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

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.2.h777 ◽

2001 ◽

Vol 280 (2) ◽

pp. H777-H785 ◽

Cited By ~ 58

Author(s):

D. Michael McMullan ◽

Janine M. Bekker ◽

Michael J. Johengen ◽

Karen Hendricks-Munoz ◽

Rene Gerrets ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Inhaled Nitric Oxide ◽

Protein Levels ◽

Acute Withdrawal ◽

Clinically Significant ◽

Inhaled No

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 ETA 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-1α, and ETA and ETB 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 ETA 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.

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Inhaled Nitric Oxide at Birth Reduces Pulmonary Vascular Resistance and Improves Oxygenation in Preterm Lambs

Children ◽

10.3390/children8050378 ◽

2021 ◽

Vol 8 (5) ◽

pp. 378

Author(s):

Satyan Lakshminrusimha ◽

Sylvia F. Gugino ◽

Krishnamurthy Sekar ◽

Stephen Wedgwood ◽

Carmon Koenigsknecht ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Preterm Infants ◽

Vascular Resistance ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Inhaled No ◽

Birth Preterm

Resuscitation with 21% O2 may not achieve target oxygenation in preterm infants and in neonates with persistent pulmonary hypertension of the newborn (PPHN). Inhaled nitric oxide (iNO) at birth can reduce pulmonary vascular resistance (PVR) and improve PaO2. We studied the effect of iNO on oxygenation and changes in PVR in preterm lambs with and without PPHN during resuscitation and stabilization at birth. Preterm lambs with and without PPHN (induced by antenatal ductal ligation) were delivered at 134 d gestation (term is 147–150 d). Lambs without PPHN were ventilated with 21% O2, titrated O2 to maintain target oxygenation or 21% O2 + iNO (20 ppm) at birth for 30 min. Preterm lambs with PPHN were ventilated with 50% O2, titrated O2 or 50% O2 + iNO. Resuscitation with 21% O2 in preterm lambs and 50%O2 in PPHN lambs did not achieve target oxygenation. Inhaled NO significantly decreased PVR in all lambs and increased PaO2 in preterm lambs ventilated with 21% O2 similar to that achieved by titrated O2 (41 ± 9% at 30 min). Inhaled NO increased PaO2 to 45 ± 13, 45 ± 20 and 76 ± 11 mmHg with 50% O2, titrated O2 up to 100% and 50% O2 + iNO, respectively, in PPHN lambs. We concluded that iNO at birth reduces PVR and FiO2 required to achieve target PaO2.

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Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00019.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. L359-L366 ◽

Cited By ~ 37

Author(s):

Peter Oishi ◽

Albert Grobe ◽

Eileen Benavidez ◽

Boaz Ovadia ◽

Cynthia Harmon ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Inhaled Nitric Oxide ◽

In Vivo Studies ◽

Acute Increase ◽

No Signaling ◽

Oxide Synthase ◽

Inhaled No

Previous in vivo studies indicate that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity and that this decrease is associated with significant increases in pulmonary vascular resistance (PVR) upon the acute withdrawal of inhaled NO (rebound pulmonary hypertension). In vitro studies suggest that superoxide and peroxynitrite production during inhaled NO therapy may mediate these effects, but in vivo data are lacking. The objective of this study was to determine the role of superoxide in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy in vivo. In control lambs, 24 h of inhaled NO (40 ppm) decreased NOS activity by 40% ( P < 0.05) and increased endothelin-1 levels by 64% ( P < 0.05). Withdrawal of NO resulted in an acute increase in PVR (60.7%, P < 0.05). Associated with these changes, superoxide and peroxynitrite levels increased more than twofold ( P < 0.05) following 24 h of inhaled NO therapy. However, in lambs treated with polyethylene glycol-conjugated superoxide dismutase (PEG-SOD) during inhaled NO therapy, there was no change in NOS activity, no increase in superoxide or peroxynitrite levels, and no increase in PVR upon the withdrawal of inhaled NO. In addition, endothelial NOS nitration was 18-fold higher ( P < 0.05) in control lambs than in PEG-SOD-treated lambs following 24 h of inhaled NO. These data suggest that superoxide and peroxynitrite participate in the decrease in NOS activity and rebound pulmonary hypertension associated with inhaled NO therapy. Reactive oxygen species scavenging may be a useful therapeutic strategy to ameliorate alterations in endogenous NO signaling during inhaled NO therapy.

