Endothelial alterations during inhaled NO in lambs with pulmonary hypertension

Implications for rebound hypertension

Gregory A. Ross, Peter Oishi, Anthony Azakie, Sohrab Fratz, Robert K. Fitzgerald, Michael J. Johengen, Cynthia Harmon, Karen Hendricks-Munoz, Jie Xu, Stephen M. Black, Jeffrey R. Fineman

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 β-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume288
Issue number1 32-1
DOIs
StatePublished - Jan 1 2005

Fingerprint

Pulmonary Hypertension
Nitric Oxide
Hypertension
Endothelin-1
Nitric Oxide Synthase
Vascular Resistance
Pulmonary Circulation
Type 5 Cyclic Nucleotide Phosphodiesterases
Lung
Proteins
Nitric Oxide Synthase Type III
Blood Vessels
Western Blotting
Transplants

Keywords

  • Endothelin-1
  • Endothelium-derived factors
  • Nitric oxide
  • Pulmonary heart disease

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

Cite this

Endothelial alterations during inhaled NO in lambs with pulmonary hypertension : Implications for rebound hypertension. / Ross, Gregory A.; Oishi, Peter; Azakie, Anthony; Fratz, Sohrab; Fitzgerald, Robert K.; Johengen, Michael J.; Harmon, Cynthia; Hendricks-Munoz, Karen; Xu, Jie; Black, Stephen M.; Fineman, Jeffrey R.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 288, No. 1 32-1, 01.01.2005.

Research output: Contribution to journalArticle

Ross, GA, Oishi, P, Azakie, A, Fratz, S, Fitzgerald, RK, Johengen, MJ, Harmon, C, Hendricks-Munoz, K, Xu, J, Black, SM & Fineman, JR 2005, 'Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: Implications for rebound hypertension', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 288, no. 1 32-1. https://doi.org/10.1152/ajplung.00144.2004
Ross, Gregory A. ; Oishi, Peter ; Azakie, Anthony ; Fratz, Sohrab ; Fitzgerald, Robert K. ; Johengen, Michael J. ; Harmon, Cynthia ; Hendricks-Munoz, Karen ; Xu, Jie ; Black, Stephen M. ; Fineman, Jeffrey R. / Endothelial alterations during inhaled NO in lambs with pulmonary hypertension : Implications for rebound hypertension. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2005 ; Vol. 288, No. 1 32-1.
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abstract = "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 β-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.",
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AU - Oishi, Peter

AU - Azakie, Anthony

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AU - Fitzgerald, Robert K.

AU - Johengen, Michael J.

AU - Harmon, Cynthia

AU - Hendricks-Munoz, Karen

AU - Xu, Jie

AU - Black, Stephen M.

AU - Fineman, Jeffrey R.

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