Inhibition of Nitric Oxide Synthesis Improves the Vasoconstrictive Effect of Noradrenaline in Sepsis

Effect of L-NAME, an Inhibitor of Nitric Oxide Synthesis, on Cardiopulmonary Function in Human Septic Shock

“…1 Increased production of NO by the CHEST / 113 / 6 / JUNE, 1998 inducible NO synthase has been implicated as a major contributor to the cardiovascular dysfunction of endotoxin-and cytokine-induced shock in animals. [11][12][13] The present study shows that NO is responsible, at least in part, for the hemodynamic derangements in patients with severe sepsis. Prolonged inhibition of NO synthesis with L-NAME could improve cardiovascular status and pulmonary gas exchange in these severely ill patients and may provide a new treatment modality in the management of septic shock.…”

“…In addition, the detrimental effects are dose dependent and mostly seen in studies using extremely high doses of the NO synthase inhibitor. 29 In our study, patients received L-NAME, 1 mg/ kg/h, for 12 h, resulting in a total dose of 12 mg/kg of L-NAME, which is relatively low compared with the doses of NO inhibitors used in most animal studies 12,13 and comparable to the doses used in studies in humans. [14][15][16]30 Animal studies have shown that L-NAME is probably a prodrug that is converted to the active L-NNA, which is much more stable and has a high plasma half-life.…”

“…[12][13][14][15][16] So far, the precise mechanism underlying this reduction in CO remains unclear. In our study, it could partially have resulted from a reflex change due to the increased SVR and afterload, or a reduction in vasopressor support.…”

“…Indeed, in prior pilot experiments, we found that higher doses of L-NAME resulted in severe pulmonary hypertension. The pulmonary vasoconstriction seen with L-NAME and other inhibitors of NO synthase [12][13][14][15] may limit their clinical application, especially in patients with high PAP. Since NO inhalation may improve oxygenation in patients with ARDS, we hypothesized that inhibition of NO synthesis might lead to problems in pulmonary gas exchange.…”

“…9,10 Infusion of these analogues of L-arginine can reverse endotoxin-or cytokine-induced hypotension and can restore reactivity to catecholamines in animals. [11][12][13] In patients with septic shock, short-term administration of these inhibitors of NO synthesis has been shown to increase BP and systemic vascular resistance (SVR). [14][15][16] Furthermore, methylene blue, an inhibitor of soluble guanylate cyclase that is the effector enzyme of NO, has been shown to temporarily raise BP in patients with sepsis.…”