Impact of chronic ethanol consumption in the cardiac and vascular damages induced by experimental sepsis: evaluation of the role of iNOS

• Grant number: 17/24123-5
• Support Opportunities: Regular Research Grants
• Start date: May 01, 2018
• End date: April 30, 2020
• Field of knowledge: Biological Sciences - Pharmacology - Cardiorenal Pharmacology
• Principal Investigator: Carlos Renato Tirapelli
• Grantee: Carlos Renato Tirapelli
• Host Institution: Escola de Enfermagem de Ribeirão Preto (EERP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated researchers: Alisson Martins de Oliveira

Abstract

Sepsis is defined as an organ dysfunction, with a potential risk of death, caused by a dysregulated host response to an infection. Sepsis impairs the cardiovascular function with a progressive loss of response to vasoconstrictors, hypotension, myocardial depression and circulatory shock. These responses occur through mechanisms associated with the induction of inducible nitric oxide (NO) synthase (iNOS), with a consequent increase in NO levels. The experimental model of cecal ligation and puncture (CLC) is considered the most similar to human sepsis and has been widely used to study the mechanisms whereby sepsis affects the cardiovascular system. The results of these experimental studies have shown that sepsis induces myocardial damage, hypotension and vascular hyporeactivity to vasoconstrictor agents (vasoplegia). The induction of iNOS, with further increase in NO production is a central mechanism by which sepsis induces its cardiac and vascular effects. Additionally, sepsis induces an increase in the generation of proinflammatory cytokines and reactive oxygen species (ROS), and these responses may lead to lipoperoxidation, protein nitration and tissue dysfunction. Chronic ethanol consumption is associated to an increased incidence of infections and individuals who consume ethanol frequently have higher mortality rates in response to sepsis. In addition, chronic ethanol consumption alters the cardiac and circulatory functions being considered as an important risk factor for the development of cardiovascular diseases. In the cardiovascular system, chronic ethanol consumption induces the expression of iNOS, increases the generation of ROS and proinflammatory cytokines, and these actions lead to tissue damage, which results in functional alterations. Therefore, both sepsis and ethanol consumption have an important impact in cardiac and vascular structure and function and iNOS stands out as an important mediator of these responses. However, there are no studies describing the impact of ethanol consumption in the cardiovascular changes induced by sepsis or the mechanisms involved in this response. The hypothesis of this study is that chronic ethanol consumption will induce iNOS expression in the heart and vessels, and this response will cause important cardiovascular changes that will contribute to the worsening of sepsis. In addition to iNOS induction, ethanol consumption would increase proinflammatory cytokines and ROS that would lead to tissue damage by lipoperoxidation and protein nitration, thus contributing to the increased cardiovascular dysfunction and susceptibility to sepsis. Although it has been described that chronic ethanol consumption worse sepsis, there are no studies evaluating whether the cardiovascular changes caused by ethanol consumption are important in this process. Therefore, the present project was designed to investigate the impact of ethanol consumption in the cardiac and vascular damages (including vasoplegia) induced by sepsis and the possible role of iNOS in such responses. (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)

SOUSA, ARTHUR H.; DO VALE, GABRIEL T.; DA SILVA, CARLA B. P.; AWATA, WANESSA M. C.; PINHEIRO, LUCAS C.; TIRAPELLI, CARLOS R.. Ethanol and cyclophosphamide induce similar nephrotoxic effects: possible role for Nox4 and superoxide. Canadian Journal of Physiology and Pharmacology, v. 99, n. 7, p. 744-751, JUL 2021. (17/24123-5)

DO VALE, GABRIEL T.; SOUSA, ARTHUR H.; GONZAGA, NATALIA A.; DE OLIVEIRA, MARIANA G.; JUSTO, ALBERTO F. O.; ALEXANDRE, EDUARDO C.; TANUS-SANTOS, JOSE E.; ANTUNES, EDSON; TIRAPELLI, CARLOS R.. Chronic ethanol consumption induces micturition dysfunction and alters the oxidative state of the urinary bladder. Canadian Journal of Physiology and Pharmacology, v. 97, n. 12, p. 1103-1114, DEC 2019. (17/24123-5)

SOUSA, ARTHUR H.; DO VALE, GABRIEL T.; NASCIMENTO, JOSE A.; AWATA, WANESSA M. C.; SILVA, CARLA B. P.; ASSIS, VICTOR O.; ALVES, V, JULIANO; TOSTES, RITA C.; TIRAPELLI, CARLOS R.. Inhibition of inducible nitric oxide synthase protects against the deleterious effects of sub-lethal sepsis and ethanol in the cardiorenal system. Canadian Journal of Physiology and Pharmacology, v. 99, n. 12, p. 1324-1332, DEC 2021. (17/24123-5, 18/06583-1, 18/23985-6)

AWATA, WANESSA M. C.; GONZAGA, NATALIA A.; BORGES, VANESSA F.; SILVA, CARLA B. P.; TANUS-SANTOS, JOSE E.; CUNHA, FERNANDO Q.; TIRAPELLI, CARLOS R.. Perivascular adipose tissue contributes to lethal sepsis-induced vasoplegia in rats. European Journal of Pharmacology, v. 863, NOV 15 2019. (17/24123-5)