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1 Department of Anesthesia and Critical Care, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114; and 2 National Cancer Institute, Frederick, Maryland 21702
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ABSTRACT |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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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 (>102 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.
nitric oxide adducts; sodium nitroprusside; sheep
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INTRODUCTION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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INHALED NITRIC OXIDE (NO) gas is a selective pulmonary vasodilator that reverses pulmonary hypertension without reducing systemic arterial blood pressure (9, 24). The proposed mechanism of selective pulmonary vasodilation is inactivation of NO by its rapid interaction with oxyhemoglobin within the pulmonary circulation (9, 14). The long-term administration of inhaled NO may be problematic. The continuous delivery of inhaled NO requires specially designed breathing circuits to minimize NO2 formation and environmental contamination and to ensure a stable inhaled concentration of NO. Ambulatory administration of inhaled NO gas may be cumbersome. The potential toxicity of NO and its metabolites (particularly in conjunction with breathing increased O2 concentrations by injured lungs) is unknown and might restrict long-term clinical use of inhaled NO gas (23). An interesting alternative strategy to the continuous inhalation of NO is the intermittent inhalation of a "prodrug" that could be safely inhaled and would then slowly release NO into the pulmonary vasculature without producing systemic effects. Such drugs might permit intermittent dosing schedules and reduce toxicity.
Diazeniumdiolates (nucleophile/NO adducts) nonenzymatically generate NO
in predictable amounts at predictable rates (17). These compounds
contain ions of structure
X[N(O)NO],
where X is a nucleophile residue. Compounds containing this structural
unit theoretically may generate as much as 2 mol of NO/mol of
diazeniumdiolate. Hampl et al. (10) have already shown the potential
usefulness of one of these compounds, diethylenetriamine/NO (a
long-acting NO adduct) in a chronic pulmonary hypertension model induced by monocrotaline injection. Inhaled sodium
1-(N,N-diethylamino)diazen-1-ium-1,2-diolate {DEA/NO; Et2N[N(O)NO]Na} may
provide an attractive alternative to inhaled NO gas because of its
short half-life (2.1 min) at 37°C and pH 7.4 (17). When
administered intravenously during acute pulmonary hypertension induced
by intravenously infusing the thromboxane analog
9,11-dideoxy-9
,11-methanoepoxy prostaglandin F2
(U-46619) into intact
newborn lambs, DEA/NO produces nonselective pulmonary and systemic
vasodilation (30). This effect is similar to the nonselective
vasodilation noted after the intravenous administration of
nitrosovasodilators such as nitroprusside or nitroglycerin (3, 16, 19,
34). Because of its short half-life, we hypothesized that DEA/NO might
induce selective pulmonary vasodilation if the drug were
administered by inhalation. We therefore studied the hemodynamic effects of DEA/NO when administered by inhalation to
awake sheep with acute pulmonary hypertension induced by the intravenous infusion of U-46619. We compared the effects of
DEA/NO with the hemodynamic effects of inhaled NO gas and a standard NO
donor compound, sodium nitroprusside (SNP), administered as an aerosol.
To confirm the release of NO gas, we also measured the levels of NO
exhaled from the lungs during and after DEA/NO or SNP inhalation.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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These investigations were approved by the Subcommittee for Research Animal Studies of the Massachusetts General Hospital (Boston, MA).
