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

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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Ontogeny of NO activity and response to inhaled NO in the developing ovine pulmonary circulation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.267.5.h1955 ◽

1994 ◽

Vol 267 (5) ◽

pp. H1955-H1961 ◽

Cited By ~ 5

Author(s):

J. P. Kinsella ◽

D. D. Ivy ◽

S. H. Abman

Keyword(s):

Nitric Oxide ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Pulmonary Circulation ◽

Hemodynamic Effects ◽

Fetal Sheep ◽

Pulmonary Vasodilation ◽

Ovine Fetus ◽

Pulmonary Arterial ◽

Inhaled No

To determine maturation-related changes in nitric oxide (NO) activity in the developing pulmonary circulation, we studied the hemodynamic effects of endogenous NO inhibition under basal conditions in the premature ovine fetus and the response to birth-related stimuli and exogenous NO in 30 fetal sheep at three different gestational ages. At 0.95 term, pulmonary vasodilation during inhaled NO (20 parts per million) was equivalent to the dilator response to 100% O2, but at 0.86 term vasodilation during inhaled NO was greater than the dilator response to 100% O2 (P < 0.05). At 0.78 term, left pulmonary arterial flow (QLPA) did not increase with exposure to either NO or 100% O2. Intrapulmonary infusion of nitro-L-arginine (L-NA) increased basal pulmonary vascular resistance 38% in the premature fetus at 0.78 term. L-NA treatment decreased the ventilation-induced rise in QLPA by 60% compared with controls (P < 0.05). Inhaled NO but not 100% O2 increased QLPA after L-NA treatment to levels achieved with ventilation alone in the controls. We conclude that in the premature pulmonary circulation (0.78 term) 1) basal pulmonary vascular resistance is modulated by endogenous NO, 2) pulmonary vasodilation at birth is partly mediated by endogenous NO activity, and 3) inhaled NO causes potent vasodilation.

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Selective Pulmonary Vasodilation by Intravenous Infusion of an Ultrashort Half-life Nucleophile/Nitric Oxide Adduct

Anesthesiology ◽

10.1097/00000542-199801000-00027 ◽

1998 ◽

Vol 88 (1) ◽

pp. 190-195 ◽

Cited By ~ 10

Author(s):

Christophe Adrie ◽

Mona W. Hirani ◽

Alexandra Holzmann ◽

Larry Keefer ◽

Warren M. Zapol ◽

...

Keyword(s):

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Pulmonary Circulation ◽

Half Life ◽

Pulmonary Vasculature ◽

Prostaglandin F2alpha ◽

Pulmonary Vasodilation ◽

Pulmonary Vasodilator ◽

Healthy Sheep ◽

Inhaled No

Background PROLI/NO (C5H7N3O4Na2 x CH3OH) is an ultrashort-acting nucleophile/NO adduct that generates NO (half-life 2 s at 37 degrees C and pH 7.4). Because of its short half-life, the authors hypothesized that intravenous administration of this compound would selectively dilate the pulmonary vasculature but cause little or no systemic hypotension. Methods In eight awake healthy sheep with pulmonary hypertension induced by 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F2alpha, the authors compared PROLI/NO with two reference drugs-inhaled NO, a well-studied selective pulmonary vasodilator, and intravenous sodium nitroprusside (SNP), a nonselective vasodilator. Sheep inhaled 10, 20, 40, and 80 parts per million NO or received intravenous infusions of 0.25, 0.5, 1, 2, and 4 microg x kg-1 x min-1 of SNP or 0.75, 1.5, 3, 6, and 12 microg x kg-1 x min-1 of PROLI/NO. The order of administration of the vasoactive drugs (NO, SNP, PROLI/NO) and their doses were randomized. Results Inhaled NO selectively dilated the pulmonary vasculature. Intravenous SNP induced nonselective vasodilation of the systemic and pulmonary circulation. Intravenous PROLI/NO selectively vasodilated the pulmonary circulation at doses up to 6 microg x kg-1 x min-1, which decreased pulmonary vascular resistance by 63% (P < 0.01) from pulmonary hypertensive baseline values without changing systemic vascular resistance. At 12 microg x kg-1 x min-1, PROLI/NO decreased systemic and pulmonary vascular resistance and pressure. Exhaled NO concentrations were higher during PROLI/NO infusion than during SNP infusion (P < 0.01 with all data pooled). Conclusions The results suggest that PROLI/NO could be a useful intravenous drug to vasodilate the pulmonary circulation selectively.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.5.h1849 ◽

