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Modulation played by C-type natriuretic peptide (CNP) on the contractile response induced by phenylephrine on thoracic aorta and mesenteric resistance arteries isolated from rats submitted to septic shock

Grant number: 11/11205-7
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): February 01, 2012
Effective date (End): June 30, 2015
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:Lusiane Maria Bendhack
Grantee:Laena Pernomian
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Septic shock is a systemic inflammatory syndrome secondary to an infectious process, in which the dysfunction of endothelial and vascular smooth muscle cells contributes to an insufficient blood supply to vital organs, with consequent systemic hypotension, multiple organ failure and death. This condition is the major cause of death for patients in intensive care units (ICUs). It is widely known that although the mechanisms underlying cardiovascular disorders resulted from the process of sepsis are complex, they partially involve the excessive production of nitric oxide (NO) and cytokines such as IL-1a, IL-1b, TNF-a and TGF-b. The sustained production of NO after induction of iNOS and oxidative stress are related to prolonged vasodilation of vascular smooth muscle and to a hyporesponsiveness for vasoconstrictor agonists during sepsis. However, although the administration of ascorbic acid and nonselective inhibitors of NOS isoforms in animals have been favorable in reversing and decreasing the effects of septic shock, clinical use of nonselective NOS inhibitors caused increased mortality of patients in septic shock. In patients with severe sepsis and septic shock, plasma levels of natriuretic peptides ANP, BNP and CNP are elevated. In this context, knockout mice to NPR-A / B receptors showed reversal of vascular hyporesponsiveness to contractile agents and of hypotension due to exposure to LPS. Therefore, the hypothesis of the present study is that in the model of sepsis induced by cecal ligation and puncture (CLP) in rats there will be a vascular hyporesponsiveness to the ±1-adrenergic contractile agonist Phenylephrine and this effect will be attenuated by inhibiting the signaling triggered by the CNP and strongly modulated by cytokines such as IL-1a, IL-1b, TNF-a and TGF-b and oxidative stress. So, the aims of the present study are: 1) to study the modulation promoted by CNP on contractile response induced by phenylephrine on thoracic aorta and mesenteric resistance arteries of healthy control animals (CO) and CLP, 2)to assess the survival and charactristic systemic hypotension response observed on septic shock after the treatment with NPR-A/B antagonist HS-142-1 or NPR-C antagonist M372049 in healthy control animals (CO) and CLP. Parallel, the level of protein expression of iNOS, plasma natriuretic peptides, cytokines and metabolites of NO and the contribution of oxidative stress in these responses will be evaluated.

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)
PERNOMIAN, LARISSA; PERNOMIAN, LAENA; GOMES, MAYARA S.; DA SILVA, CARLOS H. T. P. Pharmacological significance of the interplay between angiotensin receptors: MAS receptors as putative final mediators of the effects elicited by angiotensin ATi receptors antagonists. European Journal of Pharmacology, v. 769, p. 143-146, DEC 15 2015. Web of Science Citations: 3.
MOREIRA, JOSIMAR D.; PERNOMIAN, LARISSA; GOMES, MAYARA S.; PERNOMIAN, LAENA; MOREIRA, RAFAEL P.; DO PRADO, ALEJANDRO F.; DA SILVA, CARLOS H. T. P.; DE OLIVEIRA, ANA M. Acute restraint stress increases carotid reactivity in type-I diabetic rats by enhancing Nox4/NADPH oxidase functionality. European Journal of Pharmacology, v. 765, p. 503-516, OCT 15 2015. Web of Science Citations: 10.
PERNOMIAN, LARISSA; GOMES, MAYARA S.; PERNOMIAN, LAENA; MOREIRA, RAFAEL P.; CORREA, FERNANDO M. A.; DE OLIVEIRA, ANA M. Vasoprotective effects of neurocompensatory response to balloon injury during diabetes involve the improvement of Mas signaling by TGF beta(1) activation. VASCULAR PHARMACOLOGY, v. 64, p. 36-48, JAN 2015. Web of Science Citations: 5.
PERNOMIAN, LAENA; PERNOMIAN, LARISSA; ARAUJO RESTINI, CAROLINA BARALDI. Counter-regulatory effects played by the ACE - Ang II-AT1 and ACE2-Ang-(1-7) - Mas axes on the reactive oxygen species-mediated control of vascular function:perspectives to pharmacological approaches in controlling vascular complications. Vasa-European Journal of Vascular Medicine, v. 43, n. 6, p. 404-414, NOV 2014. Web of Science Citations: 16.

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