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The Effects of Cilostazol on Tissue Oxygenation upon an Ischemic-reperfusion Injury in the Mouse Cerebrum

  • Takayuki Morikawa
  • Katsuji Hattori
  • Mayumi Kajimura
  • Makoto Suematsu
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 662)

Abstract

Although cilostazol, an inhibitor of cyclic nucleotide phosphodiesterase 3 (PDE3), is known to exert a potent antiplatelet function by raising intracellular cAMP concentration, its effect on cerebral microcirculation upon an ischemic insult is not clearly understood. To examine effects of cilostazol on the global ischemic injury in the brain, we first measured the plasma leakage using modified Miles assay after mice had been subjected to 60 min of a bilateral common carotid artery (BCCA) occlusion followed by reperfusion for 4 h. Oral treatment with cilostazol (30 mg/kg) significantly increased plasma leakage. This result led us to examine if the treatment with cilostazol recruits more capillaries leading to an increase in surface area for exchange and oxygen transport to tissues. To do so, we simultaneously measured degrees of tissue hypoxia and vessel perfusion. Pimonidazol was injected intraperitoneally 1 h before sacrifice and capillary patency was assessed by fluorescein isothiocyanate-labeled Lycopersicon esculentum lectin bound to the endothelial surface. Treatment with cilostazol markedly increased the capillary patency which was accompanied by a reduction in the hypoxic area. Although the treatment with cilostazol caused an increase in the flux of plasma proteins across endothelial barrier that may imply an adverse role after a BCCA occlusion, this increase in protein leakage was attributable to the increased surface area for exchange which in turn brought about a reduction in tissue hypoxia. Taken together cilostazol appears to produce a protective effect against the ischemic-reperfusion injury.

Keywords

PDE3 Inhibitor Ischemic Insult Evans Blue Lacunar Infarction Cyclic Nucleotide Phosphodiesterase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Supported by Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research 19500329, Health Labour Sciences Research Grant, Research on Advanced Medical Technology from the Ministry of Health Labour and Welfare (to M. K.), and Grant-in-Aid for Creative Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan (to M.S.).

References

  1. 1.
    Yashiro Y, Ohhashi T. Effects of cilostazol, a selective cyclic AMP phosphodiesterase inhibitor on isolated rabbit spinal arterioles. Jpn J Physiol 2002;52:471–477.PubMedCrossRefGoogle Scholar
  2. 2.
    Torii H, Kubota H, Ishihara H, Suzuki M. Cilostazol inhibits the redistribution of the actin cytoskeleton and junctional proteins on the blood-brain barrier under hypoxia/reoxygenation. Pharmacol Res 2007;55:104–110.PubMedCrossRefGoogle Scholar
  3. 3.
    Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E et al. Cilostazol Stroke Prevention Study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis 2000;9:147–157.CrossRefGoogle Scholar
  4. 4.
    Huang Y, Cheng Y, Wu J, Li Y, Xu E, Hong Z et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008;7:494–499.PubMedCrossRefGoogle Scholar
  5. 5.
    Thurston G, Suri C, Smith K, McClain J, Sato TN, Yancopoulos GD et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 1999;286:2511–2514.PubMedCrossRefGoogle Scholar
  6. 6.
    Kitagawa K, Matsumoto M, Mabuchi T, Yagita Y, Ohtsuki T, Hori M et al. Deficiency of intercellular adhesion molecule 1 attenuates microcirculatory disturbance and infarction size in focal cerebral ischemia. J Cereb Blood Flow Metab 1998;18:1336–1345.PubMedCrossRefGoogle Scholar
  7. 7.
    Inai T, Mancuso M, Hashizume H, Baffert F, Haskell A, Baluk P et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol 2004;165:35–52.PubMedCrossRefGoogle Scholar
  8. 8.
    Michel CC, Curry FE. Microvascular permeability. Physiol Rev 1999;79:703–761.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Takayuki Morikawa
    • 1
  • Katsuji Hattori
    • 1
  • Mayumi Kajimura
    • 1
  • Makoto Suematsu
    • 1
  1. 1.Department of Biochemistry and Integrative Medical BiologyKeio University School of MedicineTokyoJapan

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