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Angiotensin 1-7 and Mas decrease thrombosis in Bdkrb2-/- mice by increasing NO and prostacyclin to reduce platelet spreading and glycoprotein VI activation.

Abstract
Bradykinin B2 receptor-deleted mice (Bdkrb2(-/-)) have delayed carotid artery thrombosis times and prolonged tail bleeding time resulting from elevated angiotensin II (AngII) and angiotensin receptor 2 (AT2R) producing increased plasma nitric oxide (NO) and prostacyclin. Bdkrb2(-/-) also have elevated plasma angiotensin-(1-7) and messenger RNA and protein for its receptor Mas. Blockade of Mas with its antagonist A-779 in Bdkrb2(-/-) shortens thrombosis times (58 ± 4 minutes to 38 ± 4 minutes) and bleeding times (170 ± 13 seconds to 88 ± 8 seconds) and lowers plasma nitrate (22 ± 4 μM to 15 ± 5 μM), and 6-keto-PGF1α (259 ± 103 pg/mL to 132 ± 58 pg/mL). Bdkrb2(-/-) platelets express increased NO, guanosine 3',5'-cyclic monophosphate, and cyclic adenosine monophosphate with reduced spreading on collagen, collagen peptide GFOGER, or fibrinogen. In vivo A-779 or combined L-NAME and nimesulide treatment corrects it. Bdkrb2(-/-) platelets have reduced collagen-related peptide-induced integrin α2bβ3 activation and P-selectin expression that are partially corrected by in vivo A-779, nimesulide, or L-NAME. Bone marrow transplantations show that the platelet phenotype and thrombosis time depends on the host rather than donor bone marrow progenitors. Transplantation of wild-type bone marrow into Bdkrb2(-/-) hosts produces platelets with a spreading defect and delayed thrombosis times. In Bdkrb2(-/-), combined AT2R and Mas overexpression produce elevated plasma prostacyclin and NO leading to acquired platelet function defects and thrombosis delay.
AuthorsChao Fang, Evi Stavrou, Alec A Schmaier, Nadja Grobe, Mariana Morris, Andrew Chen, Marvin T Nieman, Gregory N Adams, Gretchen LaRusch, Yihua Zhou, Matthew L Bilodeau, Fakhri Mahdi, Mark Warnock, Alvin H Schmaier
JournalBlood (Blood) Vol. 121 Issue 15 Pg. 3023-32 (Apr 11 2013) ISSN: 1528-0020 [Electronic] United States
PMID23386129 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 7-Ala-angiotensin (1-7)
  • Peptide Fragments
  • Platelet Aggregation Inhibitors
  • Platelet Membrane Glycoproteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Receptor, Angiotensin, Type 2
  • Receptor, Bradykinin B2
  • Receptors, G-Protein-Coupled
  • Sulfonamides
  • platelet membrane glycoprotein VI
  • Angiotensin II
  • Nitric Oxide
  • Angiotensin I
  • Epoprostenol
  • Cyclic AMP
  • Cyclic GMP
  • angiotensin I (1-7)
  • nimesulide
  • NG-Nitroarginine Methyl Ester
Topics
  • Angiotensin I (blood)
  • Angiotensin II (analogs & derivatives, pharmacology)
  • Animals
  • Bleeding Time
  • Blood Platelets (drug effects, metabolism)
  • Bone Marrow Transplantation
  • Cyclic AMP (blood)
  • Cyclic GMP (blood)
  • Epoprostenol (blood)
  • Immunoblotting
  • Mice
  • Mice, 129 Strain
  • Mice, Knockout
  • NG-Nitroarginine Methyl Ester (pharmacology)
  • Nitric Oxide (blood)
  • Peptide Fragments (blood, pharmacology)
  • Platelet Aggregation Inhibitors (pharmacology)
  • Platelet Membrane Glycoproteins (metabolism)
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins (blood, genetics)
  • Receptor, Angiotensin, Type 2 (blood)
  • Receptor, Bradykinin B2 (deficiency, genetics)
  • Receptors, G-Protein-Coupled (blood, genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides (pharmacology)
  • Thrombosis (blood)
  • Time Factors

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