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© 1997 American Heart Association, Inc.
Articles |
Pulmonary Vasoconstriction and Hypertension in Mice With Targeted Disruption of the Endothelial Nitric Oxide Synthase (NOS 3) Gene
From the Department of Anaesthesia and Critical Care (W.S., F.I., W.E.H., R.C.J., W.M.Z.) and the Cardiovascular Research Center (P.L.H., M.C.F.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass, and the Department of Pharmacology (J.A.B.), University of Vermont College of Medicine, Burlington.
Correspondence to Warren M. Zapol, MD, Reginald Jenney Professor of Anaesthesia, Department of Anaesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, 32 Fruit St, Boston, MA 02114.
Abstract NO, synthesized in endothelial cells by endothelial NO synthase (NOS 3), is believed to be an important endogenous pulmonary vasodilator substance that contributes to the normal low pulmonary vascular resistance. To selectively investigate the role of NOS 3 in the pulmonary circulation, mice with targeted disruption of the NOS 3 gene were studied. Pulmonary hemodynamics were studied by measuring pulmonary artery pressure, left ventricular end-diastolic pressure, and lower thoracic aortic flow by using a novel open-chest technique. Transient partial occlusion of the inferior vena cava was used to assess the pulmonary artery pressure-flow relationship. Tension developed by isolated pulmonary artery segments after acetylcholine stimulation was measured in vitro. The histological appearance of NOS 3–deficient and wild-type murine lungs was compared. NOS 3–deficient mice (n=27), when compared with wild-type mice (n=32), had pulmonary hypertension (pulmonary artery pressure, 19.0±0.8 versus 16.4±0.6 mm Hg [mean±SE]; P<.05) that was due to an increased total pulmonary resistance (62±6 versus 33±2 mm Hg·min·g·mL-1; P<.001). In vitro, acetylcholine induced vasodilation in the main pulmonary arteries of wild-type but not NOS 3–deficient mice. The morphology of the lungs of NOS 3–deficient mice did not differ from that of wild-type mice. We conclude that NOS 3 is a key enzyme responsible for providing basal pulmonary NO release. Congenital NOS 3 deficiency produces mild pulmonary hypertension in mice.
Key Words: targeted nitric oxide synthase 3 gene disruption • pulmonary vascular resistance • nitric oxide • mouse • acetylcholine
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