Sodium nitrite and nitrate: from mechanisms to antihypertensive therapy

• Grant number: 14/23946-0
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2015
• End date: September 30, 2021
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Jose Eduardo Tanus dos Santos
• Grantee: Jose Eduardo Tanus dos Santos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Carlos Renato Tirapelli ; Claudio Miguel da Costa Neto ; Michele Mazzaron de Castro ; Vitor Marcel Faça
• Associated scholarship(s): 18/12423-7 - INVOLVEMENT OF PROTEIN NITROSILATION IN THE ANTIHYPERTENSIVE MECHANISMS OF TREATMENT WITH SODIUM NITRITE, BP.PD; 18/14112-9 - VASCULAR NITROSOPROTEOMIC ANALYSIS IN A MODEL OF ARTERIAL HYPERTENSION IN TREATED RATS WITH SODIUM NITRITE, BP.PD; 17/10415-4 - Study of antiproliferative effects and mechanisms of sodium nitrite in experimental renovascular hypertension, BP.PD; 15/22228-9 - Protein nitrosylation in the antihypertensive mechanisms of treatment with sodium nitrite, BP.PD

Abstract

In contrast to what it was usually believed in the last decades, many studies carried out in the last years have shown that the anions nitrate and nitrite are not simply inert biological products of nitric oxide (NO) oxidation. In fact, nitrates are secreted by salivary glands into saliva after their absortion in the gastrointestinal system, and nitrates are reduced to nitrites by oral bacteria. Nitrites are converted into NO in the stomach. These transformations correspond to the entero-salivary cycle of nitrates and nitrites, which promote NO formation to supplement the canonical, enzymatic NO formation pathways (NO synthases). While a variety of cardiovascular effects of these ions have been shown, the mechanisms explaining their bioactivation are still poorly understood. Recent studies by our group have shown that the acid conditions of the stomach play a major role in the anti-hypertensive effects of sodium nitrite, even though the mechanisms explaining those effects are not clear. An interesting possibility that has not been explored yet is that the oral administration of sodium nitrite causes the formation of NO-related species, particularly NO+, NO2 e N2O, which can generate nitrosothiols (RSNO) and potentially lead to nitros(yl)ation of proteins (enzymes) and receptors involved in hypertension, thus lowering blood pressure. This projects aims at identifying mechanisms activated by treatment with sodium nitrite or nitrate in animal models of hypertension, cell culture approaches, and nitrosoproteomics thus offering an interdisciplinary and translational perspective. Therefore, this project aims at contributing to the knowledge regarding the following particular issues: 1) to determine the mechanisms involved in the chronic antihypertensive effects of sodium nitrite in rats, particularly the involvement of nitrosothiols (RSNO); 2) to determine whether the formation of RSNO promotes the nitro(sy)lation and inhibition of tissue renin-angiotensin system affecting cell signaling; 3) to determined whether therapy with sodium nitrite or nitrate attenuates the erectile dysfunction associated with hypertension; 4) to determined whether sodium nitrite prevents the vascular remodeling associated with hypertension, possibly as a result of matrix metalloproteinase 2 (MMP-2) inhibition; 5) to determine whether sodium nitrite reverses mitochondrial dysfunction in the vessels and heart from hypertensive animals; 6) to start studies aiming to determine which proteins are nitrosilated in the vessels and heart from animals treated with sodium nitrite by using nitrosoproteomic approaches and validate these findings. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MESCHIARI, CESAR A.; PINHEIRO, LUCAS C.; GUIMARAES, DANIELLE A.; GERLACH, RAQUEL F.; TANUS-SANTOS, JOSE E.. Sodium nitrite attenuates MMP-9 production by endothelial cells and may explain similar effects of atorvastatin. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, v. 389, n. 2, p. 223-231, FEB 2016. (14/23946-0)

GUIMARAES, DANIELLE A.; BATISTA, ROSE I. M.; TANUS-SANTOS, JOSE E.. Nitrate and nitrite-based therapy to attenuate cardiovascular remodelling in arterial hypertension. BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, v. 128, n. 1, AUG 2020. (18/12423-7, 14/23946-0)

GONZAGA, NATALIA A.; DO VALE, GABRIEL T.; DA SILVA, CARLA B. P.; PINHEIRO, LUCAS C.; LEITE, LETICIA N.; CARNEIRO, FERNANDO S.; TANUS-SANTOS, JOSE E.; TIRAPELLI, CARLOS R.. Treatment with nitrite prevents reactive oxygen species generation in the corpora cavernosa and restores intracavernosal pressure in hypertensive rats. NITRIC OXIDE-BIOLOGY AND CHEMISTRY, v. 94, p. 19-26, JAN 1 2020. (14/23946-0)

DA SILVA-NETO, PEDRO, V; DO VALLE, VALERIA B.; FUZO, CARLOS A.; FERNANDES, TALITA M.; TORO, DIANA M.; FRAGA-SILVA, THAIS F. C.; BASILE, PATRICIA A.; DE CARVALHO, JONATAN C. S.; PIMENTEL, VINICIUS E.; PEREZ, MALENA M.; et al. Matrix Metalloproteinases on Severe COVID-19 Lung Disease Pathogenesis: Cooperative Actions of MMP-8/MMP-2 Axis on Immune Response through HLA-G Shedding and Oxidative Stress. BIOMOLECULES, v. 12, n. 5, p. 20-pg., 2022-05-01. (14/07125-6, 20/08534-8, 20/05270-0, 14/23946-0, 21/04590-3, 20/05207-6)