Phosphodiesterase inhibition with dipyridamole augments and prolongs the pulmonary vasodilator response to inhaled nitric oxide in adults with chronic pulmonary hypertension

A literature review on nitric oxide would identify thousands of citations on the biological implications of this molecule. From the perspective of respiratory care, the effect inhaled nitric oxide has on pulmonary vasculature is the most intriguing. Over the past five years inhaled nitric oxide has been shown to be useful in the management of oxygenation during acute respiratory distress syndrome, alternation of pulmonary vascular tone in persistent pulmonary hypertension in the newborn, and in the management of chronic pulmonary hypertension in both heart and lung transplant candidates, as well as other potential clinical uses. The key physioligical response is vasodilation of pulmonary vessels in communication with well ventilated lung units and the absence of systemic vascular effects by rapid binding to hemoglobin. Nitric oxide therapy is considered experimental. A delivery system is not commercially available. This has resulted in the development of makeshift delivery systems, many of which may have the potential for adverse effects.

Download Full-text

Radical Scavengers Protect Murine Lungs from Endotoxin-induced Hyporesponsiveness to Inhaled Nitric Oxide

Anesthesiology ◽

10.1097/00000542-200204000-00021 ◽

2002 ◽

Vol 96 (4) ◽

pp. 926-933 ◽

Cited By ~ 6

Author(s):

Yehuda Raveh ◽

Fumito Ichinose ◽

Pini Orbach ◽

Kenneth D. Bloch ◽

Warren M. Zapol

Keyword(s):

Nitric Oxide ◽

Reactive Oxygen Species ◽

Polyethylene Glycol ◽

Reactive Oxygen ◽

Inhaled Nitric Oxide ◽

Oxygen Species ◽

Pulmonary Vasodilation ◽

Vasodilator Response ◽

Pulmonary Vasodilator ◽

Inhaled No

Background Sepsis is associated with an impaired pulmonary vasodilator response to inhaled nitric oxide (NO). A combination of NO and other inflammatory mediators appears to be responsible for endotoxin-induced pulmonary vascular hyporesponsiveness to inhaled NO. The authors investigated whether scavengers of reactive oxygen species could preserve inhaled NO responsiveness in endotoxin-challenged mice. Methods The vasorelaxation to inhaled NO was studied in isolated, perfused, and ventilated lungs obtained from mice 16 h after an intraperitoneal challenge with saline or 50 mg/kg Escherichia coli lipopolysaccharide. In some mice, challenge with saline or lipopolysaccharide was followed by intraperitoneal administration of N-acetylcysteine, dimethylthiourea, EUK-8, or polyethylene glycol-conjugated catalase. Results The pulmonary vasodilator response of U46619-preconstricted isolated lungs to ventilation with 0.4, 4, and 40 ppm inhaled NO in lipopolysaccharide-challenged mice was reduced to 32, 43, and 60%, respectively, of that observed in saline-challenged mice (P < 0.0001). Responsiveness to inhaled NO was partially preserved in lipopolysaccharide-challenged mice treated with a single dose of N-acetylcysteine (150 or 500 mg/kg) or 20 U/g polyethylene glycol-conjugated catalase (all P < 0.05 vs. lipopolysaccharide alone). Responsiveness to inhaled NO was fully preserved by treatment with either dimethylthiourea, EUK-8, two doses of N-acetylcysteine (150 mg/kg administered 3.5 h apart), or 100 U/g polyethylene glycol-conjugated catalase (all P < 0.01 vs. lipopolysaccharide alone). Conclusions When administered to mice concurrently with lipopolysaccharide challenge, reactive oxygen species scavengers prevent impairment of pulmonary vasodilation to inhaled NO. Therapy with scavengers of reactive oxygen species may provide a means to preserve pulmonary vasodilation to inhaled NO in sepsis-associated acute lung injury.

Download Full-text

Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00119.2005 ◽

2005 ◽

Vol 289 (5) ◽

pp. L798-L806 ◽

Cited By ~ 49

Author(s):

