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(Chest. 2003;123:869-874.)
© 2003 American College of Chest Physicians

Two Aerosolized Nitric Oxide Adducts as Selective Pulmonary Vasodilators for Acute Pulmonary Hypertension*

Chen F. Lam, MD; Peter V. van Heerden, PhD, FCCP; Kenneth F. Ilett, PhD; Paul Caterina, PhD and Pierre Filion, MSc

* From the Department of Pharmacology (Drs. Lam and Ilett), University of Western Australia, Crawley; Department of Intensive Care (Dr. van Heerden), Sir Charles Gairdner Hospital, Perth; and Department of Anatomical Pathology (Dr. Caterina and Mr. Filion), The Western Australia Center for Pathology and Medical Research, Nedlands, Australia.

Correspondence to: Chen F. Lam, MD, Department of Pharmacology, University of Western Australia, Crawley, WA 6009, Australia; e-mail: cflam{at}cyllene.uwa.edu.au


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Study objectives: To determine the selective vasodilatory effects of two inhaled "NONOate" aerosols in a closed chest pig model of acute pulmonary hypertension (APH).

Methods: APH was induced by IV infusion of the prostaglandin H2/thromboxane A2 receptor agonist (U46619). Aerosolized diethylenetriamine nitric oxide (NO) adduct (DETA/NO, n = 4), dipropylenetriamine NO adduct (DPTA/NO, n = 4) [60 µmol each], or placebo (n = 4) was delivered via the trachea. Hemodynamic parameters and blood samples were measured before and after inhalation therapy.

Results: Compared to control animals, pulmonary vascular resistance and pulmonary arterial pressure were significantly reduced from 10 to 105 min after DETA/NO administration and from 10 to 45 min after DPTA/NO aerosol administration (p < 0.05). Both aerosols had no significant effect on systemic vascular resistance or systemic BP. Serum nitrite significantly increased after the inhalation of both NONOates (p < 0.01). There was a tendency for reduced intrapulmonary shunting, particularly after treatment with DETA/NO.

Conclusion: Both DETA/NO and DPTA/NO administered as aerosols selectively reduced pulmonary hypertension induced by U46619.

Key Words: ARDS • NONOates • pulmonary hypertension • selective pulmonary vasodilators


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Selective pulmonary vasodilators (SPVs) dilate the pulmonary vasculature without causing systemic hypotension and without worsening ventilation/perfusion (/) matching.1 Established SPVs, such as inhaled nitric oxide (NO) and inhaled aerosolized prostacyclin, are used in the treatment of hypoxemia and pulmonary hypertension in conditions such as ARDS.2 SPVs reduce pulmonary arterial pressure (PAP), improve right-heart function, and improve oxygenation in patients with ARDS.3 To date, inhaled NO is the most widely used SPV. It has minimal effects on the systemic circulation, improves / matching, and thereby improves oxygenation.1 4 However, inhaled NO has some major disadvantages: (1) since it has a very short half-life and is rapidly inactivated, it has to be delivered continuously to be effective5 ; (2) abrupt discontinuation of therapy can lead to acute rebound pulmonary hypertension with significant morbidity6 ; and (3) high concentrations of NO and its oxidant products (such as nitrogen dioxide [NO2-]) are toxic and require complex delivery and environmental monitoring systems to protect patients and medical attendants from unwanted exposure.5 7

"NONOates," or diazeniumdiolates, are chemical compounds that carry the [N(O)NO]- functional group.8 When dissolved in physiologic solutions or buffers, they spontaneously release 2 mol of NO per mole of parent compound. The half-lives of NO generation from NONOates vary from 1 min to 1 day under normal physiologic conditions.8 9 NONOates may prove to be superior to gaseous NO as SPVs in clinical therapeutics in that: (1) the longer decomposition half-lives may allow intermittent therapy, (2) theoretically rebound pulmonary hypertension is less likely because of the gradual reduction in tissue levels of NO, and (3) NONOates are stable in solid form and highly water soluble. In addition, they can be delivered to the lung using a small-volume nebulizer and do not require safety monitoring systems.