Animal Preparation
Fourteen Suffolk lambs weighing 25-30 kg were anesthetized by inhalation of halothane in O2. Their tracheae were intubated, and their lungs were mechanically ventilated at 15 breaths/min and 15 ml/kg tidal volume by using a large-animal ventilator (Harvard Apparatus, Natick, MA). A femoral artery was cannulated with a polyvinyl chloride catheter (2 mm inner diameter) advanced 20 cm into the aorta for continuous arterial pressure monitoring and arterial blood sampling. A tracheotomy was performed, and an 8.0-mm inner diameter cuffed tracheotomy tube (Portex, Keene, NH) was inserted. A thermodilution pulmonary artery catheter (model 131H-7F, Baxter, Irvine, CA) was placed via the right external jugular vein through an 8-Fr introducer (Cordis, Miami, FL). The lambs were housed in a Babraham cage with free access to food and water and allowed 2 h to recover from anesthesia. Animals meeting any of the following criteria of sepsis were excluded from study: a peripheral white blood cell count <4,000 or >12,000/mm3, mean pulmonary arterial pressure (PAP) >20 mmHg, or a core temperature >40.1°C.Hemodynamic Measurements
Systemic arterial pressure (SAP), PAP, and central venous pressure were measured continuously, and pulmonary capillary wedge pressure was measured intermittently by using calibrated pressure transducers (Cobe Laboratories, Lakewood, CO) zeroed at the midthoracic level. After amplification of pressure signals (model 7700, Hewlett-Packard), the values were recorded (Western Graphtec, Irvine, CA). Mean measurements were obtained at end expiration. Cardiac output was measured by thermodilution as the average of two determinations after injection of 5 ml 0°C Ringer lactate. Pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) were computed by using standard formulas. The duration of the vasodilating response to inhaled NO donor compounds was determined by measuring the elapsed time from the cessation of inhalation until the mean PAP returned to its baseline value.NO Donor Compound Delivery
A two-way nonrebreathing valve (Hans Rudolph, Kansas City, MO) was attached to the tracheotomy to separate inspired from expired gas. The lambs breathed 100% O2 administered through a 5-liter rubber reservoir bag. The aerosols of DEA/NO or SNP were administered by using an O2-powered nebulizer (AereoTech II, CIS-US, Bedford, MA). The O2 flow supplied to the nebulizer chamber was kept constant at a flow rate of 8 l/min in all experiments. NO gas was introduced into the inspiratory limb of the breathing circuit immediately before the reservoir bag. The inspired concentration of NO was continuously measured by chemiluminescence (model 14A, Thermo Environmental Instruments, Franklin, MA) (8) at the inhalation port of the nonrebreathing valve. Exhaled gas was scavenged and discarded by continuous aspiration. After baseline measurements were taken, an intravenous infusion of the potent pulmonary vasoconstrictor U-46619 was administered at a rate of 0.4-0.8 µg · kg1 · min1
to increase the mean PAP to 30 mmHg.
Animal Groups
Group 1 (NO and DEA/NO inhalation).
Seven sheep were studied. Incremental NO inhalations [5, 10, 20, and 40 parts/million (ppm) by volume] were administered for 6 min
separated by 6-min NO-free intervals. All hemodynamic parameters returned to baseline values within the 6-min period. Prior studies have
documented that hemodynamic parameters return to baseline within this
time and do not measurably affect the response to subsequent NO
exposures (9). Twenty minutes after these NO inhalations, incremental
DEA/NO inhalations (104,
103, and
102 M) were administered
for 15 min, with allowance for 20-min intervals between doses because
all hemodynamic parameters returned to baseline within the 20-min
period. Cardiac output was measured every 3 min. Arterial blood samples
for the measurement of methemoglobin concentrations were obtained at
baseline and at the end of each NO or DEA/NO inhalation. The amounts of
DEA/NO that were nebulized were measured by weighing the nebulizer
before and after each administration.
Group 2 (SNP inhalation).
Seven additional sheep were studied. Incremental SNP inhalations (5 × 103, 1 × 102, 2 × 102, and 4 × 102 M) were administered
for 15 min each, followed by 20-min drug-free intervals. All of the
hemodynamic parameters returned to baseline within the 20-min drug-free
interval. Blood methemoglobin and plasma thiocyanate levels were
measured before the first inhalation and at the end of each inhalation.
The amounts of SNP that were nebulized were measured by weighing the
nebulizer before and after each administration.
Exhaled NO Measurements
The chemiluminescence analyzer was calibrated by using certified NO [440 parts/billion (ppb) by volume; Airco, Hingham, MA] mixed with 100% O2 (0 ppb NO) by precision flowmeters (Air Products and Chemicals, Allentown, PA), as described previously (12). Exhaled gas was sampled from the exhalation port of the two-way valve during the inhalation of DEA/NO or SNP. Before analysis, the exhaled gas was passed through a solid CO2-cooled (79°C) glass
vapor trap (Thomas Scientific, Swedesboro, NJ) to remove any moisture.