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Inhaled nitric oxide does not alter the longitudinal distribution of pulmonary vascular resistance

Journal of Applied Physiology ◽

10.1152/jappl.1995.78.1.341 ◽

1995 ◽

Vol 78 (1) ◽

pp. 341-348 ◽

Cited By ~ 20

Author(s):

D. M. Lindeborg ◽

B. P. Kavanagh ◽

K. Van Meurs ◽

R. G. Pearl

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Dose Range ◽

Venous Occlusion ◽

Inhaled Nitric Oxide ◽

Longitudinal Distribution ◽

Perfused Lung ◽

Inhaled No

Because the effects of inhaled nitric oxide (NO) may be localized to its site of delivery, we studied the effects of inhaled NO on the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension in perfused rabbit lungs. Before NO administration, pulmonary hypertension was produced by infusion of the thromboxane A2 mimetic U-46619 in all lungs. Pulmonary vascular resistance was divided into arterial, microvascular, and venous components by arterial and venous occlusion techniques. In the buffer-perfused lung, all doses of inhaled NO (5, 20, and 80 ppm) produced small decreases (approximately 3 mmHg) in pulmonary arterial pressure (Ppa), with equivalent proportional reductions in all segmental vascular resistances. Similar results were obtained after an extended inhaled NO dose range of 20, 80, and 240 ppm. In the buffer-perfused lung, inhibition of endogenous NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) potentiated the effects of U-46619. Subsequent inhaled NO administration produced larger decreases (approximately 7 mmHg) in Ppa with equivalent proportional reductions in all segmental vascular resistances. In the blood-perfused lung, L-NAME did not alter baseline pulmonary pressures. Administration of inhaled NO during U-46619-induced pulmonary hypertension produced dose-related decreases in Ppa. The highest dose (80 ppm) of inhaled NO decreased Ppa by 3.5 mmHg, with equivalent proportional reductions in all segmental vascular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)

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EFFECT OF INHALED NITRIC OXIDE (NO) AND pH ON PULMONARY VASCULAR RESISTANCE(PVR) IN THROMBOXANE INDUCED PULMONARY HYPERTENSION. 1974

Pediatric Research ◽

10.1203/00006450-199604001-01998 ◽

1996 ◽

Vol 39 ◽

pp. 332-332

Author(s):

Fabien G Eyal ◽

Charles R Hamm ◽

Michael M Zayek ◽

Kristen O'Donnell ◽

Richard M Whitehurst

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Inhaled Nitric Oxide

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Ultra Pure Nitric Oxide Generated Through Ascorbic Acid Reduction Of Nitrogen Dioxide Reverses Pulmonary Hypertension And Pulmonary Vascular Resistance In Hypoxemic Swine

10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a5973 ◽

2011 ◽

Author(s):

Mark A. Lovich ◽

Natalie K. Bruno ◽

Abraham E. Wei ◽

Richard J. Gilbert

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Ascorbic Acid ◽

Nitrogen Dioxide ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Acid Reduction

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Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension

Journal of Applied Physiology ◽

10.1152/jappl.1998.84.2.435 ◽

1998 ◽

Vol 84 (2) ◽

pp. 435-441 ◽

Cited By ~ 30

Author(s):

Christophe Adrie ◽

Fumito Ichinose ◽

Alexandra Holzmann ◽

Larry Keefer ◽

William E. Hurford ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Vascular Resistance ◽

