Protective role of cGMP in early sepsis

Abstract

Septic shock, which is triggered by microbial products, is mainly characterised by inadequate tissue perfusion, which can lead to multiple organ dysfunction and death. An intense release of vasoconstrictors agents occurs in the early stages of shock, which can lead to ischemic injury. In this scenario, cGMP could play a key role in counterbalancing these agents and preventing tissue damage. Sildenafil, which is a phosphodiesterase-5 inhibitor, increases cGMP in smooth muscle cells and promotes vasodilation. Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male rats were submitted to either cecal ligation and puncture (CLP) or a sham procedure. Eight h after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10mg/kg, gavage) or vehicle, and twelve or twenty-four h later the inflammatory, biochemical and haemodynamic parameters were evaluated. Sepsis significantly increased levels of plasma nitrate/nitrite (NOx), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, creatine kinase and lactate. Additionally, sepsis led to hypotension, hyporesponsiveness to vasoconstrictor, renal blood flow reduction and also increased lung and kidney myeloperoxidase. Sildenafil increased renal blood flow and reduced the plasma levels of creatinine, lactate and creatine kinase, as well as reducing lung myeloperoxidase. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper time.

Keywords: Guanylate cyclase; Nitric oxide; Phosphodiesterase; Sepsis; Sildenafil.