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Effect of doxycycline on cardiocirculatory autonomic control in heart failure induced by myocardial infarction in rats

Grant number: 22/00203-8
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2022
Effective date (End): April 30, 2023
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Rubens Fazan Junior
Grantee:Lucas Patrick Rocha Costa
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:20/06043-7 - Autonomic (sympathetic and parasympathetic) modulation of cardiovascular and inflammatory responses under physiopathological clinical and experimental conditions, AP.TEM

Abstract

Rationale. Doxycycline (DOXI), a large spectrum antibiotic, when administered in low doses (non-antimicrobial) has an inhibitory effect on extracellular matrix metalloproteinases (MMP), inflammatory mediators and effector molecules associated with myocardial infarction (MI). Studies have shown that DOXI reduces ventricular remodeling and decreases the susceptibility to cardiac arrhythmias after MI. The increase in MMP is possibly one of the factors that contribute to the increase in inflammatory mediators and reactive oxygen species, accordingly, to the increase in cardiac sympathetic activity and baroreflex dysfunction in MI. The inhibition of MMP may attenuate the progression of autonomic dysfunction caused by MI by reducing oxidative stress and the local and systemic inflammatory process.Objective. To evaluate whether DOXI inhibition of MMP prevents autonomic changes and baroreflex dysfunction during the establishment of heart failure caused by MI, through anti-inflammatory and antioxidant effects.Methods. It will be used Wistar rats submitted to MI caused by surgical ligation of the left coronary artery, or fictitious surgery (controls), treated or not with DOXI (30 mg/kg/day, p.o.) for four weeks. At the end of the treatment, the cardiac function will be assessed by echocardiography, and following the rats will be implanted with ECG electrodes. After 24h, the ECG will be recorded in conscious animals to analyze the variability of the iRR and to determine the cardiac autonomic tone using autonomic blockers (methylatropine and propranolol). After the ECG recording, the animals will be implanted with catheters into the femoral artery and vein, and, on the next day, their blood pressure (BP) will be recorded to assess the baroreflex function and blood pressure variability. At the end of the experimental protocols, the animals' plasma, heart, and lung will be collected for the calculation of the cardiac and pulmonary index and biochemical analyzes. The activity of MMP-2, cytokines, and the generation of reactive oxygen species will be evaluated in the heart and plasma using the techniques of gel zimography, ELISA, and TBAR, respectively. Histological analysis of the hearts will be performed to assess the size of the infarction, myocyte diameter, and the relative amount of collagen.Expected Results. It is expected that the inhibition of MMP by DOXI will prevent autonomic changes and baroreflex dysfunction during the establishment of heart failure caused by MI, through anti-inflammatory and antioxidant effects.

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