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Effects of doxycycline on sistemic and vascular angiontensin converting enzyme in experimental hypertension 2K1C

Grant number: 12/04169-7
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): June 01, 2012
Effective date (End): May 31, 2013
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Elen Rizzi Sanchez
Grantee:Stefania Bovo Minto
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Hypertension is a health public problem. Inhibitors of angiotensin-converting enzyme (ACE) are widely used for the treatment of hypertension. These effects may be due to decreasing the activation of the renin-angiotensin aldosterone system (RAAS). Evidence has shown that ACE inhibitors (ACEi) are antioxidants through the reduction in the formation of angiotensin II. This peptide may promote the increased formation of reactive oxygen species (ROS) mainly by activating b-nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathways. In addition, there are other effects induced by ACEi, such as inhibition of extracellular matrix metalloproteinases (MMPs), which seem to be associated with benefits effects in the antihypertensive therapies. In this regard, non-specific inhibitors of MMPs, such as doxycycline, have been suggested as important pharmacological tools for cardiovascular disease treatment. Studies have indicated that doxycycline attenuated hypertension-induced cardiac and vascular alterations or other disorders such as myocardial infarction. Besides inhibiting MMPs, doxycycline has antioxidant effects which may contribute to the beneficial effects shown in several studies. Based on the importance and the benefits of doxycycline treatment in cardiovascular disease more studies are required to elucidate this antioxidant mechanism that remains totally unclear. In this sense, some evidence has shown biochemical similarities between doxycycline and ACEi suggesting a possible ACE inhibition mediated by doxycycline. For example, ACEi may inhibit MMPs by direct interaction with these proteases, like doxycycline. Moreover, and more sustained in the literature, doxycycline is a chelating of divalent metals, such as calcium and zinc, which are essential for the activity of ACE. Because of these similarities and due to doxycycline-induced antioxidant in hypertensive rats, we hypothesized that doxycycline is able to inhibit ACE, decreasing the activity of NADPH oxidase (induced by activation of the RAAS), promoting the reduction in ROS formation that was evidenced in previous studies. To examine this hypothesis, plasma and aorta samples will be collected from 2-kidney and 1-clip (2K1C) hypertensive rats treated with doxycycline or with the vehicle for 4 weeks. These samples will be evaluated: (1) ACE activity vascular and systemic, and (2) NADPH oxidase activity. Furthermore, the plasma of hypertensive rats treated with a vehicle will be used to assess the possible doxycycline propriety in inhibiting ACE in vitro assay (incubating directly in the plasma of these animals, suggests that it could inhibit ACE due to its ability to chelate zinc).(AU)

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