Teflon connecting tubes were used to avoid any interaction with NO.
Separate breathing circuits and valves were used during the
administration of the NO donor compounds and between inhalations to
avoid any NO release by residual tubing contamination. In
group 1, because of the difficulties
of calibrating the chemiluminescence analyzer at both low (ppb) and
high (ppm) NO levels during the same day, three sheep were studied
again the next day and the DEA/NO inhalations were repeated with
exhaled NO measurements. In group 2,
we measured the concentration of exhaled NO during the inhalation of
SNP in three sheep.
Drug Preparation and Administration
Ten milligrams of the stable endoperoxide analog of thromboxane U-46619 (Cayman Chemical, Ann Arbor, MI) were dissolved in 50 ml of lactated Ringer solution just before administration. NO was obtained from Airco (Murray Hill, NJ) as a mixture of 800 ppm NO in nitrogen. Less than 1% of the stock NO gas was present as NO2. NO was mixed with O2 in the 5-liter reservoir bag just before the inhalation port of the two-way valve. The sodium salt of the DEA/NO ion {Et2N[N(O)NO]Na, Chem. Abstr. Service Registry No. 92382-74-6} was prepared as previously described (17) and dissolved at a final concentration of 0.5 M in iced saline containing 1 mM NaOH. To decrease the pH and initiate the release of NO (5), a large amount of phosphate-buffered solution was added to this solution immediately before administration. SNP (Elkins-Sinn, Cherry Hill, NJ) was dissolved in lactated Ringer solution just before administration.Statistical Analysis
Values for the hemodynamic variables at the end of each period are reported as means ± SE. Because baseline hemodynamic measurements before and after each drug administration did not change significantly, the effects of inhalation of each NO donor agent (DEA/NO, NO, SNP) were compared with the averaged baseline values. Differences among treatments were analyzed with a repeated-measures analysis of variance. Paired or unpaired Student's t-tests were performed, as appropriate, with use of Bonferroni's correction for multiple comparisons. Differences were considered significant at P < 0.05.| |
RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Hemodynamic Effects of U-46619
Hemodynamic parameters at baseline of groups 1 (Table 1) and 2 (Table 2) were similar. The U-46619 infusion induced a similar increase in mean PAP in both groups. During the U-46619 infusion, PVR, SAP, SVR, central venous pressure, and pulmonary capillary wedge pressure were similarly increased, and cardiac output was decreased in both groups (see Tables 1 and 2).
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Effects of Inhaled NO Gas
At all dose levels, NO inhalation produced a prompt and stable reduction in pulmonary hypertension in a dose-dependent manner (see Figs. 1 and 2). The onset of pulmonary vasodilation occurred within seconds after NO inhalation was begun, and the vasodilator effect was maximal within 3 min. The prior level of pulmonary vasoconstriction returned within 3-6 min of termination of NO inhalation. NO inhalation, at the doses we tested, produced selective pulmonary vasodilation because mean SVR and SAP were unchanged (see Table 1). Methemoglobin levels remained <1.5% at all levels of NO administration.
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Effects of DEA/NO Inhalation
The quantities of DEA/NO nebulized over 15 min at 104,
103, and
102 M were 0.03 ± 0.01, 0.33 ± 0.04, and 3.2 ± 4.9 (SE) mg, respectively. DEA/NO
inhalation decreased both SVR and PVR in a dose-dependent manner (see
Figs. 1 and 2 and Table 3). The duration of
the pulmonary vasodilator response to DEA/NO was dose dependent and
longer than the pooled duration of the vasodilator response to inhaled
NO (6.6 ± 0.5 vs. 1.8 ± 0.2 min for DEA/NO and NO,
respectively, P < 0.01; see Fig.
3). Exhaled NO levels were as high as 300 ppb during the largest dose of DEA/NO inhalation (baseline value: 4 ± 1 ppb). Wide variations in exhaled NO concentration were observed during DEA/NO administration, a finding that makes interpretation of
these levels difficult. Methemoglobin levels remained <1.5% at all
administered DEA/NO doses.
