Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension

Abstract

Life-threatening increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO), although the mechanisms remain unknown. In vitro data suggest that exogenous NO exposure inhibits endothelial NO synthase (NOS) activity. Thus the objectives of this study were to determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb. Six 1-mo-old lambs were mechanically ventilated and instrumented to measure vascular pressures and left pulmonary blood flow. Inhaled NO (40 ppm) acutely decreased left pulmonary vascular resistance by 27. 5 +/- 4.7% (P < 0.05). This was associated with a 207% increase in plasma cGMP concentrations (P < 0.05). After 6 h of inhaled NO, NOS activity was reduced to 44.3 +/- 5.9% of pre-NO values (P < 0.05). After acute withdrawal of NO, pulmonary vascular resistance increased by 52.1 +/- 11.6% (P < 0.05) and cGMP concentrations decreased. Both returned to pre-NO values within 60 min. One hour after NO withdrawal, NOS activity increased by 48.4 +/- 19.1% to 70% of pre-NO values (P < 0.05). Western blot analysis revealed that endothelial NOS protein levels remained unchanged throughout the study period. These data suggest a role for decreased endogenous NOS activity in the rebound pulmonary hypertension noted after acute withdrawal of inhaled NO.

Inhaled nitric oxide in 2003: a review of its mechanisms of action

“…Most studies have demonstrated that eNOS levels in the pulmonary vascular endothelium remain unchanged during iNO withdrawal, suggesting that inactivation or down-regulation of eNOS is one of the mechanisms of rebound pulmonary hypertension. 72,73 Inhaled NO also increases plasma endothelin-1 concentrations without enhancing gene expression in lamb. Endothelin-1 receptor blockade prevents the increase in pulmonary vascular resistance after NO withdrawal, indicating a role for endothelin-1 in rebound pulmonary hypertension.…”

“…A reaction between NO and O 2 -would produce peroxynitrite, which could then inactivate eNOS protein. 72,74,76 Endothelin-1 receptor antagonists may prevent rebound pulmonary hypertension by protecting endogenous eNOS activity during iNO therapy. 74 To prevent rebound pulmonary hypertension, iNO should be tapered off progressively without any attempt to terminate it if FIO 2 is higher than 50%.…”

Cyclooxygenase inhibitor blocks rebound response after NO inhalation in an endotoxin model

“…NO stimulates the release of soluble guanylate cyclase from the tissues, with a consequent increase in cGMP. INO reduces the endogenous NO production as a negative feedback mechanism, and this mechanism is assumed to be related to the rebound reaction to INO withdrawal (1,2,9). We have previously found that the production and/or release of the vasoconstrictor peptide endothelin-1 (ET-1) and possibly of other vasoconstrictors is also related to the rebound, and this may be even more important than the downregulation of endogenous NO production by INO (5).…”

“…In addition, ET-1-stimulated secondary release of TxA 2 is one of the main modes of signal transduction in ET-1-induced vasoconstriction (21). PGI 2 and TxA 2 , and PGF 2␣ , are important mutually antagonistic vasodilator and vasoconstrictor products, respectively, of arachidonic acid. They are synthesized via a cyclooxygenase (COX)-dependent pathway.…”

“…On the basis of these observations, we hypothesized that the rebound response to INO withdrawal is related to COX-derived vasoconstrictor products such as TxA 2 and PGF 2␣. The purpose of the present study was to determine whether a COX inhibitor could prevent a rebound reaction to INO withdrawal in a porcine endotoxin shock model.…”