ENDOTOXIN ALTERS THE SYSTEMIC DISPOSITION OF NITRIC-OXIDE SYNTHASE INHIBITORS IN THE AWAKE SHEEP

1. We evaluated the haemodynamic effects and systemic disposition of t he nitric oxide synthase (NOS) inhibitor N-L-nitro-L-arginine (NOLA) a fter intravenous (i,v,) administration of two different doses (5 and 2 0 mg/kg) in awake healthy sheep and awake sheep given a continuous i,v , infusion of endotoxin (lipopolysaccharide, 12 ng/kg per h, i,v,, for 18 h), In addition, we determined the systemic disposition of another NOS inhibitor, NL-nitro-L-arginine methylester (L-NAME; 20mg/kg, i,v, ) in awake healthy sheep only. 2. NL-Nitro-L-arginine produced a dose- dependent decrease in heart rate (HR) and cardiac output (CO) together with a dose-dependent increase in mean arterial pressure (MAP) and pe ripheral vascular resistance (PVR) when compared to baseline, In endot oxic sheep NOLA produced a greater increase in MAP and mean pulmonary arterial pressure (MPAP), 3, In healthy sheep there was a dose-related increase in total body clearance (Cl) of NOLA, The Cl increased from 0.028 L/min after the lower dose to 0.032 L/min after the higher dose, The infusion of endotoxin caused an increase in Cl of NOLA to 0.040 a nd 0.047 L/min, respectively, and a decrease in plasma slow half-life ltd from 825 to 546 min and from 780 to 453 min, respectively, 4. NL-N itro-L-arginine methylester was rapidly cleared from the plasma with a slow half-life of approximately 7.5 min and there was a simultaneous appearance of NOLA in the plasma, 5, These results support the view th at nitric oxide has a significant role in regulating vascular tone in healthy and endotoxic sheep and indicate that the increases in Cl of N OLA with an increase in its dose and the presence of endotoxin will be important in influencing appropriate dosage regimens in clinical stud ies.