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Effects of Inhaled Nitroprusside
The nebulization of 5 × 103, 1 × 102, 2 × 102, and 4 × 102 M SNP over 15 min
corresponded to the administration of 5.8 ± 0.7, 11.8 ± 1.1, 24.1 ± 2.5, and 45.9 ± 4.4 mg SNP, respectively. At 5 × 103 and 1 × 102 M, SNP selectively
decreased PAP and PVR without producing any change in SAP and SVR (see
Figs. 1 and 2 and Table 2). At larger inhaled concentrations, the
vasodilation induced by SNP was less selective; 2 × 102 and 4 × 102 M SNP inhalation failed
to decrease the PAP or PVR further, but SAP and SVR decreased
significantly (see Figs. 1 and 2 and Table 2). The duration of the
pulmonary vasodilator response to SNP was longer than the duration of
vasodilation induced by either DEA/NO or inhaled NO (all data pooled;
Fig. 3). Exhaled NO concentrations varied widely (up to 200 ppb) during
SNP inhalation (baseline value: 4 ± 1 ppb). Methemoglobin
concentrations remained <1.5% at all levels of SNP inhalation.
Thiocyanate levels remained low (<0.5 mg/dl) at all levels of SNP
inhalation.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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The present study demonstrates that in awake sheep inhaled SNP aerosols
at concentrations up to 1 × 102 M dilate the pulmonary
vasculature constricted by a U-46619 infusion without significantly
decreasing SAP. Inhaling an aerosol containing the short-half-life
compound DEA/NO dilated both the pulmonary and systemic circulation
(see Figs. 1 and 2). The duration of pulmonary vasodilation produced by
inhaling either of these NO donor compounds (DEA/NO or SNP)
was longer than the pulmonary vasodilator effect induced by inhaling NO
gas (see Fig. 3).
The successful use of vasodilators for the treatment of left ventricular failure has fostered interest in the application of the same principle in the treatment of right ventricular dysfunction (18, 22, 27, 28). The infusion of intravenous vasodilators to produce pulmonary vasodilation is limited by concomitant systemic vasodilation, which can cause peripheral hypotension, right ventricular ischemia, heart failure, and shock (3, 34). In addition, the intravenous administration of nitroglycerin and nitroprusside reverses hypoxic pulmonary vasoconstriction and can decrease the arterial O2 tension of patients with adult respiratory distress syndrome (2, 34).
The administration of drugs by inhalation has the theoretical advantage of acting, in high concentrations, on the pulmonary circulation and also preferentially targeting well-ventilated lung regions. Inhaled administration of vasodilators might improve pulmonary gas exchange, as already described for NO gas (9, 26). Inhaled prostacyclin has been reported to selectively dilate the pulmonary circulation during hypoxic pulmonary hypertension produced in a canine model (33) and to improve gas exchange in patients with acute respiratory failure (32). But when inhaled in larger quantities, prostacyclin can produce systemic hypotension (32, 33). SNP administered by inhalation was previously investigated as a bronchodilator in guinea pigs. Unfortunately, inhaled SNP significantly decreased the SAP while producing only minor bronchodilation (15, 20). We studied whether DEA/NO could serve as a reliable agent for producing spontaneous but predictable and controllable delivery of NO in a biological system (17) such as the pulmonary vasculature. However, inhaling DEA/NO also produced systemic vasodilation.
Inhaling SNP for 15 min at doses 1 × 102 M selectively dilated
the pulmonary circulation in the present study. Despite a short half-life (~2.1 min in water at 37°C and pH 7.4), inhaled DEA/NO produced less selective pulmonary vasodilation than SNP. Inhaling nitroprusside at low doses had a duration of action similar to that
with intravenous SNP administration but caused less systemic vasodilation at a similar level of pulmonary vasodilation than DEA/NO,
perhaps because fewer intact molecules of SNP were taken up into the
circulation from the airway.