1999 ◽

Vol 277 (5) ◽

pp. H1849-H1856 ◽

Cited By ~ 23

Author(s):

Stephen M. Black ◽

R. Scott Heidersbach ◽

D. Michael McMullan ◽

Janine M. Bekker ◽

Michael J. Johengen ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Inhaled Nitric Oxide ◽

Protein Levels ◽

Acute Withdrawal ◽

Inhaled No

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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Abstract 17912: Importance of Acute Hemodynamic Effects of Inhaled Nitric Oxide in Optimization of Heart Failure Treatment in Patients with Pulmonary Hypertension due to Left Heart Disease

Circulation ◽

10.1161/circ.130.suppl_2.17912 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Shunsuke Tatebe ◽

Koichiro Sugimura ◽

Kotaro Nochioka ◽

Tatsuo Aoki ◽

Masanobu Miura ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Pulmonary Hypertension ◽

Heart Disease ◽

Arterial Pressure ◽

Vascular Resistance ◽

Inhaled Nitric Oxide ◽

Left Heart ◽

Hemodynamic Effects ◽

Left Heart Disease

Background: Pulmonary hypertension (PH) due to left heart disease (LHD) is a major category of the disorder. We have recently reported that elevated pulmonary vascular resistance (PVR) in patients with post-capillary PH (pc-PH: defined as mean pulmonary arterial pressure (mPAP)≥25mmHg and pulmonary capillary wedge pressure (PCWP)>15mmHg) is associated with poor prognosis compared with those with no PH or pc-PH without elevated PVR. Although new treatment is required for targeting pulmonary vascular disease (PVD), thereis a concern about raising PCWP. In this study, we thus examined acute hemodynamic effects of inhaled nitric oxide (iNO) in patients with PH due to LHD and whether optimal heart failure (HF) treatment ameliorates pc-PH. Methods: We examined 60 consecutive pc-PH patients with chronic heart failure (63±14[SD] years, M/F 38/22, NYHA≥2) who underwent acute vasoreactivity test by iNO (40 ppm for 10 min) under right heart catheterization at our hospital from June 2011 to May 2014. Among them, 25 had valvular heart disease (VHD) and 35 had non-VHD. PVD (defined as PVR> 240dynes/s/cm -5 ) was noted in 18. We also evaluated right ventricular systolic pressure (RVSP) by echocardiography after optimization of HF treatment such as medications and valvular surgery. Results: iNO significantly decreased mPAP (-1.7±0.5 mmHg; P<0.01) and PVR (-66 ±14dyne/s/cm -5 , P<0.01) without altering cardiac output. iNO significantly increased PCWP (1.3±0.5 mmHg, P=0.01) only in non-VHD patients, while it significantly increased mean arterial pressure and systemic vascular resistance in VHD patients than in non-VHD patients (both P<0.05). Pc-PH patients with PVD were re-classified as having pc-PH without PVD in 9 and no PH in 1. Eight patients remained pc-PH with PVD. After the optimal medical treatment for 7.6 months, RVSP was significantly decreased in both non-VHD and VHD patient (-8±3mmHg, P=0.04, -19±8mmHg, P=0.01, respectively). However, in non-VHD group, significant reduction in RVSP was noted only in pc-PH patients without PVD (-8±3mmHg, P=0.03). Conclusions: These results indicate that elevated PVR in patients with pc-PH and non-VHD could be a novel therapeutic indication for NO-related pulmonary vasodilators in the current practice of HF.

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Oral prostacyclin enhances the pulmonary vasodilatory effect of nitric oxide in children with pulmonary hypertension

Cardiology in the Young ◽

10.1017/s1047951100004340 ◽

1997 ◽

Vol 7 (4) ◽

pp. 362-369 ◽

Cited By ~ 1

Author(s):

Kei-ichiro Uese ◽

Fukiko Ichida ◽

Shin-ichi Tsubata ◽

Ikuo Hashimoto ◽

Yuji Hamamichi ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Vascular Resistance ◽

