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Blood, 1 July 2006, Vol. 108, No. 1, pp. 192-199. Prepublished online as a Blood First Edition Paper on March 2, 2006; DOI 10.1182/blood-2006-01-0094. This Article Full Text (PDF) All Versions of this Article: 2006-01-0094v1 108/1/192    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Shariat-Madar, Z. Articles by Schmaier, A. H Search for Related Content PubMed PubMed Citation Articles by Shariat-Madar, Z. Articles by Schmaier, A. H Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 9, 2006 Accepted February 23, 2006 Bradykinin B2 receptor knockout mice are protected from thrombosis by increased nitric oxide and prostacyclin Zia Shariat-Madar, Fakhri Mahdi, Mark Warnock, Jonathon W Homeister, Sujata Srikanth, Yelena Krijanovski, Laine J Murphey, Ayad A Jaffa, and Alvin H Schmaier* Hematology/Oncology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA Department of Pathology, University of Michigan, Ann Arbor, MI, USA Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN, USA Department of Internal Medicine, Medical University of South Carolina, Charleston, SC, USA Hematology/Oncology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA * Corresponding author; email: Schmaier{at}case.edu. Bradykinin (BK) liberates nitric oxide, prostacyclin, and tissue plasminogen activator from endothelial cells. We hypothesized that BK B2 receptor KO mice (BKB2R-/-) have increased thrombosis risk. Paradoxically, the BKB2R-/- have long bleeding times and delayed carotid artery thrombosis, 78±6.7 min vs 31±2.7 min control. The mechanism(s) for thrombosis protection was sought. In BKB2R-/- plasma coagulation, fibrinolysis and anticoagulant proteins are normal except for an increased prekallikrein and decreased factor XI. BKB2R-/- have elevated BK 1-5, (160±75 fmol/ml vs 44±29 fmol/ml control) and angiotensin II (182±41 pg/ml vs 49±7 pg/ml control). Ramipril treatment shortens vessel occlusion time. BKB2R-/- have elevated plasma 6-keto-PGF1 (666±232 ng/ml vs 23±5.3 ng/ml control) and serum nitrate (61±5.3 µM vs 24±1.8 µM control). Treatment with L-NAME or nimesulide shortens the thrombosis time. BKB2R-/- have increased angiotensin receptor 2 (AT2R) mRNA and protein expression. Treatment with an AT2R antagonist, PD123319, normalizes the thrombosis time and nitrate and 6-keto-PGF1. The long bleeding times in BKB2R-/- also corrects with L-NAME and nimesulide therapy. In BKB2R-/-, angiotensin II binding to an over-expressed AT2R promotes thromboprotection by elevating nitric oxide and prostacyclin. These investigations indicate a pathway for thrombosis risk reduction via the plasma kallikrein/kinin and renin angiotensin systems. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Is the plasma kallikrein-kinin system antithrombotic? Robert W. Colman Blood 2006 108: 1-2. [Full Text] [PDF] This article has been cited by other articles: C. Kleinschnitz, S. Braeuninger, M. Pham, M. Austinat, I. Nolte, T. Renne, B. Nieswandt, M. Bendszus, and G. Stoll Blocking of Platelets or Intrinsic Coagulation Pathway-Driven Thrombosis Does Not Prevent Cerebral Infarctions Induced by Photothrombosis Stroke, April 1, 2008; 39(4): 1262 - 1268. [Abstract] [Full Text] [PDF] S. Merkulov, W.-M. Zhang, A. A. Komar, A. H. Schmaier, E. Barnes, Y. Zhou, X. Lu, T. Iwaki, F. J. Castellino, G. Luo, et al. Deletion of murine kininogen gene 1 (mKng1) causes loss of plasma kininogen and delays thrombosis Blood, February 1, 2008; 111(3): 1274 - 1281. [Abstract] [Full Text] [PDF] D. Gailani and T. Renne Intrinsic Pathway of Coagulation and Arterial Thrombosis Arterioscler Thromb Vasc Biol, December 1, 2007; 27(12): 2507 - 2513. [Abstract] [Full Text] [PDF] Y. Tan, J.-S. Keum, B. Wang, M. B. McHenry, S. R. Lipsitz, and A. A. Jaffa Targeted deletion of B2-kinin receptors protects against the development of diabetic nephropathy Am J Physiol Renal Physiol, October 1, 2007; 293(4): F1026 - F1035. [Abstract] [Full Text] [PDF] N. Toda, K. Ayajiki, and T. Okamura Interaction of Endothelial Nitric Oxide and Angiotensin in the Circulation Pharmacol. Rev., March 1, 2007; 59(1): 54 - 87. [Abstract] [Full Text] [PDF]

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