Nitric oxide synthase inhibition restores vasopressor effects of norepinephrine in ovine hyperdynamic sepsis.

Abstract

To investigate the hypothesis that nitric oxide synthase (NOS) inhibition restores the vasopressor response to norepinephrine (NE) in ovine hyperdynamic sepsis, eight sheep were chronically instrumented. In the non-septic portion of the study, NE was titrated to achieve an increase in mean arterial pressure (MAP) by 15 mm Hg ("small dose"). Small-dose NE was repeated 1 h after administration of the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME; bolus 5 mg/kg, followed by 1 mg.kg-1.h-1). After 3 days of recovery, sepsis was induced by a continuous endotoxin infusion (Salmonella typhosa, 10 ng.kg-1.h-1). Three animals died during this period (data excluded). After 24 h, small-dose NE was given. If MAP increased less than 15 mm Hg, the NE dose was increased to achieve the targeted MAP change ("large dose"). Finally, both doses of NE were given after L-NAME administration. To increase MAP by 15 mm Hg in nonseptic animals, the rate of NE infusion was 0.18 +/- 0.03 microgram.kg-1.min-1 (small dose). During L-NAME infusion, this NE dose increased MAP by 32 +/- 8 mm Hg. In septic animals, small-dose NE increased MAP by only 9 +/- 2 mm Hg (P < 0.05 versus nonseptic state). To increase MAP by 15 mm Hg, the NE dose had to be increased to 0.34 +/- 0.06 microgram.kg-1.min-1 (large dose). During L-NAME infusion, NE administration increased MAP by 16 +/- 2 mm Hg and 28 +/- 4 mm Hg (small and large dose, respectively). Thus, L-NAME restored the vasopressor response to NE in sepsis, and increased the vasopressor response to NE in a similar fashion in healthy and septic sheep.