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1 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
2 Department of Cardiothoracic Surgery, University of California, San Francisco, San Francisco, CA, USA
3 Department of Pediatrics, New York University, New York, NY, USA
4 Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, USA
5 Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Department of Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: jfineman{at}pedcard.ucsf.edu.
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 pre-existing pulmonary hypertension secondary to increased pulmonary blood flow. Eight fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt lambs). Four weeks after delivery, the shunt lambs were mechanically ventilated with iNO (40 ppm) for 24 hours. After 24 hours of inhaled NO, plasma ET-1 levels increased by 34.8% independent 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 eNOS protein levels decreased by 43% such that NOS activity relative to protein levels actually increased during iNO (P<0.05). In addition, the beta sub-unit of soluble guanylate cyclase decreased by 70% while PDE5 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.
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