Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1.

Abstract

Clinically significant increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO). Endothelin (ET)-1 is a vasoactive peptide produced by the vascular endothelium that may participate in the pathophysiology of pulmonary hypertension. The objectives of this study were to determine the effects of inhaled NO on endogenous ET-1 production in vivo in the intact lamb and to determine the potential role of ET-1 in the rebound pulmonary hypertension associated with the withdrawal of inhaled NO. Seven 1-mo-old vehicle-treated control lambs and six PD-156707 (an ET(A) receptor antagonist)-treated lambs were mechanically ventilated. Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn. After 24 h of inhaled NO, plasma ET-1 levels increased by 119.5 +/- 42.2% (P < 0.05). Western blot analysis revealed that protein levels of preproET-1, endothelin-converting enzyme-1alpha, and ET(A) and ET(B) receptors were unchanged. On acute withdrawal of NO, pulmonary vascular resistance (PVR) increased by 77.8% (P < 0.05) in control lambs but was unchanged (-5.5%) in PD-156707-treated lambs. Inhaled NO increased plasma ET-1 concentrations but not gene expression in the intact lamb, and ET(A) receptor blockade prevented the increase in PVR after NO withdrawal. These data suggest a role for ET-1 in the rebound pulmonary hypertension noted on acute withdrawal of inhaled NO.

• Authors: D M McMullan, J M Bekker, M J Johengen, K Hendricks-Munoz, R Gerrets, S M Black, J R Fineman
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 280 Issue 2 Pg. H777-85 (Feb 2001) ISSN: 0363-6135 [Print] United States
• PMID: 11158977 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Dioxoles
• Endothelin Receptor Antagonists
• Endothelin-1
• PD 156707
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin
• Nitric Oxide
• Metalloendopeptidases

Topics

• Administration, Inhalation
• Animals
• Animals, Newborn
• Blotting, Western
• Dioxoles (pharmacology)
• Endothelin Receptor Antagonists
• Endothelin-1 (physiology)
• Endothelium, Vascular (drug effects, metabolism)
• Hypertension, Pulmonary (chemically induced, metabolism, physiopathology)
• Lung (blood supply, chemistry, enzymology)
• Metalloendopeptidases (analysis)
• Nitric Oxide (pharmacology)
• Pulmonary Circulation (drug effects, physiology)
• Receptor, Endothelin A
• Receptor, Endothelin B
• Receptors, Endothelin (analysis, physiology)
• Respiration, Artificial
• Sheep
• Substance Withdrawal Syndrome (metabolism, physiopathology)
• Vascular Resistance (drug effects, physiology)