Cyclic Gmp ◽

Venous Blood ◽

Combined Treatment ◽

Systemic Resistance ◽

Pulmonary Vasodilation ◽

Beraprost Sodium ◽

Combined Administration

AbstractTo evaluate the potential efficacy of the combined administration of inhaled nitric oxide and oral beraprost sodium in producing pulmonary vasodilation, we studied 20 patients with pulmonary hypertension during cardiac catheterization. We also evaluated some of the mechanisms of vasodilation under these circumstances by investigating the levels of cyclic GMP and AMP in the pulmonary venous blood. A significant decrease in pulmonary vascular resistance was observed after the administration of nitric oxide (−37 ± 6%, p<0.01), and more intense decrease was observed after the combined administration of nitric oxide and beraprost sodium (−46 ± 6%, p<0.05). In addition, the ratio of pulmonary-to-systemic resistance also decreased to a greater extent with combined administration than with nitric oxide alone (−34 ± 6% vs −42 ± 7%, p<0.05). Conversely, systemic vascular resistance showed no change, neither after loading with nitric oxide nor after combined administration. Although equivalent increases in levels of cyclic GMP were observed after inhalation of nitric and the combined administration (mean 78% vs 65%), greater increases in levels of cyclic AMP were observed with the combined use (mean 15% vs 69%). Combined treatment with nitric oxide and beraprost sodium may prove markedly beneficial in patients with primary and postoperative pulmonary hypertension who do not respond adequately to inhalation of nitric oxide alone or conventional modes of treatment.

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Inhaled nitric oxide improves hemodynamics in patients with acute pulmonary hypertension after high-risk cardiac surgery

Perfusion ◽

10.1177/026765919901400106 ◽

1999 ◽

Vol 14 (1) ◽

pp. 37-42 ◽

Cited By ~ 32

Author(s):

J R Beck ◽

L B Mongero ◽

R M Kroslowitz ◽

A F Choudhri ◽

J M Chen ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Cardiac Surgery ◽

High Risk ◽

Right Ventricular ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Left Ventricular ◽

Ventricular Assist ◽

Acute Pulmonary Hypertension

Severe pulmonary hypertension and right-sided circulatory failure (RSCF) represent an increasing cause of morbidity and mortality in patients undergoing high-risk cardiac surgery. Increased pulmonary vascular resistance in the setting of cardiopulmonary bypass (CPB) may further lead to decreased blood flow across the pulmonary vascular bed; thereby decreasing left ventricular filling and cardiac output. Current management techniques for RSCF include both nonspecific vasodilator and inotropic agents (often limited by systemic hypotension) and the placement of right ventricular assist devices (associated with increased perioperative morbidity). Inhaled nitric oxide (NOi) represents a novel, specific pulmonary vasodilator that has been proven efficacious in these clinical settings. We evaluated 34 patients in 38 operations who underwent cardiac surgery at Columbia Presbyterian Medical Center, and who received NOi (20 ppm) through a modified ventilatory circuit for hemodynamically significant elevations in pulmonary vascular resistance. Nine patients underwent cardiac transplantation, three patients bilateral lung transplantation, 16 patients left ventricular assist device placement and 10 patients routine cardiac surgery. Patients receiving NOi exhibited substantial reductions in mean pulmonary artery pressure (mPAP) (34.6 ± 2.0 to 26.0 ± 1.7 mmHg, p < 0.0001), with improvements in systemic hemodynamics, mean arterial pressure (68 ± 3.1 to 75.9 ± 2.0 mmHg, p = 0.006). In five cases, patients could not be weaned from CPB until NOi was administered. Patients were maintained on NOi from 6 to 240 h postoperatively (median duration 36 h). Inhaled NO induces substantial reductions in mPAP and increases in both cardiac index and systemic blood pressure in patients displaying elevated pulmonary hemodynamics after high-risk cardiac surgery. NO is, therefore, a useful adjunct in these patients in whom acute pulmonary hypertension threatens right ventricular function and hemodynamic stability.

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Nitric oxide inhalation: effects on the ovine neonatal pulmonary and systemic circulations

Reproduction Fertility and Development ◽

10.1071/rd9960431 ◽

1996 ◽

Vol 8 (3) ◽

pp. 431 ◽

Cited By ~ 7

Author(s):

