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Am J Physiol Lung Cell Mol Physiol 288: L27-L35, 2005. First published September 3, 2004; doi:10.1152/ajplung.00144.2004
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Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension

Gregory A. Ross,1,* Peter Oishi,1,* Anthony Azakie,2 Sohrab Fratz,1 Robert K. Fitzgerald,1 Michael J. Johengen,1 Cynthia Harmon,1 Karen Hendricks-Munoz,3 Jie Xu,4 Stephen M. Black,4 and Jeffrey R. Fineman1,5

Departments of 1Pediatrics and 2Cardiothoracic Surgery and the 5Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; 3Department of Pediatrics, New York University, New York, New York; and 4Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, Montana

Submitted 20 April 2004 ; accepted in final form 30 August 2004

Clinically significant increases in pulmonary vascular resistance (PVR) have been noted upon acute withdrawal of inhaled nitric oxide (iNO). Previous studies in the normal pulmonary circulation demonstrate that iNO increases endothelin-1 (ET-1) levels and decreases endogenous nitric oxide synthase (NOS) activity, implicating an endothelial etiology for the increase in resistance upon iNO withdrawal. However, the effect of iNO on endogenous endothelial function in the clinically relevant pulmonary hypertensive circulation is unknown. The objective of this study was to determine the effects of iNO on endogenous NO-cGMP and ET-1 signaling in lambs with preexisting pulmonary hypertension secondary to increased pulmonary blood flow. Eight fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt lambs). After delivery (4 wk), the shunt lambs were mechanically ventilated with iNO (40 ppm) for 24 h. After 24 h of inhaled NO, plasma ET-1 levels increased by 34.8% independently of changes in protein levels (P < 0.05). Contrary to findings in normal lambs, total NOS activity did not decrease during iNO. In fact, Western blot analysis demonstrated that tissue endothelial NOS protein levels decreased by 43% such that NOS activity relative to protein levels actually increased during iNO (P < 0.05). In addition, the {beta}-subunit of soluble guanylate cyclase decreased by 70%, whereas phosphodiesterase 5 levels were unchanged (P < 0.05). Withdrawal of iNO was associated with an acute increase in PVR, which exceeded baseline PVR by 45%, and a decrease in cGMP concentrations to levels that were below baseline. These data suggest that the endothelial response to iNO and the potential mechanisms of rebound pulmonary hypertension are dependent upon the underlying pulmonary vasculature.

endothelium-derived factors; pulmonary heart disease; nitric oxide; endothelin-1


Address for reprint requests and other correspondence: J. R. Fineman, Medical Center at UC San Francisco, 505 Parnassus Ave., Box 0106, San Francisco, CA 94143-0106 (E-mail: jfineman{at}pedcard.ucsf.edu)




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