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

Abstract

INTRODUCTION AND 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.METHOD: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).CONCLUSION: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.

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

“…Ang-(1-7) is recognized to have an antithrombotic effect. 12,19,27,28 Ang-(1-7) mediates its effect through Mas. 11 Our previous studies reported no increase in renal Mas but a 1.62-fold increase in liver Mas in Bdkrb2 2/2 mice.…”

Oral Formulation of Angiotensin-(1–7) Improves Lipid Metabolism and Prevents High-Fat Diet–Induced Hepatic Steatosis and Inflammation in Mice

“…This novel compound was denominated [hydroxypropylβ-cyclodextrin/Ang-(1-7) -HPβCD/Ang-(1-7)] (20). It has been described that Ang-(1-7) incorporated into this hydroxypropylβ-cyclodextrin (HPβCD) cavity, can be protected during the passage through the gastrointestinal tract after oral administration (21). A pharmacokinetic test was conducted in rats to estimate the bioavailability of the heptapeptide in the circulation after oral administration of aqueous solution.…”

“…This novel compound was denominated hydroxypropylβ-cyclodextrin [HPβCD]/Ang-(1-7). [20][21][22] A pharmacokinetic test was conducted in rats to estimate the bioavailability of the compound, showing that oral formulation significantly increased plasma levels of Ang-(1-7) 12-fold over baseline with the observation for 6 hours after its administration 22 (detailed Material is available in the online-only Data Supplement).Importantly, the potential mechanism underlying the fat hepatoprotective effects of Ang-(1-7) included in HPβCD/ Ang-(1-7) in vivo still remains unclear. Thus, the purpose of this study is to evaluate the effect of oral administration of Ang-(1-7) on hepatic functions and on the expression of liver inflammatory markers in mice consuming a HFD.…”

“…This novel compound was denominated hydroxypropylβ-cyclodextrin [HPβCD]/Ang-(1-7). [20][21][22] A pharmacokinetic test was conducted in rats to estimate the bioavailability of the compound, showing that oral formulation significantly increased plasma levels of Ang-(1-7) 12-fold over baseline with the observation for 6 hours after its administration 22 (detailed Material is available in the online-only Data Supplement).…”

New Components of the Renin-Angiotensin-Aldosterone System and Oxidative Stress

“…But its clinical use is limited because of short half-life in vivo. Cyclized Ang-(1-7) (thioether-bridged Ang- (1-7)) and angiotensin-(1-7) inclusion in cyclodextrin (Ang-(1-7)-CyD) exhibited better pharmacokinetic profile in vivo but in experimental models [79,80]. A synthetic analog of Ang-(1-7) TXA127 is in clinical trial for the treatment of PAH.…”