Diethylenetriamine NO adduct (DETA/NO) and dipropylenetriamine NO adduct (DPTA/NO) are NONOates with NO-generating half-lives of approximately 20 h and 3 h, respectively, at 37°C.8 9 Compared to the extremely short biological half-life of NO (< 5 s), the slow and continuous release of NO from these novel compounds potentially makes them very useful agents for the treatment of pulmonary hypertension and hypoxemia in such conditions as ARDS. The aim of this study was to investigate the selective pulmonary vasodilatory effects of DETA/NO and DPTA/NO in an acute pulmonary hypertension (APH) model.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Twelve white, Landrace-cross, female piglets weighing 19 to 25 kg were obtained from the Animal Resources Center, Murdoch, Western Australia. The study was approved by the Animal Experimentation Ethics Committee of the University of Western Australia.

The piglets were anesthetized with 3% halothane in oxygen-enriched air (fraction of inspired oxygen, 0.5). Anesthesia was maintained with halothane, 0.5 to 1%, in air/oxygen (fraction of inspired oxygen, 0.5). They received mechanical ventilation (Siemens Servo 900B; Siemens; Elema, Sweden) throughout the study period via a 6-mm endotracheal tube in the assist-control ventilation mode. Tidal volumes were <= 10 mL/kg, and minute ventilation was adjusted to achieve normocapnia. Vecuronium bromide was infused IV at 2 to 6 mg/h to facilitate mechanical ventilation. Hydration was maintained by infusing isotonic saline solution via an ear vein at a rate of 5 mL/kg/h.

A single-lumen catheter was inserted into the femoral artery and connected to a monitor (Sirecust 404; Siemens) to continuously monitor the systemic BP (SBP). A five-lumen 7.5F gauge, balloon-tipped, flow-directed pulmonary artery catheter (Arrow Model AH-05050-H; Arrow International; Reading, PA) was placed via the femoral vein. The catheter was advanced into the inferior vena cava, and the tip of catheter was ultimately placed in the right or left pulmonary artery, verified by typical pressure-wave forms. The proximal end of the five-lumen catheter measured the pressure at the level of the superior vena cava (central venous pressure), while the distal end of the catheter monitored the mean PAP (MPAP). Pulmonary capillary wedge pressure (PCWP) was measured following inflation of the distal catheter balloon with not more than 1.5 mL of air. PCWP was measured at the end of expiration and immediately before measuring the cardiac output in each instance. A cardiac output measuring set (CritikitTM-SP4500; Becton Dickinson, Critical Care Systems; Singapore) was connected to the infusion port of the pulmonary artery catheter. Cardiac output was measured using a thermodilution technique, by injection of a 5 mL bolus of cold sterile 5% dextrose water into the right atrium. Cardiac output was calculated from the detected change in temperature at the thermistor in the pulmonary artery by the internal algorithm of the monitor (utilizing the Stewart-Hamilton equation).10 Values of cardiac output were divided by body mass (in kilograms) to obtain a cardiac index (CI), expressed in units of liters per minute per kilogram. Blood samples for gas analysis were drawn from the femoral arterial line (arterial blood gas) and the distal port of the pulmonary artery catheter (mixed venous blood gas). These blood samples were analyzed by a blood gas analyzer (ABL 520; Radiometer; Copenhagen, Denmark) within 10 min of being drawn. The intrapulmonary shunt (percentage) was calculated from the blood gas measurements using the standard equation. Arterial blood was also collected for analysis of total serum nitrite (nitrate was reduced to NO2- before assay) concentrations using the Griess reaction as described by Giovannoni et al.11

Baseline measurements of hemodynamic parameters and blood samples for NO2- quantification were obtained after the anesthetized animals had been stabilized for at least 20 min. Once all the baseline data had been collected, APH was induced by IV infusion of a prostaglandin H2/thromboxane A2 receptor agonist (U46619; Cayman Chemical; Ann Arbor, MI). U46619 (10 mg) was dissolved in 10 mL of isotonic phosphate buffer (WA Hospital Central Pharmaceutical Manufacturing Facility; Perth, Australia) [pH 7.4] and diluted to 50 mL in normal saline solution to a final concentration of 0.2 mg/mL. U46619 was then infused continuously via the femoral vein at an initial rate of 0.01 µg/kg/min, and increased every 6 min in the following steps: 0.05, 0.1, 0.25, 0.5, 1, 2.5, 5, and 10 µg/kg/min.12 Hemodynamic parameters were measured every 6 min, and the infusion rate was increased step-wise until the target pulmonary vascular resistance index (PVRI) of >= 1.5 times above the baseline value was achieved. PVRI was calculated as 79.9 x (MPAP - PCWP)/CI, expressed in dynes per second per centimeter5 per kilogram. U46619 was then infused continuously, throughout the study at the same rate used to achieve the target PVRI. The cumulative dose of U46619 for each animal from the achievement of target PVRI to the end of the study was noted.