Philippe Deruelle ◽

Theresa R. Grover ◽

Steven H. Abman

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Soluble Guanylate Cyclase ◽

Ductus Arteriosus ◽

Vascular Effects ◽

Pulmonary Vasodilation ◽

Pulmonary Vasodilator ◽

Cgmp Signaling ◽

Chronic Pulmonary Hypertension ◽

Direct Activator

Persistent pulmonary hypertension of the newborn (PPHN) is partly due to impaired nitric oxide (NO)-cGMP signaling. BAY 41-2272 is a novel direct activator of soluble guanylate cyclase, but whether this drug may be an effective therapy for PPHN is unknown. We hypothesized that BAY 41-2272 would cause pulmonary vasodilation in a model of severe PPHN. To test this hypothesis, we compared the hemodynamic response of BAY 41-2272 to acetylcholine, an endothelium-dependent vasodilator, and sildenafil, a selective inhibitor of PDE5 in chronically instrumented fetal lambs at 1 and 5 days after partial ligation of the ductus arteriosus. After 9 days, we delivered the animals by cesarean section to measure their hemodynamic responses to inhaled NO (iNO), sildenafil, and BAY 41-2272 alone or combined with iNO. BAY 41-2272 caused marked pulmonary vasodilation, as characterized by a twofold increase in blood flow and a nearly 60% fall in PVR at day 1. Effectiveness of BAY 41-2272-induced pulmonary vasodilation increased during the development of pulmonary hypertension. Despite a similar effect at day 1, the pulmonary vasodilator response to BAY 41-2272 was greater than sildenafil at day 5. At birth, BAY 41-2272 dramatically reduced PVR and augmented the pulmonary vasodilation induced by iNO. We concluded that BAY 41-2272 causes potent pulmonary vasodilation in fetal and neonatal sheep with severe pulmonary hypertension. We speculate that BAY 41-2272 may provide a novel treatment for severe PPHN, especially in newborns with partial response to iNO therapy.

Download Full-text

Combined inhaled nitric oxide and inhaled prostacyclin during experimental chronic pulmonary hypertension

Journal of Applied Physiology ◽

10.1152/jappl.1999.86.4.1160 ◽

1999 ◽

Vol 86 (4) ◽

pp. 1160-1164 ◽

Cited By ~ 42

Author(s):

Laureen L. Hill ◽

Ronald G. Pearl

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Synergistic Effects ◽

Systemic Arterial Pressure ◽

Inhaled Nitric Oxide ◽

Dependent Manner ◽

Chronic Pulmonary Hypertension ◽

Inhaled Prostacyclin ◽

Change In Mean ◽

Inhaled No

Inhaled nitric oxide (NO) and inhaled prostacyclin (PGI2) produce selective reductions in pulmonary vascular resistance (PVR) through differing mechanisms. NO decreases PVR via cGMP, and PGI2 produces pulmonary vasodilation via cAMP. As a general pharmacological principle, two drugs that produce similar effects via different mechanisms should have additive or synergistic effects when combined. We designed this study to investigate whether combined inhaled NO and PGI2 therapy results in additive effects during chronic pulmonary hypertension in the rat. Monocrotaline injected 4 wk before study produced pulmonary hypertension in all animals. Inhaled NO (20 parts/million) reversibly and selectively decreased pulmonary artery pressure (Ppa) with a mean reduction of 18%. Four concentrations of PGI2were administered via inhalation (5, 10, 20, and 80 μg/ml), both alone and combined with inhaled NO. Inhaled PGI2 alone decreased Ppa in a dose-dependent manner with no change in mean systemic arterial pressure. Combined inhaled NO and PGI2 selectively and significantly decreased Ppa more did than either drug alone. The effects were additive at the lower concentrations of PGI2 (5, 10, and 20 μg/ml). The combination of inhaled NO and inhaled PGI2 may be useful in the management of pulmonary hypertension.

Download Full-text

Congenital NOS2 Deficiency Protects Mice from LPS-induced Hyporesponsiveness to Inhaled Nitric Oxide

Anesthesiology ◽

10.1097/00000542-199912000-00028 ◽

1999 ◽

Vol 91 (6) ◽

pp. 1744-1744 ◽

Cited By ~ 22

Author(s):

Jörg Weimann ◽

Kenneth D. Bloch ◽

Masao Takata ◽

Wolfgang Steudel ◽

Warren M. Zapol

Keyword(s):

