Inosine Infusion Prevents Mortality in Endotoxic Shock

Abstract

Substances that inhibit Na/K ATPase activity appear in plasma during severe septic shock causing Na and fluid to move into cells and K to move out, resulting in cell swelling and an elevation of plasma K. These changes contribute to the morbidity of sepsis. Recently, we reported that inosine and other purine nucleosides stimulate Na/K ATPase activity, prolong survival in hemorrhagic shock, and lower the plasma potassium in that condition. Here, we determine whether inosine prolongs survival in lipopolysaccharide-induced sepsis shock. Pentobarbital-anesthetized rats underwent cannulation of a femoral artery and vein, and lipopolysaccharide was injected by intravenous bolus (10 mg/kg). Rats were than resuscitated (5 mL/hr) with inosine (5 mmol/L) in saline, saline alone, inosine with S-4-nitrobenzyl-6-thioinosine (NBTI, 10 micromol/L, an equilibrative nucleoside transporter blocker), NBTI alone, or no resuscitation. Inosine significantly and dramatically prolongs survival of rats in endotoxic shock as compared with saline resuscitation or to no resuscitation. Furthermore, resuscitation with NBTI (10 micromol/L) prevented prolonged survival with inosine. Inosine prevents mortality in lipopolysaccharide-induced septic shock in rats. The mechanism of action must be intracellular, as blockers of the equilibrative nucleoside transporter prevented prolonged survival with inosine.