After target pulmonary hypertension had been achieved and stabilized for at least 20 min, hemodynamic measurements were made and blood samples were obtained for NO2- measurement. Animals were then treated with placebo (n = 4), DETA/NO (n = 4), or DPTA/NO (n = 4) aerosol. DETA/NO and DPTA/NO (60 µmol; Sigma Chemical; St. Louis, MO) solutions (12 mM) were freshly prepared by dissolving each drug in 5 mL of phosphate buffer (WA Hospital Central Pharmaceutical Manufacturing Facility) [pH 7.4] immediately before inhalation therapy. The dose used in this study was derived from the data of Cornfield et al,13 adjusted for body weight. Normal saline, DETA/NO, or DPTA/NO solutions were aerosolized into the respiratory tract via a Sidestream Jet Nebuliser (Medic-Aid; West Sussex, UK) driven by 100% oxygen at a flow rate of 2 to 3 L/min. Aerosols were delivered into the lungs over 20 min by connecting the nebulizer to the inspiratory limb of the breathing circuit. Hemodynamic measurements were repeated at 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 180, and 240 min after aerosol therapy was commenced. Further blood samples for NO2- measurement were collected at 15, 30, 45, 60, 75, 90, 180, and 240 min. Piglets were killed with IV pentobarbitone at the end of study.

Selective pulmonary vasodilation was defined as a reduction in pulmonary vascular resistance (with a lack of effect on SBP). Reduction in intrapulmonary shunting was a secondary end point, as this was not a hypoxemic animal model primarily.

Data were analyzed using SigmaStat Scientific Software (Version 2.0; Jandel Corporation; San Rafael, CA). All data were first tested for normality and equivalence of variance. Nonnormal distributed variables were log transformed. All the data were analyzed by two-way repeated-measures analysis of variance (ANOVA). All data are presented as mean ± SEM.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
APH was successfully induced in four piglets in the control group, three piglets in the DETA/NO group, and four piglets in the DPTA/NO group. Due to failure in the placement of the pulmonary artery catheter, pulmonary hypertension was not induced in one of the piglets in the DETA/NO group. However, all piglets received inhaled therapy (placebo, DETA/NO, or DPTA/NO), and serum NO2- concentrations were measured in all 12 animals.

Induction of APH
The mean doses of U46619 infused to achieve target PVRI in the control, DETA/NO-treated, and DPTA/NO-treated groups were 73 ± 7.9 µg, 78 ± 15 µg, and 79 ± 17 µg, respectively. The cumulative doses of U46619 at the end of the study were 880 ± 65 µg, 827 ± 100 µg, and 906 ± 75 µg, respectively, for control, DETA/NO-treated, and DPTA/NO-treated groups. There were no significant differences in the doses of U46619 used in each group.

The mean baseline values of PVRI for the control, DETA/NO-treated, and DPTA/NO-treated animals were 8.6 ± 0.6 dyne · s-1 · cm-5 · kg-1, 8.6 ± 0.2 dyne · s-1 · cm-5 · kg-1, and 7.9 ± 0.4 dyne · s-1 · cm-5 · kg-1, respectively. Immediately before aerosol administration (zero time), PVRI had risen to 19 ± 0.6 dyne · s-1 · cm-5 · kg-1, 25 ± 2.3 dyne · s-1 · cm-5 · kg-1, and 20 ± 2.7 dyne · s-1 · cm-5 · kg-1 in the control, DETA/NO-treated, and DPTA/NO-treated groups, respectively. There were no significant differences in PVRI between either of the NONOate groups and the control group at these two time points (baseline and zero time).

