COMPARATIVE STUDY OF THE EFFECTS OF VALSARTAN MONOTHERAPY VERSUS THE ASSOCIATIONS VALSARTAN/HYDROCHLOROTHIAZIDE AND VALSARTAN/SACUBITRIL ON HEMODYNAMIC AND MORPHOFUNCTIONAL CARDIAC PARAMETERS OF HYPERTENSIVE RATS

• Grant number: 23/09282-0
• Support Opportunities: Scholarships in Brazil - Master
• Start date: July 01, 2024
• End date: April 30, 2026
• Field of knowledge: Health Sciences - Physiotherapy and Occupational Therapy
• Principal Investigator: Hugo Celso Dutra de Souza
• Grantee: Tallys Eduardo Velasco Paixão
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Introduction: Systemic arterial hypertension (SAH) is a highly prevalent disease in the adult population. Morphological and functional cardiac impairments are frequent, and if not contained, they can result in heart failure, favoring a poor prognosis. The search for a more efficient pharmacological and non-pharmacological therapy has been constant. In this regard, monotherapy with AT1 receptor blockers, such as valsartan, as well as its association with diuretics, are commonly used in the treatment of SAH, as well as changes in lifestyle involving new dietary practices and physical exercise. More recently, a new pharmacological combination has been widely used in the treatment of heart failure, with excellent results, especially in relation to ejection fraction. This is the association of valsartan with sacubitril. However, little is known about this pharmacological combination in relation to the treatment of hypertension, especially regarding the parameters of ventricular contractility and reactivity of the coronary bed, which are often impaired in the hypertensive heart. Our hypothesis is that this pharmacological combination promotes greater benefits on cardiac function when compared to another widely used pharmacological combination involving valsartan and a diuretic, such as hydrochlorothiazide. Furthermore, we also hope that the association of both therapies with aerobic physical training can potentiate left ventricular contractility, however with more prominent results for the valsartan-sacubitril combination. Objective: To investigate the effects of the combined pharmacological treatment of valsartan with sacubitril on the reactivity of the coronary bed and cardiac contractility, as well as the therapeutic role of aerobic physical training on the same parameters in spontaneously hypertensive rats. Methods: Spontaneously hypertensive adult male rats (N=64), aged 16 weeks (200-220g), will be divided into four groups (N=16) and will be submitted to a treatment protocol for 12 weeks; vehicle-treated control group (Vehicle Group); group treated with valsartan (30 mg·kg1·d1) (Valsartan Group); group treated with valsartan (30 mg·kg1·d1) associated with hydrochlorothiazide (10 mg·kg1·d1) (Valsartan-Hydrochlorothiazide Group); group treated with valsartan (30 mg·kg1·d1) associated with sacubitril (38 mg·kg1·d1) (Valsartan-Sacubitrile Group). Half of each group (N=08) will undergo aerobic physical training through swimming for 12 weeks. All groups will undergo the following experimental procedures; recording of blood pressure and heart rate using plethysmography to be performed at the 18th, 22nd, 26th and 30th weeks of life; cardiac morphofunctional assessment through two-dimensional echocardiography at the 18th and 32nd weeks; analysis of coronary bed reactivity and left ventricular contractility in an isolated heart by means of increased flow and administration of beta-adrenergic agonists, dobutamine (0.5 - 50 nmol) and salbutamol (1 - 100 nmol); quantification of the expression of cardiac beta-adrenergic receptors; and cardiac histological analysis.