An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect

• Published in: Clinics (São Paulo, Brazil) Brazil), 2011-01, Vol.66 (5), p.837-841
• Main Authors: Fraga-Silva, Rodrigo Araujo, Costa-Fraga, Fabiana P, De Sousa, Frederico B, Alenina, Natalia, Bader, Michael, Sinisterra, Ruben D, Santos, Robson A S
• Format: Article
• Language: English
• Subjects: Angiotensin I - therapeutic use; Angiotensin-(1-7); Animals; antithrombotic; Basic Research; cyclodextrin; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolytic Agents - therapeutic use; Male; MEDICINE, GENERAL & INTERNAL; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments - therapeutic use; Rats; Rats, Inbred SHR; receptor Mas; renin-angiotensin-system; Venous Thrombosis - drug therapy
• ISSN: 1807-5932; 1980-5322; 1980-5322
• DOI: 10.1590/S1807-59322011000500021

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. 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. 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). 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.