EFEITO DO CILOSTAZOL SOBRE AS ALTERAÇÕES VASCULARES E DANO TECIDUAL INDUZIDOS POR MODELO EXPERIMENTAL DE SEPSE

Abstract

Sepsis is characterized by a multiple organ dysfunction caused by an unregulated immune response to infection, associated with high incidence and mortality rate. Advancing new therapeutic approaches remains a challenge because of the complexity of the syndrome. Studies show that, although deleterious in the late phase of the syndrome, the basal production of nitric oxide (NO) in the early sepsis presents a protective role of hemodynamic control and perfusion to the tissues. The effects of NO, in particular, vasodilation are mediated by the cGMP nucleotide which together with cAMP controls various cellular responses and signaling. Phosphodiesterases (PDEs) act in the inactivation of cyclic nucleotides, thus controlling the cellular signaling mediated by these second messengers, being, therefore, the target of possible pharmacological approaches in sepsis. The present study evaluated the effect of treatment with cilostazol, a PDE3 inhibitor, which controls cAMP and cGMP signaling in the early sepsis. Male Wistar rats were submitted to cecal ligation and puncture (CLP) or false surgery (Sham). Six hours after the procedure the animals received cilostazol (15 mg/kg, gavage) or vehicle (peanut oil, 1 mL/kg, gavage). After 24 hours, the animals submitted to the CLP surgical procedure reproduced the cardiovascular characteristics of sepsis, such as hypotension, hyporesponsiveness to vasoconstrictors, tachycardia, decreased renal blood flow (RBF), and inflammatory manifestations such as increased NO production, myeloperoxidase (MPO) activity in tissues and histopathological changes. The treatment with cilostazol improved vascular reactivity to vasoconstrictors, observed in vivo and in isolated aortic rings, and restored heart rate response in the septic animals. There was an improvement in the tissue perfusion observed by the increase of basal RBF in the septic animals, demonstrating a hemodynamic improvement, besides the treatment to prevent hemoconcentration in the septic animals. The neutrophil recruitment to the lung was also reduced with the treatment proven by MPO analysis and histopathology, evidencing an improvement in inflammatory tissue response. The treatment with cilostazol also prevented lactate elevation in septic animals, is this an important marker of tissue perfusion. The results demonstrate that the use of inhibitors of PDEs such as cilostazol may represent an important pharmacological strategy in the treatment of sepsis if administered at the right moment during the syndrome development.