PULMONARY VASOCONSTRICTION AND HYPERTENSION IN MICE WITH TARGETED DISRUPTION OF THE ENDOTHELIAL NITRIC-OXIDE SYNTHASE (NOS-3) GENE

NO, synthesized in endothelial cells by endothelial NO synthase (NOS 3 ), is believed to be an important endogenous pulmonary vasodilator sub stance that contributes to the normal low pulmonary vascular resistanc e. To selectively investigate the role of NOS 3 in the pulmonary circu lation, mice with targeted disruption of the NOS 3 gene were studied. Pulmonary hemodynamics were studied by measuring pulmonary artery pres sure, left ventricular end-diastolic pressure, and lower thoracic aort ic flow by using a novel open-chest technique. Transient partial occlu sion of the inferior vena cava was used to assess the pulmonary artery pressure-flow relationship. Tension developed by isolated pulmonary a rtery segments after acetylcholine stimulation was measured in vitro. The histological appearance of NOS 3-deficient and wild-type murine lu ngs was compared. NOS 3-deficient mice (n=27), when compared with wild -type mice (n=32), had pulmonary hypertension (pulmonary artery pressu re, 19.0+/-0.8 versus 16.4+/-0.6 mm Hg [mean+/-SE]; P<.05) that was du e to an increased total pulmonary resistance (62+/-6 versus 33+/-2 mm Hg . min . g mL(-1); P<.001). In vitro, acetylcholine induced vasodila tion in the main pulmonary arteries of wild-type but not NOS 3-deficie nt mice. The morphology of the lungs of NOS 3-deficient mice did not d iffer from that of wild-type mice. We conclude that NOS 3 is a key enz yme responsible for providing basal pulmonary NO release. Congenital N OS 3 deficiency produces mild pulmonary hypertension in mice.