Effects on the Pulmonary Vasculature
Compared to control animals, PVRIs were significantly reduced at 10, 15, 20, 25, 30, 45, and 60 min after aerosol delivery in the DETA/NO-treated group (p < 0.05; Fig 1 ). PVRIs were also significantly reduced at 10, 15, 20, 25, 30, and 45 min after aerosol delivery in the DPTA/NO-treated group (p < 0.05; Fig 1 ).



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  		Figure 1. PVRI in control, DETA/NO-treated, and DPTA/NO-treated groups after aerosol administration. BL = baseline values; *p < 0.05 control vs DETA/NO group; +p < 0.05 control vs DPTA/NO group. The time axis is shown as a categorical scale.

 
There were no significant differences in MPAP between either of the NONOate-treated groups and the control group at baseline and zero time. MPAP was significantly reduced compared to control animals from 10 to 105 min after treatment in the DETA/NO-treated group and from 10 to 45 min after treatment in the DPTA/NO-treated group (p < 0.05; Fig 2 ). PVRI and MPAP were not significantly reduced compared to their values at zero time in the control group. However, MPAP and PVRI were significantly lower compared to zero time values in the DETA/NO-treated group from 10 to 60 min after aerosol delivery (p < 0.05). Compared to zero time values, MPAP was also significantly reduced from 10 to 30 min after aerosol delivery in the DPTA/NO-treated group (p < 0.05), but none of the reductions in PVRI after DPTA/NO administration in this group reached statistical significance (Table 1 ).



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  		Figure 2. MPAP in control, DETA/NO-treated, and DPTA/NO-treated groups after aerosol administration. *p < 0.05 control vs DETA/NO group; +p < 0.05 control vs DPTA/NO group. The time axis is shown as a categorical scale.

 

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  		Table 1. Hemodynamic Effects of Inhaled DETA/NO and DPTA/NO*

 
Other Hemodynamic Effects
No significant differences were found in PCWP or CI at any time point between the three treated groups or at any time period within any group compared to respective zero time values. There were no significant differences in the systemic vascular resistance index or SBP between the three groups. The major hemodynamic effects of inhaled DETA/NO and DPTA/NO are summarized in Table 1 .

Effects on Gas Exchange
Intrapulmonary shunting after DETA/NO and DPTA/NO administration tended to be reduced (Fig 3 ). Compared to the control animals, the reduction was more marked in the DETA/NO-treated group (up to 120 min) than that in the DPTA/NO-treated group, but the differences did not reach statistical significance (p = 0.07). The alveolar-arterial oxygen partial pressure gradient also tended toward an improvement; again, this was not statistically significant (data not shown).



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  		Figure 3. Intrapulmonary shunting in control, DETA/NO-treated, and DPTA/NO-treated groups after aerosol administration. The time axis is shown as a categorical scale.

 
Serum NO Metabolites
There was an increase in the total serum NO2- concentrations after aerosol administration in both DETA/NO-treated and DPTA/NO-treated groups compared to control animals and to baseline (p < 0.01; Fig 4 ). The levels increased significantly from 15 min after aerosol administration and remained above control levels throughout the remainder of the experiment.



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  		Figure 4. Total serum NO2- concentrations for control, DETA/NO-treated, and DPTA/NO-treated groups after aerosol administration. *p < 0.01 control vs DETA/NO group; +p < 0.01 control vs DPTA/NO group. The time axis is shown as a categorical scale.

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
In this study, we have shown that both DETA/NO and DPTA/NO delivered by inhalation significantly reduced pulmonary vascular resistance without a detectable effect on the systemic circulation. The vasodilatory effect of both NONOates lasted from 45 min, up to 120 min. Total serum NO2- concentrations were significantly increased for the duration of the experiment, indicating continuous release and absorption of NO from the lung. Both NONOates also tended to reduce intrapulmonary shunting, but this effect was not statistically significant.

