Impact of tadalafil on cardiovascular and organ dysfunction induced by experimental sepsis
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Background: Sepsis is a life-threatening condition that affects the cardiovascular and renal systems. Severe hypotension during sepsis compromises tissue perfusion, which can lead to multiple organ dysfunction and death. Phosphodiesterase 5 (PDE5) degrades intracellular cyclic guanosine monophosphate (cGMP) levels which promotes vasodilatation in specific sites. Our previous studies show that inhibiting cGMP production in early sepsis increases mortality, implying a protective role for cGMP production. Then, we hypothesized that cGMP increased by tadalafil (PDE5 inhibitor) could improve microcirculation and prevent sepsis-induced organ dysfunction.Methods: Rats were submitted to cecal ligation and puncture (CLP) sepsis model and treated with tadalafil (2 mg/kg, s.c.) 8 hours after the procedure. Hemodynamic, inflammatory and biochemical assessments were performed 24 hours after sepsis induction. Moreover, the effect of tadalafil on the survival of septic rats was evaluated for 5 days.Results: Tadalafil treatment improves basal renal blood flow during sepsis and preserves it during noradrenaline infusion. Sepsis induces hypotension, impaired response to noradrenaline, and increased cardiac and renal neutrophil infiltration, in addition to increased levels of plasma nitric oxide and lactate. None of these dysfunctions were changed by tadalafil. Additionally, tadalafil treatment did not increase the survival rate of septic rats.Conclusions: Tadalafil improved microcirculation of septic animals; however, no beneficial effects were observed on macrocirculation and inflammation parameters. Then, the potential benefit of tadalafil in the prognosis of sepsis should be evaluated within a therapeutic strategy covering all sepsis injury mechanisms.
Abstract
Background: Sepsis is a life-threatening condition that affects the cardiovascular and renal systems. Severe hypotension during sepsis compromises tissue perfusion, which can lead to multiple organ dysfunction and death. Phosphodiesterase 5 (PDE5) degrades intracellular cyclic guanosine monophosphate (cGMP) levels which promotes vasodilatation in specific sites. Our previous studies show that inhibiting cGMP production in early sepsis increases mortality, implying a protective role for cGMP production. Then, we hypothesized that cGMP increased by tadalafil (PDE5 inhibitor) could improve microcirculation and prevent sepsis-induced organ dysfunction.Methods: Rats were submitted to cecal ligation and puncture (CLP) sepsis model and treated with tadalafil (2 mg/kg, s.c.) 8 hours after the procedure. Hemodynamic, inflammatory and biochemical assessments were performed 24 hours after sepsis induction. Moreover, the effect of tadalafil on the survival of septic rats was evaluated for 5 days.Results: Tadalafil treatment improves basal renal blood flow during sepsis and preserves it during noradrenaline infusion. Sepsis induces hypotension, impaired response to noradrenaline, and increased cardiac and renal neutrophil infiltration, in addition to increased levels of plasma nitric oxide and lactate. None of these dysfunctions were changed by tadalafil. Additionally, tadalafil treatment did not increase the survival rate of septic rats.Conclusions: Tadalafil improved microcirculation of septic animals; however, no beneficial effects were observed on macrocirculation and inflammation parameters. Then, the potential benefit of tadalafil in the prognosis of sepsis should be evaluated within a therapeutic strategy covering all sepsis injury mechanisms.