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Byline: Thomas Hoehn (1,6), Anthony A. Preston (2), Allan R. McPhaden (3), Brigitte Stiller (4), Martin Vogel (5), Christoph Buhrer (1), Roger M. Wadsworth (2) Keywords: Persistent pulmonary hypertension of the newborn; Inducible nitric oxide synthase; Nitrotyrosine; Endothelial cells; Inhaled nitric oxide Abstract: Objective To provide evidence for the upregulation of endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS) in the assumed imbalance in the pathophysiology of rapid progressive pulmonary hypertension of the newborn (RPPHN), which is characterized by abnormal hypertrophy of the pulmonary arterioles and arteries leading to increased pulmonary vascular resistance. Furthermore, to determine the cellular source and topographic distribution of eNOS and iNOS. Material and Methods Lung biopsies were taken from two term neonates with clinical and echocardiographic evidence of RPPH and of three controls. Biopsies were obtained at an early stage of the disease as well as at post mortem and examined immunohistochemically for the presence of eNOS, iNOS and nitrotyrosine. Results The endothelial cells of pulmonary arterioles stained significantly for eNOS protein in RPPHN patients. This was not the case in the control infants. There were no differences for nitrotyrosine or iNOS between RPPHN patients and controls. Conclusion Rapid progressive pulmonary hypertension of the newborn leads to compensatory induction of eNOS synthesis specifically in endothelial cells of the pulmonary arterioles. This mechanism of compensation can lead to delayed presentation of RPPHN during the late neonatal period. Exogenous inhaled nitric oxide therapy does not lead to suppression of the endogenous synthesis of nitric oxide. Author Affiliation: (1) Department of Neonatology, Humboldt University, Charite Virchow Hospital, Augustenburger Platz 1, 13353, Berlin, Germany (2) Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde Institute for Biomedical Sciences, Arbuthnott Building, G4 0NR, Glasgow , Scotland, UK (3) Department of Pathology, Glasgow Royal Infirmary, Castle Street, G4 0SF, Glasgow , Scotland, UK (4) German Heart Institute, Augustenburger Platz 1, 13353, Berlin, Germany (5) Department of Paidopathology and Placentology, Humboldt University, Charite Virchow Hospital, Augustenburger Platz 1, 13353 , Berlin, Germany (6) Neonatology and Pediatric Intensive Care, Children's Hospital, Heinrich Heine University, Moorenstrasse 5, 40225 , Dusseldorf, Germany Article History: Received Date: 28/08/2002 Accepted Date: 27/05/2003 Online Date: 02/08/2003

Research was conducted to study the vascular and cardiac response of nitric oxide synthase blockade in vivo in rats. Blood pressure was determined by tail-cuff plethysmography in conscious, restrained rats while the aorta was dissected and prepared for aortic rings for functional studies. Results indicated that nitric oxide deficiency in vivo results in the development of vascular and cardiac hypertrophy. They also showed that no significant difference in nitric oxide expression in the aorta or heart despite marked functional and structural changes.