Effects of a selective nitric oxide synthase inhibitor on endotoxin-induced alteration in hypoxic pulmonary vasoconstriction in sheep

It has been suggested that overproduction of nitric oxide (NO) by nitric oxide synthase (NOS) contributes to blunted hypoxic pulmonary vasoconstriction (HPV) during endotoxemia. We investigated the effect of a selective inducible NOS (iNOS) inhibitor, ONO-1714, on the loss of HPV during endotoxemia in awake sheep to clarify the role of iNOS. We prepared 11 intubated, awake sheep with hemodynamic monitoring. Hypoxic challenges (FiO2; 12%) were performed before, and 5, 24, 48, 72 hours after endotoxin (1 mug/kg) infusion for 15 minutes. Pulmonary artery (Ppa) and left atrial pressure (Pla) were continuously measured and cardiac output (CO) was measured by the thermodilution method. Pulmonary vascular resistance (PVR) was calculated by (Ppa - Pla)/CO. The percent change in PVR (%PVR) before (pre-PVR) and after (post-PVR) hypoxia was calculated as (post-PVR - pre-PVR)/pre-HPV x 100. ONO-1714 (0.1 mg/kg, n = 5, Exp 1) or normal saline (n = 6, Exp 2) was administered 5 hours before hypoxic challenge every day. ONO-1714 did not affect the baseline pulmonary hemodynamics before endotoxin administration. % PVR before and after hypoxic exposure was significantly decreased 5 hours after endotoxin administration and gradually improved to baseline at 72 hours. Treatment with iNOS inhibition significantly restored % HPV (24.7 +/- 5.5% in Exp 1 versus -3.1 +/- 3.6% in Exp 2, 5 hours, 25.3 +/- 2.5% in Exp 1 versus 7.7 +/- 2.2% in Exp 2, 24 hours). It is suggested that inducible nitric oxide is related to pulmonary vascular hyporesponsiveness to hypoxia during endotoxemia in sheep.