The mechanism by which SNP releases NO has recently been discussed. It was previously believed that NO release occurred spontaneously (6, 7). However, Bates et al. (1) reported that a one-electron reduction with accompanying cyanide loss was required before NO could be released. The rate of release of NO from nitroprusside would therefore depend on the tissues or hemoproteins that it contacts. The precise mechanism of NO release remains obscure. Others have noted that the relatively small amounts of NO released by SNP do not seem to be sufficient to account for its marked enzyme-activating and dilatory potency (6). As previously reported, this compound may have additional effects on other regulatory systems unrelated to the generation of NO and therefore may not be an ideal NO donor compound (6).
Exhaled NO levels increased up to 200 and 300 ppb during the inhalation of either SNP or DEA/NO, respectively, confirming the production of NO within the lung in our study. There were wide variations in the exhaled NO level during a single administration, especially at the highest doses of both drugs. This could be related to an inconstant rate of NO release, or to variations of ventilation and uptake. Because the release of NO from DEA/NO follows first-order kinetics (17), it is likely that most of the fluctuations in exhaled NO level are related to variations in the spontaneous respiratory pattern of our experimental animals.
Circulating methemoglobin concentrations did not increase after the
inhalation of NO, DEA/NO, or SNP, despite the high inhaled doses we
studied. The inhalation of gas mixtures containing high concentrations
of NO and NO2 can cause severe
acute lung damage with pulmonary edema and marked methemoglobinemia
(4). Although there is little evidence for acute pulmonary toxicity of
inhaled NO at low concentrations (<100 ppm) after acute or chronic
exposure in rats (29) or rabbits (11), few data are available
concerning prolonged exposure in humans. Combining the administration
of NO donor compounds with an inhibitor of guanosine
3
,5-cyclic monophosphate-specific phosphodiesterase, as
previously described with use of NO donor compounds (21) or NO gas
(13), might further prolong the duration of action of inhaled NO donor
compounds. We also did not observe an increase in plasma thiocyanate
concentrations despite the high SNP concentrations that the sheep
inhaled. This may be explained by the brief period of administration
and the likelihood that only a small amount of drug reaches the lung
after nebulization. SNP may produce pulmonary toxicity directly by
contact of pulmonary tissue with cyanide ions. Systemic toxicity of SNP depends on the duration and concentration of the infusion (5, 31).
Assessment of the toxicity of chronic DEA/NO inhalations would require
further investigations. This compound can degrade to the carcinogen
N-nitrosodiethylamine (25).
The toxicities of SNP and DEA/NO may therefore limit their clinical use. Nevertheless, they remain useful as experimental prodrugs for the generation of NO in biological systems. NO-releasing compounds administered by inhalation may eventually prove useful as long-acting selective pulmonary vasodilators. The selectivity of pulmonary vasodilation induced by inhalation of such compounds does not appear to depend solely on the physical half-life or the duration of action of the drug.
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ACKNOWLEDGEMENTS |
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The authors thank Melahat Kavosi for technical assistance, Dr. Allan Zaslavski for statistical assistance, and Dr. Joseph Saavedra for providing the DEA/NO.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-42397 (W. M. Zapol) and a grant from the Société de Réanimation de Langue Française (C. Adrie).
Address for reprint requests: W. M. Zapol, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114.
Received 10 October 1996; accepted in final form 29 September 1997.
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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 M. Y. Kirov, O. V. Evgenov, V. N. Kuklin, L. Virag, P. Pacher, G. J. Southan, A. L. Salzman, C. Szabo, and L. J. Bjertnaes Aerosolized Linear Polyethylenimine-Nitric Oxide/Nucleophile Adduct Attenuates Endotoxin-induced Lung Injury in Sheep Am. J. Respir. Crit. Care Med., December 1, 2002; 166(11): 1436 - 1442. [Abstract] [Full Text] [PDF]
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 D. C. Stuesse, G. D. Giraud, A. A. Vlessis, A. Starr, and D. D. Trunkey Hemodynamic effects of S-nitrosocysteine, an intravenous regional vasodilator J. Thorac. Cardiovasc. Surg., August 1, 2001; 122(2): 371 - 377. [Abstract] [Full Text] [PDF]
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