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.

The only way to fill the gap: Combinations of repurposed drugs against antibiotic resistance and lethal sepsis

“…In 2017, other groups confirmed the effects of PDE5 inhibitors. Kovalski et al confirmed the protective effect of sildenafil in the rat CLP model of sepsis featuring significantly increased levels of plasma nitrate/nitrite (NO x ), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, creatine kinase and lactate [79]. At a functional level, the sepsis led to hypotension, hyporesponsiveness to vasoconstrictor, and renal blood flow reduction.…”

Phosphodiesterase Inhibitors in Acute Lung Injury: What Are the Perspectives?

“…Nevertheless, PDE5 inhibitors have been effective in the indirect lung injury, as well. In a model of CLP-induced sepsis in rats, administration of sildenafil 8 h after the insult elevated a renal blood flow and decreased the plasma levels of creatinine, lactate, and creatine kinase, and lung myeloperoxidase [171]. In acute pancreatitis-associated ALI in rats sildenafil reduced an extent of the lung injury and inflammation, elevated an expression of proliferation-related markers, and suppressed an expression of apoptosis-related markers [172].…”

Agentes inibidores da fosfodiesterase no tratamento da sepse e choque séptico

“…Depois disso, o paciente passa para um estágio imunossuprimido (Kumar, 2020;Coopersmith et al, 2018). O sistema circulatório também sofre mudanças durante a sepse e choque séptico, passando de uma vasoconstrição inicial intensa para vasodilatação generalizada que pode não responder a vasoconstritores naturais, gerando hipotensão e hipoperfusão (Kovalski et al, 2017;Russell, Rush & Boyd, 2018).…”

“…Esses nucleotídeos são metabolizados pelas enzimas fosfodiesterases (PDE), a qual é dividida em 11 famílias com diferentes especificidades de substrato. Diante disso, a inibição da PDE pode ser uma estratégia para prevenir lesão isquêmica e diminuir a resposta inflamatória em pacientes sépticos (Kovalski et al, 2017;Pan et al, 2019).…”

“…Os iPDE-3, como amrinona, milrinona e oprinona e inibidores inespecíficos, como a pentoxifilina e teofilina, foram pioneiros nas pesquisas préclínicas e clínicas do manejo da sepse (Németh et al, 1997;Schimidt et al, 2000a;Miyakawa et al, 2004). Nos últimos anos, foram realizados estudos em modelos animais com o inibidor da PDE-5 sildenafil (Kovalski et al, 2017;Özer, Topal & Sem, 2020) e iPDE-4 como rolipram e roflumilaste (Sims et al, 2017;Lu et al, 2020;Xu et al, 2020). Devido as recentes descobertas, e visto que a sepse e o choque representam um problema de saúde de alta incidência e difícil manejo, o objetivo desse trabalho foi relatar o uso de inibidores da fosfodiesterase nas condições de sepse observando as metodologias empregas, desfechos dos estudos e perspectivas futuras.…”