Nitric oxide synthase inhibition vs. scavenging with hemoglobin in ovine sepsis: Effect on hypoxic pulmonary vasoconstriction (HPV)

Nitric oxide (NO) mediates generalized vasodilation in hyperdynamic sepsis. HPV is blunted in sepsis. In normal persons, inhaled NO abolishes HPV. We investigated the effect of NO synthase inhibition or scavenging on HPV in sepsis. Sheep received an 48-hr infusion of 6×10⁶ colony-forming-units/kg/h Pseudomonas aeruginosa. After 24 hrs 8 sheep received N^G-monomethyl-L-arginine (L-NMMA) at 6.6 mg/kg/h; 8 sheep 20 mg/kg/h pyridoxalated hemoglobin polyoyxethylene conjugate (PHP). Left pulmonary flow during left lung hypoxia with 100% nitrogen with the right lung receiving 100% oxygen was measured with an ultrasonic flow probe around the left pulmonary artery. HPV was assessed as the decrease in left pulmonary blood flow during hypoxia in % from baseline normoxic conditions. At 24 hrs all sheep showed a hyperdynamic circulatory state which was reversed by L-NMMA and PHP at 28 hrs. HPV fell from baseline values of 56±4% (L-NMMA) and 50±8% (PHP) to 26±4% and 23±6%. At 28 hrs it rose to 38±4% in the L-NMMA group (p<0.05 vs. 24 hrs and vs. PHP group), but stayed at 20±5% in the PHP group. After stopping L-NMMA and PHP, both groups showed equally depressed HPV at 48 hrs. Values for the calculated intrapulmonary shunt showed a similar pattern. Our data show that in sepsis depressed HPV can be partially restored by NO synthase inhibition indicating a role for NO in HPV regulation in sepsis. PHP, on the other hand, did not restore HPV. Hemoglobin has been proposed to act as a NO donor in certain vascular beds which could explain its lack of effect on HPV in sepsis. (Funded in pan by a grant from Apex Pharmaceuticals.).