecola Oxygen-Glucose Deprivation Induces Inducible Nitric Oxide Synthase and Nitrotyrosine Expression in Cerebral Endothelial Cells Editorial Comment Stroke, July 1, 2000; 31(7): 1744 - 1751. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Castillo, R. Rama, and A. Davalos Nitric Oxide-Related Brain Damage in Acute Ischemic Stroke Stroke, April 1, 2000; 31(4): 852 - 857. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Shareef, A. Sawada, and A. H. Neufeld Isoforms of Nitric Oxide Synthase in the Optic Nerves of Rat Eyes with Chronic Moderately Elevated Intraocular Pressure Invest. Ophthalmol. Vis. Sci., November 1, 1999; 40(12): 2884 - 2891. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Davis and D. Barer Neuroprotection in acute ischaemic stroke. II: Clinical potential Vascular Medicine, August 1, 1999; 4(3): 149 - 163. [Abstract] [PDF]
|
|
|
|
 |
|
 C. Iadecola, C. A. Salkowski, F. Zhang, T. Aber, M. Nagayama, S. N. Vogel, and M. Elizabeth Ross The Transcription Factor Interferon Regulatory Factor 1 Is Expressed after Cerebral Ischemia and Contributes to Ischemic Brain Injury J. Exp. Med., February 15, 1999; 189(4): 719 - 727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Cho, B. T. Volpe, Y. Bae, O. Hwang, H. J. Choi, J. Gal, L. C. H. Park, C. K. Chu, J. Du, and T. H. Joh Blockade of Tetrahydrobiopterin Synthesis Protects Neurons after Transient Forebrain Ischemia in Rat: A Novel Role for the Cofactor J. Neurosci., February 1, 1999; 19(3): 878 - 889. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Marrelli, A. Khorovets, T. D. Johnson, W. F. Childres, and R. M. Bryan Jr. P2 purinoceptor-mediated dilations in the rat middle cerebral artery after ischemia-reperfusion Am J Physiol Heart Circ Physiol, January 1, 1999; 276(1): H33 - H41. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Galea, S. B. Glickstein, D. L. Feinstein, E. V. Golanov, and D. J. Reis Stimulation of cerebellar fastigial nucleus inhibits interleukin-1beta -induced cerebrovascular inflammation Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2053 - H2063. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nogawa, C. Forster, F. Zhang, M. Nagayama, M. E. Ross, and C. Iadecola Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia PNAS, September 1, 1998; 95(18): 10966 - 10971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Y. Calingasan, L. C. H. Park, L. L. Calo, R. R. Trifiletti, S. E. Gandy, and G. E. Gibson Induction of Nitric Oxide Synthase and Microglial Responses Precede Selective Cell Death Induced by Chronic Impairment of Oxidative Metabolism Am. J. Pathol., August 1, 1998; 153(2): 599 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Galea, E. V. Golanov, D. L. Feinstein, K. A. Kobylarz, S. B. Glickstein, and D. J. Reis Cerebellar stimulation reduces inducible nitric oxide synthase expression and protects brain from ischemia Am J Physiol Heart Circ Physiol, June 1, 1998; 274(6): H2035 - H2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, C. Louden, T.-L. Yue, J. A. Ellison, F. C. Barone, H. A. Solleveld, and G. Z. Feuerstein Delayed Expression of Osteopontin after Focal Stroke in the Rat J. Neurosci., March 15, 1998; 18(6): 2075 - 2083. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. FARACI and D. D. HEISTAD Regulation of the Cerebral Circulation: Role of Endothelium and Potassium Channels Physiol Rev, January 1, 1998; 78(1): 53 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Iadecola, F. Zhang, R. Casey, M. Nagayama, and M. E. Ross Delayed Reduction of Ischemic Brain Injury and Neurological Deficits in Mice Lacking the Inducible Nitric Oxide Synthase Gene J. Neurosci., December 1, 1997; 17(23): 9157 - 9164. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nogawa, F. Zhang, M. E. Ross, and C. Iadecola Cyclo-Oxygenase-2 Gene Expression in Neurons Contributes to Ischemic Brain Damage J. Neurosci., April 15, 1997; 17(8): 2746 - 2755. [Abstract] [Full Text] [PDF]
|
|