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To evaluate the multitherapeutic action of AT1 receptor antagonist associated with neprilysin inhibitor in the treatment of cardiovascular and urogenital dysfunction in heart failure rats


Heart failure (HF) is the common final outcome of several cardiovascular diseases and has been shown to be closely related to the development of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED). Epidemiological studies have shown that up to 85% of HF patients reported an episode of ED, where approximately 75% reported libido impairment and 30% complete absence of sexual activity. In addition, studies of patients with HF showed that 34% of men and 62% of women reported having LUTS, and approximately 57% had overactive bladder syndrome. Despite the high rates of ED and LUTS in HF patients, the molecular mechanisms responsible for the development of these urogenital dysfunctions associated with this disorder need to be further explored. Several studies show that HF, ED and LUTS present similar risk factors, being associated with autonomic nervous system dysfunction and alterations in important signaling pathways, especially the nitric oxide (NO) signaling pathway. However, HF is mainly due to the activation of compensatory neurohumoral mechanisms, such as the activation of the renin angiotensin-aldosterone system (SARS), which releases Angiotensin-II (ANG-II) promoting an excessive vasoconstrictor effect, increased oxidative stress, metabolic and extracellular matrix changes, as well as reduced effectiveness of the natriuretic peptide (SPN) system resulting in an antinatriuretic effect with reduced vasodilator effect. However, to date, there is no evidence in experimental or human models evaluating the impact of SARS and SPN on HF and LUTS associated with HF. Contemporary pharmacological therapies aim to restore the neurohumoral balance in HF, inhibiting the activation of the RAAS and the sympathetic nervous system (SNS), in addition to enhancing the effects of the SPN. Among these new proposals stands out LCZ696 (Entresto® - Novartis), which consists of the association of the Valsartana molecule (ANG-II receptor antagonist, AT1R) with a Sacubitril molecule (neprilisin inhibitor [responsible for degrading the natriuretic peptides]), which showed better clinical results when compared to conventional therapy (Enalapril) in HF patients. In addition, due to the complexity of the HF pathophysiology, healthcare professionals have been discussing the need for multi-therapeutic drugs, since polypharmacy (use of various medications) is common in this condition and increases with the progression of HF. Thus, preliminary results obtained in our laboratory show that LCZ696 may be a possible multi-therapeutic agent in cardiovascular, urinary and erectile disorders. Thus, the project proposes to investigate the acute effect of LCZ696 (valsartan+sacubitril) on the reactivity of the vascular smooth, detrusor and cavernous muscles of control rats, as well as the multi-therapeutic contribution of chronic LCZ696 treatment to cardiovascular, urinary and erectile dysfunctions, of Sprague Dawley rats with HF, exploring the molecular, biochemical, proteomic and metabolomic changes. (AU)