V DeMarco ◽

JW Skimming ◽

TM Ellis ◽

S Cassin

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Arterial Pressure ◽

Pulmonary Circulation ◽

Pulmonary Arterial Pressure ◽

Hypoxic Pulmonary Vasoconstriction ◽

Minimum Concentration ◽

Pulmonary Vasoconstriction ◽

Pulmonary Arterial ◽

Inhaled No

Others have shown that inhaled nitric oxide causes reversal of pulmonary hypertension in anaesthetized perinatal sheep. The present study examined haemodynamic responses to inhaled NO in the normal and constricted pulmonary circulation of unanaesthetized newborn lambs. Three experiments were conducted on each of 7 lambs. First, to determine a minimum concentration of NO which could reverse acute pulmonary hypertension caused by infusion of the thromboxame mimic U46619, the haemodynamic effects of 5 different doses of inhaled NO were examined. Second, the effects of inhaling 80 ppm NO during hypoxic pulmonary vasoconstriction were examined. Finally, to determine if tachyphalaxis occurs during NO inhalation, lambs were exposed to 80 ppm NO for 3 h during which time pulmonary arterial pressure was doubled by infusion of U46619. Breathing NO (80 ppm) caused a slight but significant decrease in pulmonary vascular resistance (PVR) in lambs with normal pulmonary arterial pressure (PAP). Nitric oxide, inhaled at concentrations between 10 and 80 ppm for 6 min (F1O2 = 0.60), caused decreases in PVR when PAP was elevated with U46619. Nitric oxide acted selectively on the pulmonary circulation, i.e. no changes occurred in systemic arterial pressure or any other measured variable. Breathing 80 ppm NO for 6 min reversed hypoxic pulmonary vasoconstriction. In the chronic exposure study, inhaling 80 ppm NO for 3 h completely reversed U46619-induced pulmonary hypertension. Although arterial methaemoglobin increased during the 3-h exposure to 80 ppm NO, there was no indication that this concentration of NO impairs oxygen loading. These data demonstrate that NO, at concentrations as low as 10 ppm, is a potent, rapid-action, and selective pulmonary vasodilator in unanaesthetized newborn lambs with elevated pulmonary tone. Furthermore, these data support the use of inhaled NO for treatment of infants with pulmonary hypertension.

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Sildenafil Is a Pulmonary Vasodilator in Awake Lambs with Acute Pulmonary Hypertension

Anesthesiology ◽

10.1097/00000542-200006000-00030 ◽

2000 ◽

Vol 92 (6) ◽

pp. 1702-1712 ◽

Cited By ~ 158

Author(s):

Jörg Weimann ◽

Roman Ullrich ◽

Jonathan Hromi ◽

Yuji Fujino ◽

Martin W. H. Clark ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pde5 Inhibitor ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Pulmonary Vasculature ◽

No Production ◽

Pulmonary Vasodilation ◽

Pulmonary Vasodilator ◽

Acute Pulmonary Hypertension ◽

Inhaled No

Background Phosphodiesterase type 5 (PDE5) hydrolyzes cyclic guanosine monophosphate in the lung, thereby modulating nitric oxide (NO)/cyclic guanosine monophosphate-mediated pulmonary vasodilation. Inhibitors of PDE5 have been proposed for the treatment of pulmonary hypertension. In this study, we examined the pulmonary and systemic vasodilator properties of sildenafil, a novel selective PDE5 inhibitor, which has been approved for the treatment of erectile dysfunction. Methods In an awake lamb model of acute pulmonary hypertension induced by an intravenous infusion of the thromboxane analog U46619, we measured the effects of 12.5, 25, and 50 mg sildenafil administered via a nasogastric tube on pulmonary and systemic hemodynamics (n = 5). We also compared the effects of sildenafil (n = 7) and zaprinast (n = 5), a second PDE5 inhibitor, on the pulmonary vasodilator effects of 2.5, 10, and 40 parts per million inhaled NO. Finally, we examined the effect of infusing intravenous l-NAME (an inhibitor of endogenous NO production) on pulmonary vasodilation induced by 50 mg sildenafil (n = 6). Results Cumulative doses of sildenafil (12.5, 25, and 50 mg) decreased the pulmonary artery pressure 21%, 28%, and 42%, respectively, and the pulmonary vascular resistance 19%, 23%, and 45%, respectively. Systemic arterial pressure decreased 12% only after the maximum cumulative sildenafil dose. Neither sildenafil nor zaprinast augmented the ability of inhaled NO to dilate the pulmonary vasculature. Zaprinast, but not sildenafil, markedly prolonged the duration of pulmonary vasodilation after NO inhalation was discontinued. Infusion of l-NAME abolished sildenafil-induced pulmonary vasodilation. Conclusions Sildenafil is a selective pulmonary vasodilator in an ovine model of acute pulmonary hypertension. Sildenafil induces pulmonary vasodilation via a NO-dependent mechanism. In contrast to zaprinast, sildenafil did not prolong the pulmonary vasodilator action 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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