Pulmonary Circulation ◽

Half Life ◽

Hemodynamic Effects ◽

Pulmonary Vasodilation ◽

Short Half Life ◽

Acute Pulmonary Hypertension ◽

Inhaled No

Adrie, Christophe, Fumito Ichinose, Alexandra Holzmann, Larry Keefer, William E. Hurford, and Warren M. Zapol. Pulmonary vasodilation by nitric oxide gas and prodrug aerosols in acute pulmonary hypertension. J. Appl. Physiol. 84(2): 435–441, 1998.—Sodium 1-( N, N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} is a compound that spontaneously generates nitric oxide (NO). Because of its short half-life (2.1 min), we hypothesized that inhaling DEA/NO aerosol would selectively dilate the pulmonary circulation without decreasing systemic arterial pressure. We compared the pulmonary selectivity of this new NO donor with two other reference drugs: inhaled NO and inhaled sodium nitroprusside (SNP). In seven awake sheep with pulmonary hypertension induced by the infusion of U-46619, we compared the hemodynamic effects of DEA/NO with those of incremental doses of inhaled NO gas. In seven additional awake sheep, we examined the hemodynamic effects of incremental doses of inhaled nitroprusside (i.e., SNP). Inhaled NO gas selectively dilated the pulmonary vasculature. Inhaled DEA/NO produced nonselective vasodilation; both systemic vascular resistance (SVR) and pulmonary vascular resistance (PVR) were reduced. Inhaled SNP selectively dilated the pulmonary circulation at low concentrations (≤10−2 M), inducing a decrease of PVR of up to 42% without any significant decrease of SVR (−5%), but nonselectively dilated the systemic circulation at larger doses (>10−2 M). In conclusion, despite its short half-life, DEA/NO is not a selective pulmonary vasodilator compared with inhaled NO. Inhaled SNP appears to be selective to the pulmonary circulation at low doses but not at higher levels.

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Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lungs

Journal of Applied Physiology ◽

10.1152/jappl.1990.68.2.735 ◽

1990 ◽

Vol 68 (2) ◽

pp. 735-747 ◽

Cited By ~ 51

Author(s):

S. L. Archer ◽

K. Rist ◽

D. P. Nelson ◽

E. G. DeMaster ◽

N. Cowan ◽

...

Keyword(s):

Nitric Oxide ◽

Methylene Blue ◽

Pulmonary Hypertension ◽

Feedback Inhibition ◽

Pressor Response ◽

Pulmonary Vasculature ◽

Hemodynamic Effects ◽

Isolated Lung

The effects of endothelium-dependent vasodilation on pulmonary vascular hemodynamics were evaluated in a variety of in vivo and in vitro models to determine 1) the comparability of the hemodynamic effects of acetylcholine (ACh), bradykinin (BK), nitric oxide (NO), and 8-bromo-guanosine 3′,5′-cyclic monophosphate (cGMP), 2) whether methylene blue is a useful inhibitor of endothelium-dependent relaxing factor (EDRF) activity in vivo, and 3) the effect of monocrotaline-induced pulmonary hypertension on the responsiveness of the pulmonary vasculature to ACh. In isolated rat lungs, which were preconstricted with hypoxia, ACh, BK, NO, and 8-bromo-cGMP caused pulmonary vasodilation, which was not inhibited by maximum tolerable doses of methylene blue. Methylene blue did not inhibit EDRF activity in any model, despite causing increased pulmonary vascular tone and responsiveness to various constrictor agents. There were significant differences in the hemodynamic characteristics of ACh, BK, and NO. In the isolated lung, BK and NO caused transient decreases of hypoxic vasoconstriction, whereas ACh caused more prolonged vasodilation. Pretreatment of these lungs with NO did not significantly inhibit ACh-induced vasodilation but caused BK to produce vasoconstriction. Tachyphylaxis, which was agonist specific, developed with repeated administration of ACh or BK but not NO. Tachyphylaxis probably resulted from inhibition of the endothelium-dependent vasodilation pathway proximal to NO synthesis, because it could be overcome by exogenous NO. Pretreatment with 8-bromo-cGMP decreased hypoxic pulmonary vasoconstriction and, even when the hypoxic pressor response had largely recovered, subsequent doses of ACh and NO failed to cause vasodilation, although BK produced vasoconstriction. These findings are compatible with the existence of feedback inhibition of the endothelium-dependent relaxation by elevation of cGMP levels. Responsiveness to ACh was retained in lungs with severe monocrotaline-induced pulmonary hypertension. Many of these findings would not have been predicted based on in vitro studies and illustrate the importance for expanding studies of EDRF to in vivo and ex vivo models.

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