title: An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect.
abstract: OBJECTIVE
  The heptapeptide angiotensin-(1-7) is a component of the renin-angiotensin system, which promotes many beneficial cardiovascular effects, including antithrombotic activity. We have recently shown that the antithrombotic effect of angiotensin-(1-7) involves receptor Mas-mediated NO-release from platelets. Here, we describe an orally active formulation based on angiotensin-(1-7) inclusion in cyclodextrin [Ang-(1-7)- CyD] as an antithrombotic agent. Cyclodextrins are pharmaceutical tools that are used to enhance drug stability, absorption across biological barriers and gastric protection.
  
  
  METHODS
  To test the antithrombotic effect of Ang-(1-7)-CyD, thrombus formation was induced in the abdominal vena cava of spontaneously hypertensive rats that were pretreated either acutely or chronically with Ang-(1-7)-CyD. Male Mas-knockout and wild-type mice were used to verify the role of the Mas receptor on the effect of Ang-(1-7)-CyD.
  
  
  RESULTS
  Acute or chronic oral treatment with Ang-(1-7)-CyD promoted an antithrombotic effect (measured by thrombus weight; all values are, respectively, untreated vs. treated animals) in spontaneously hypertensive rats (acute: 2.86 ± 0.43 mg vs. 1.14 ± 0.40 mg; chronic: 4.27 ± 1.03 mg vs. 1.39 ± 0.68 mg). This effect was abolished in Mas-knockout mice (thrombus weight in Mas wild-type: 0.76 ± 0.10 mg vs. 0.37 ± 0.02 mg; thrombus weight in Mas-knockout: 0.96 ± 0.11 mg vs. 0.87 ± 0.14 mg). Furthermore, the antithrombotic effect of Ang-(1-7)-CyD was associated with an increase in the plasma level of Angiotensin-(1-7).
  
  
  CONCLUSIONS
  These results show for the first time that the oral formulation Ang-(1-7)-CyD has biological activity and produces a Mas-dependent antithrombotic effect.
authors.affiliation: Instituto Nacional de Ciência e Tecnologia em Nanobiofarmacêutica - Department of Physiology and Biophysics, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rodrigo Araujo
authors.initials: RA
authors.lastname: Fraga-Silva
authors.forename: Fabiana P
authors.initials: FP
authors.lastname: Costa-Fraga
authors.forename: Frederico B
authors.initials: FB
authors.lastname: De Sousa
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Sinisterra
authors.forename: Robson A S
authors.initials: RA
authors.lastname: Santos
mesh_terms: D000803:Angiotensin I / Q000627:therapeutic use*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D020246:Venous Thrombosis / Q000188:drug therapy*
chemical_list: D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D000803:Angiotensin I; C118790:angiotensin I (1-7)