NONOates are a unique class of NO donors that release NO from physiologic solutions at predictable rates. The vasodilatory effect of NONOates is derived from the NO molecules released from the parent compound.14 When inhaled, NONOates not only exhibit the advantages of gaseous NO as a selective pulmonary vasodilator, but also avoid some of the disadvantages of NO delivery and monitoring. The NO-release half-life of DPTA/NO is approximately 3 h, while that for DETA/NO is approximately 20 h.8

The pulmonary vasodilation effect of inhaled DETA/NO was first demonstrated by Hampl et al15 in rodents, where chronic pulmonary hypertension had been induced by monocrotaline. DETA/NO (50 µmol) significantly reduced the PAP and total pulmonary resistance index without affecting the systemic circulation. The same group of researchers further investigated the acute vasodilatory effect of DETA/NO in fetal lambs.13 Pulmonary arterial blood flow increased in a dose-dependent manner after 0.1 mg, 0.4 mg, and 1.0 mg of nebulized DETA/NO administration into the fetal lungs. Inhaled DETA/NO had no effect on aortic BP or heart rate.

Our study showed that following U-46619– induced pulmonary hypertension, both DETA/NO and DPTA/NO delivered as single 60 µmol dose aerosols could significantly reduce PVRI and PAP. In keeping with their respective release half-lives, DETA/NO had a greater and more prolonged effect than DPTA/NO. Neither drug caused any systemic vasodilation, presumably because the released NO is rapidly inactivated by hemoglobin once it enters the circulation,16 and also due to the very short biological half-life of NO.17 The expected small but not significant rise in SBP in response to U46619 infusion was seen in all groups (Table 1) . These changes are in keeping with previous studies.5 18

There was also a trend toward reduced intrapulmonary shunting with both DETA/NO and DPTA/NO. The effect was more noticeable with DETA/NO but was not statistically significant for either compound. The failure to detect a significant difference in this measurement may be due to the relatively small sample sizes. Alternatively, lack of a significant effect may arise because the model used in this study was not designed primarily to cause an initial high level of intrapulmonary shunting (ie, this was not a hypoxemia model). In ARDS, increased intrapulmonary shunting is a common finding.1 19 This is in effect a physiologic right to left shunt and may contribute to hypoxemia. A true selective pulmonary vasodilator should not worsen / mismatching.1 20

The release of NO from inhaled DETA/NO and DPTA/NO can be inferred from our measurements of total serum NO2-. Serum NO2- concentrations were threefold to fivefold higher in both treatment groups and persisted for the 4 h of the experiment. Baseline concentrations of NO2- (mean of 45 ± 2.7 µmol/L and 29 ± 7 µmol/L for DETA/NO and DPTA/NO, respectively) were significantly lower than those reported by Jacobs et al21 before DMAEP/NO inhalation in piglets (255 µmol/L), but were similar to those from several other studies (range, 20 to 45 µmol/L) using similar analytical methodology.11 22 23 24 The baseline concentrations in the study by Jacobs et al21 were obtained after the induction of acute lung injury by the infusion of oleic acid; in this study, the levels were obtained before the induction of APH. Mean concentrations of total NO2- in serum during the period of the experiment were 194 ± 23 µmol/L and 165 ± 22 µmol/L for a 60 µmol single aerosolized dose of DETA/NO and DPTA/NO, respectively, which is similar to the means of 261 ± 45 µmol/L and 242 ± 28 µmol/L reported 30 min and 60 min after nebulized DMAEP/NO (340 µmol).21


   Conclusion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We have shown that both inhaled DETA/NO and DPTA/NO are selective pulmonary vasodilators in a closed-chest animal model. They not only reduced the pulmonary vascular resistance, with no detectable effect on systemic circulation, but they also tended to reduce intrapulmonary shunting. DETA/NO was more effective, presumably as a result of its longer NO-generating half-life. The potential therapeutic benefit of these agents has been demonstrated in a patient with ARDS.25


   Acknowledgements
 
The authors thank Ms. Brigit Roberts and Mr. Denham Heliams in the animal laboratory.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; APH = acute pulmonary hypertension; CI = cardiac index; DETA/NO = diethylenetriamine nitric oxide adduct; DPTA/NO = dipropylenetriamine nitric oxide adduct; MPAP = mean pulmonary artery pressure; NO = nitric oxide; NO2- = nitrite; PAP = pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; PVRI = pulmonary vascular resistance index; SBP = systemic BP; SPV = selective pulmonary vasodilator; / = ventilation/perfusion

This study was performed at the University of Western Australia, Crawley, Australia.

This study was supported by the Sir Charles Gairdner Hospital Research Fund.

Received for publication February 14, 2002. Accepted for publication September 4, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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