Nitric Oxide ◽

Inhaled Nitric Oxide ◽

Wild Type ◽

Vasodilator Response ◽

Pulmonary Vasodilator ◽

Vascular Responsiveness ◽

Deficient Mice ◽

Inhaled No ◽

Lipopolysaccharide Challenge

Background In animal models, endotoxin (lipopolysaccharide) challenge impairs the pulmonary vasodilator response to inhaled nitric oxide (NO). This impairment is prevented by treatment with inhibitors of NO synthase 2 (NOS2), including glucocorticoids and L-arginine analogs. However, because these inhibitors are not specific for NOS2, the role of this enzyme in the impairment of NO responsiveness by lipopolysaccharide remains incompletely defined. Methods To investigate the role of NOS2 in the development of lipopolysaccharide-induced impairment of NO responsiveness, the authors measured the vasodilator response to inhalation of 0.4, 4, and 40 ppm NO in isolated, perfused, and ventilated lungs obtained from lipopolysaccharide-pretreated (50 mg/kg intraperitoneally 16 h before lung perfusion) and untreated wild-type and NOS2-deficient mice. The authors also evaluated the effects of breathing NO for 16 h on pulmonary vascular responsiveness during subsequent ventilation with NO. Results In wild-type mice, lipopolysaccharide challenge impaired the pulmonary vasodilator response to 0.4 and 4 ppm NO (reduced 79% and 45%, respectively, P < 0.001), but not to 40 ppm. In contrast, lipopolysaccharide administration did not impair the vasodilator response to inhaled NO in NOS2-deficient mice. Breathing 20 ppm NO for 16 h decreased the vasodilator response to subsequent ventilation with NO in lipopolysaccharide-pretreated NOS2-deficient mice, but not in lipopolysaccharide-pretreated wild-type, untreated NOS2-deficient or untreated wild-type mice. Conclusions In response to endotoxin challenge, NO, either endogenously produced by NOS2 in wild-type mice or added to the air inhaled by NOS2-deficient mice, is necessary to impair vascular responsiveness to inhaled NO. Prolonged NO breathing, without endotoxin, does not impair vasodilation in response to subsequent NO inhalation. These results suggest that NO, plus other lipopolysaccharide-induced products, are necessary to impair responsiveness to inhaled NO in a murine sepsis model.

Download Full-text

Pulmonary response of normal human subjects to inhaled vasodilator substances

Clinical Science ◽

10.1042/cs0950621 ◽

1998 ◽

Vol 95 (5) ◽

pp. 621-627 ◽

Cited By ~ 10

Author(s):

S. J. BRETT ◽

J. CHAMBERS ◽

A. BUSH ◽

M. ROSENTHAL ◽

T. W. EVANS

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Pulmonary Hypertension ◽

Pulmonary Blood Flow ◽

Inhaled Nitric Oxide ◽

Prostaglandin I2 ◽

Vascular Bed ◽

Normal Individuals ◽

Chronic Pulmonary Hypertension ◽

Pulmonary Vascular Bed

1.Inhaled vasodilators such as nitric oxide and epoprostenol (prostaglandin I2) are now widely employed as supportive therapies to improve oxygenation and reduce pulmonary vascular resistance in patients with acute and chronic pulmonary hypertension. However, few data exist concerning their effects in normal individuals. The aim of this study was to characterize the response of the pulmonary circulation in normal individuals to inhaled nitric oxide and nebulized prostaglandin I2. 2.Eight healthy volunteers were exposed to inhaled nitric oxide (0, 20 and 40 ;p.p.m.) and nebulized prostaglandin I2 (10 ;μg/ml). Changes in effective pulmonary blood flow and diffusing capacity of the lung for carbon monoxide (TLCO) were measured using respiratory mass spectrometry. Bicycle ergometry was used to increase effective pulmonary blood flow as a positive control. 3.Exercise produced significant increases in both effective pulmonary blood flow and TLCO, but neither nitric oxide nor prostaglandin I2 produced significant changes in either parameter. 4.No significant change in pulmonary haemodynamics was demonstrated in response to inhaled nitric oxide or nebulized prostaglandin I2, using doses known to be effective in patients with acute and chronic pulmonary hypertension. These data suggest that the normal pulmonary vascular bed is not amenable to vasodilatation by inhaled drugs. The study further suggests that the normal pulmonary vasodilatation seen on exercise is not mediated pharmacologically, but is a secondary consequence to the mechanical effects of a rise in pulmonary blood flow. This study thus supports the view that there is no resting vasoconstrictor tone in the pulmonary vascular bed.

Download Full-text

Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the Newborn: The Physiology Matters

PEDIATRICS ◽

10.1542/peds.96.6.1153 ◽

1995 ◽

Vol 96 (6) ◽

pp. 1153-1155

Author(s):

Steven H. Abman ◽

John P. Kinsella

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Adverse Effects ◽

Systemic Arterial Pressure ◽

Cardiac Performance ◽

Inhaled Nitric Oxide ◽

Persistent Pulmonary Hypertension ◽

Clinical Settings ◽

Intrapulmonary Shunt ◽

Pulmonary Vasodilator

The ability of inhaled nitric oxide (iNO) to acutely lower pulmonary vascular resistance (PVR) and improve oxygenation in diverse clinical settings suggests that iNO therapy may provide a unique tool to expand our current armamentariurn in treating various cardiopulmonary disorders, including persistent pulmonary hypertension of the newborn (PPHN). Treatment of severe PPHN has been limited in part by the lack of a selective pulmonary vasodilator that effectively lowers PVR without adverse effects on systemic arterial pressure, cardiac performance, or intrapulmonary shunt. In 1992, two articles were published in Lancet which reported that iNO can improve oxygenation in neonates with severe PPHN without lowering systemic pressure.1,2

Download Full-text