Relative contributions of endothelial, inducible, and neuronal NOS to tonein the murine pulmonary circulation

Nitric oxide plays an important role in modulating pulmonary vascular tone. All three isoforms of nitric oxide synthase (NOS), neuronal (nNOS, NOS I), inducible (iNOS, NOS II), and endothelial (eNOS, NOS III), are expressed i n the lung. Recent reports have suggested an important role for eNOS in the modulation of pulmonary vascular tone chronically; however, the relative c ontribution of the three isoforms to,acute modulation of pulmonary vascular tone is uncertain. We therefore tested the effect of targeted disruption o f each isoform on pulmonary vascular reactivity in transgenic mice. Isolate d perfused mouse lungs were used to evaluate the effect of selective loss o f pulmonary nNOS, iNOS, and eNOS with respect to hypoxic pulmonary vasocons triction (HPV) and endothelium-dependent and -independent vasodilation. eNO S null mice had augmented HPV (225 +/- 65% control, P < 0.02, mean +/- SE) and absent endothelium-dependent vasodilation, whereas endothelium-independ ent vasodilation was preserved. HPV was minimally elevated in iNOS null mic e and normal in nNOS null mice. Both nNOS and iNOS null mice had normal end othelium-dependent vasodilation. In wild-type lungs, nonselective NOS inhib ition doubled HPV, whereas selective iNOS inhibition had no detectable effe ct. In intact, lightly sedated mice, right ventricular systolic pressure wa s elevated in eNOS-deficient (42.3 +/- 1.2 mmHg, P < 0.001) and, to a lesse r extent, in iNOS-deficient (37.2 +/- 0.8 mmHg, P < 0.001) mice, whereas it was normal in nNOS-deficient mice (30.9 +/- 0.7 mmHg, P = not significant) compared with wild-type controls (31.3 +/- 0.7 mmHg). We conclude that in the normal murine pulmonary circulation 1) nNOS does not modulate tone, 2) eNOS-derived nitric oxide is the principle mediator of endothelium-dependen t vasodilation in the pulmonary circulation, and 3) both eNOS and iNOS play a role in modulating basal tone chronically.