Effects of chronic pulmonary overcirculation on pulmonary vasomotor tone

Background. A model of shunt-induced pulmonary hypertension was used to stu dy the effects of pulmonary overcirculation on endothelial nitric oxide syn thase (eNOS) and cytochrome P450-4A (cP450-4A) vasodilatory mechanisms and related hemodynamic responses. Methods. An aortopulmonary shunt was constructed in 6-week-old piglets (n = 7, sham-operated controls n = 8). Hemodynamic measurements were made 4 wee ks later under serial experimental conditions: baseline (fractional concent ration of oxygen, 0.4); inhaled nitric oxide, 25 ppm (INO); hypoxia (fracti onal concentration of oxygen, 0.14); hypoxia + INO; N-omega-nitro-L-arginin e methylester (L-NAME 30 mg/kg intravenously, competitive NOS inhibitor); a nd L-NAME + INO. Lung protein levels of eNOS and cP450-4A and NOS activity were compared between groups. Results, Shunted animals had a higher baseline pulmonary artery pressure (p < 0.05). L-NAME resulted in a greater increase in pulmonary vascular resis tance in shunted animals (150% +/- 26% shunt versus 69% +/- 14% control; p = 0.01). The INO administered during baseline conditions decreased pulmonar y vascular resistance only in control animals (p < 0.05). Protein levels of eNOS and NOS activity were similar in both groups; however, cP450-4A prote in levels were decreased in the shunted group (p = 0.02). Conclusions. The NO production was preserved in shunted animals but they de monstrated greater vasodilatory dependence on NO, evidenced by an exaggerat ed increase in pulmonary vascular resistance after NOS inhibition. Loss of the cP450-4A vasodilatory system may be the driving force for NO dependency in the shunted pulmonary circulation. (C) 1999 by The Society of Thoracic Surgeons.