Differential effects of nitric oxide synthase modulation on porcine systemic and pulmonary circulation in vivo.

OBJECTIVE

To study and compare the effects of inhibiting endothelial nitric oxide synthase on systemic and pulmonary circulation in an in vivo model.

DESIGN

Prospective, randomized, controlled study.

SETTING

Laboratory for experimental surgery at a university medical center.

SUBJECTS

Seventeen anesthetized, mechanically ventilated pigs.

INTERVENTIONS

To produce a stable and continuous stimulation of endothelial nitric oxide synthase, an infusion of acetylcholine was given to one group of animals (n = 5) in a dose that decreased mean arterial pressure by 15%. After 45 mins, N(G)-monomethyl-L-arginine (L-NMMA) was given in a dose of 3 mg/kg for 5 mins in order to inhibit the enzyme. A second dose of 10 mg/kg was given 30 mins later. L-arginine was then given in a dose of 100 mg/kg to reverse the inhibition. One group of animals (n = 6) received a single dose of indomethacin (2.5 mg/kg) 15 mins after the start of acetylcholine infusion. L-NMMA and L-arginine were then given. In a control group (n = 5), the effects of L-NMMA and L-arginine were studied without acetylcholine. Circulatory parameters were monitored and resistance indices were calculated via arterial, central venous, and pulmonary artery catheters.

MEASUREMENTS AND MAIN RESULTS

In control animals, 3 and 10 mg/kg of L-NMMA induced an increase in mean arterial pressure of 14% and 25%, respectively, with similar increases in systemic vascular resistance. Mean pulmonary arterial pressure increased by 22% and 48%, respectively. Acetylcholine lowered mean arterial pressure by 15% and did not affect the relative changes induced by L-NMMA. Acetylcholine had no effect on pulmonary resting tone but enhanced the pulmonary hypertension and increase in resistance induced by L-NMMA. This enhancement was abolished by indomethacin, which produced systemic hypertension while no effect on pulmonary pressure was seen.

CONCLUSIONS

A basal release of nitric oxide contributes to the maintenance of normal vascular tone in the anesthetized pig. Stimulation of endothelial nitric oxide synthase by acetylcholine did not result in any further pulmonary vasodilation as was seen in the systemic circulation. Inhibition of nitric oxide synthase had a greater effect on pulmonary pressure than on systemic pressure. However, this difference was abolished by the administration of indomethacin. Increased nitric oxide release or acetylcholine itself seems to stimulate the production of a vasoconstricting prostanoid in the pulmonary circulation.