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

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.

The cardiac renin-angiotensin system. New insights from transgenic animal models

The renin-angiotensin system (RAS) was described for more than a century as a circulating hormone system regulating blood pressure and kidney function. The advent of molecular biology has added a novel aspect to the picture of the RAS namely the local production and action of components of the system in several organs including brain, adrenal gland, vascular wall, kidney, and heart. In particular the interest has focussed on the cardiac RAS since genetic as well as pharmacologic studies have suggested an important role of angiotensin in the heart: Polymorphisms in the gene for angiotensin-converting enzyme were linked to the risk for cardiac diseases and inhibitors of this enzyme as well as angiotensin receptor antagonists turned out to be extremely effective drugs for the treatment fo heart failure. All components of the RAS are synthesized in the heart and, therefore, the local production of angiotensin II occurs in this organ. The interplay of this local system with the circulating RAS, mechanical stretch, and the sympathetic nervous system has recently been addressed by the generation of transgenic aninal models with targeted alterations in the expression of RAS components in the heart. The results are consistent with a pivotal function of the local RAS in the regulation of cardiac hypertrophy, remodelling, and fibrosis. However, there are still open questions concerning the autonomy of the RAS in these effects or its dependence on additional stimuli such as mechanical stretch or growth factors. This review summarizes the available evidence and discusses the remaining unsolved problems.