Endothelial nitric oxide synthase is a regulator of hemodynamics in sepsis

Background

While inducible nitric oxide synthase (iNOS) is believed to be the high-capacity NO-producing enzyme responsible for the detrimental hemodynamic alterations observed during sepsis, the role of endothelial nitric oxide synthase (eNOS) remains more obscure. Thus, it was the present study's aim to elucidate the influence of eNOS on hemodynamics in septic shock using eNOS^-/- mice in the clinically relevant polimicrobial cecum ligation and puncture (CLP) model of sepsis.

Methods and results

Prolonged survival was observed in eNOS^-/- mice (68 ± 25 hours vs 25 ± 6 hours in WT mice, n = 12, P < 0.001). Chronic unselective NOS inhibition with ethylthiourea (ETU) in eNOS^-/- mice after sepsis induction diminished this survival benefit, while ETU application in WT mice after CLP led to slight improvement in survival time. Cardiac output, studied by serial echocardiography, increased to a maximum of 60% over baseline at 10 hours after sepsis induction in WT mice but not in septic eNOS^-/- mice and septic mice (WT and eNOS^-/-) treated by unselective NOS inhibition. WT CLP mice were refractory to β-stimulation, while eNOS^-/- CLP mice responded comparably with sham-operated WT mice. Mean arterial blood pressure was decreased by 25 ± 8 mmHg (P < 0.001; n = 8) in WT CLP mice, with eNOS^-/- CLP mice showing no sign of hypotension. Contractility of isolated WT CLP hearts was impaired by 35% (P < 0.001, n = 8), but hearts from CLP eNOS^-/- mice remained unaltered. While eNOS expression remained stable, coronary flow studies indicated a high level of eNOS activation secondary to sepsis.

Conclusion

eNOS is a key player in the hemodynamics of sepsis. Selective eNOS inhibition appears beneficial in this model of sepsis with global nitric oxide synthase inhibition diminishing most of the observed benefit.