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Published ahead of print on May 6, 2004, doi:10.1164/rccm.200312-1663OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 450-455, (2004)
© 2004 American Thoracic Society

Original Article

Regulation of Regional Lung Perfusion by Nitric Oxide

Danguole Rimeika, Sven Nyrén, N. Peter Wiklund, Lotta Renström Koskela, Anders Tørring, Lars E. Gustafsson, Stig A. Larsson, Hans Jacobsson, Sten G. E. Lindahl and Claes U. Wiklund

Departments of Anaesthesiology and Intensive Care Medicine, Radiology, and Urology, and Section of Nuclear Medicine, Hospital Physics, Karolinska Hospital; Centre for Allergy Research and Section of Environmental Physiology, Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

Correspondence and requests for reprints should be addressed to Sten G. E. Lindahl, M.D., Ph.D., H4:06, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail: sten.lindahl{at}ks.se


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Improved oxygenation has previously been shown in patients with acute lung injury when ventilated in prone position. We hypothesized that this was due to higher regional production of nitric oxide in dorsocaudal lung regions. We measured nitric oxide synthase mRNA expression and nitric oxide production by citrulline assay in ventral and dorsal lung tissue from patients. In volunteers, regional lung perfusion in prone and supine postures was assessed by single photon emission computed tomography using 99mTc macroaggregated albumin before and after inhibition of nitric oxide synthase by NG-monomethyl-L-arginine infusion. Nitric oxide synthase mRNA expression and nitric oxide production were significantly higher in dorsal compared with ventral lung regions. In supine posture, lung perfusion was shifted to ventral parts during nitric oxide synthase inhibition, whereas in the prone posture lung perfusion remained unchanged. Our results suggest a role for endogenous nitric oxide in regulation of regional pulmonary perfusion.

Key Words: acute lung injury • NG-monomethyl-L-arginine • nitric oxide synthase • prone position • single photon emission computed tomography

Acute lung injury and acute respiratory distress syndrome are clinical syndromes that are characterized by extreme hypoxemia and high mortality (1). Earlier investigations have shown dramatically improved oxygenation in ventilator-treated patients with acute respiratory distress syndrome when turned prone (2–5). In later experimental investigations, it was shown that /Qs were more uniform in prone than in supine position, leading to a more efficient gas exchange while in the prone posture (6). Earlier studies in upright humans have shown a greater relative perfusion in dependent lung regions (7), suggesting that gravity is an important determinant of blood flow distribution. In contrast, lung perfusion heterogeneity in isogravitational planes indicates actions of regulating factors, other than gravity, on distribution of lung perfusion (8–13).

Nitric oxide (NO) is a potent vasodilator synthesized in vascular endothelial cells. NO is synthesized by three different human isoenzymes: two constitutive Ca2+-dependent nitric oxide synthases (NOSs)—neuronal NOS, endothelial NOS (eNOS)—and a Ca2+-independent inducible enzyme. NOS oxidizes L-arginine to produce NO and L-citrulline in equimolar amounts. In airways, NOS is found in many cell types, including vascular endothelial cells, airway epithelial cells, macrophages, bacteria, and neurons (14–17).

We hypothesized that NO may play a role in regulation of regional lung perfusion. We analyzed NOS mRNA and NOS activity using citrulline assay in ventral and dorsocaudal lung tissue samples from patients subjected to lung surgery. In addition, we assessed regional lung perfusion in volunteers by single photon emission computed tomography (SPECT) using 99mTc macroaggregated albumin before and after NOS inhibition.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Approval by the local ethics and radiation safety committees and informed consent were obtained.

NOS Distribution
Tissue analysis of NOS mRNA expression and NOS activity were performed on samples from normal basal regions of lungs obtained at cancer surgery. After informed consent, 21 patients (mean age, 69 years) who were scheduled for lobectomy that was caused by malignancy were included. Tissue biopsies were taken in situ, from ventral and dorsal regions of lower lobes, frozen within 1 minute in liquid nitrogen, and stored at –80°C.

Total RNA Extraction and cDNA Synthesis
The eNOS mRNA expression was assessed with real-time polymerase chain reaction in dorsal and ventral lung tissue from 13 patients (mean age, 70 years). Total RNA was isolated using the RNeasy Mini Kit (Qiagen, Hilden, Germany) and quantified by spectrophotometry. Two micrograms of total RNA were used for cDNA synthesis.

Real-time Polymerase Chain Reaction
Approximately 50 ng of cDNA was amplified by real-time polymerase chain reaction with TaqMan universal polymerase chain reaction Master Mix (PE Applied Biosystems, Foster City, CA) using primers (1 mM) and probes (0.5 mM) as described in Table 1 (Invitrogen Life Technologies, Paisley, Scotland; and PE Applied Biosystems).


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  		TABLE 1. Target primers and probes used for real-time polymerase chain reaction

 
Samples were analyzed in duplicate, and polymerase chain reaction amplification was correlated against a standard curve. eNOS mRNA expression was quantified in relationship to mRNA expression of ß-actin, selected as a housekeeping gene.

NOS Activity
The conversion of L-(U-14C)arginine to L-(U-14C)citrulline was used for measurement of NOS activity as previously described (18). The analysis was performed in the presence or absence of the calcium chelator ethyleneglycol-bis-(ß-aminoethyl ether)-N,N'-tetraacetic acid to differentiate between Ca2+-dependent and Ca2+-independent NOS activity.

SPECT
Nine healthy, nonsmoking volunteers (mean age, 31 years) were studied in supine and prone positions in random order with 2-day intervals. Lung SPECT (Figure 1A) followed the previous description (19), including attenuation correction (20). SPECT 1 after an intravenous injection of macroaggregates (50 MBq) illustrates perfusion under basal conditions. Perfusion distribution during NOS inhibition was obtained by subtracting SPECT 2 data from SPECT 3, which was performed after the second injection of macroaggregates (100 MBq). SPECT 2 was used to exclude any change in shape of basal activity. SPECT 1 and SPECT 2 were not significantly different, which made subtraction analysis possible (see online supplement for details). Intra-arterial pressure, ECG, heart rate, peripheral oxygen saturation, and blood gases were registered.




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  		Figure 1. (A) Design of study for single photon emission computed tomography (SPECT) analysis of pulmonary perfusion. Tracer administration and nitric oxide synthase (NOS) inhibitor administration are indicated. (B) Frontal view of apical and basal sections of SPECT image planes. Rectangular volumes of interest (VOIs) were defined on the interface of the apical and mid third (apical section) and the mid and basal third (basal section) of the right lung. The VOI had a width of 18 mm and a length corresponding to the depth of the right lung. The VOI was divided in two equal parts (ventral/dorsal), and activity in each part is presented as a percentage of the entire VOIs. L-NMMA = NG-monomethyl-L-arginine; 99mTcMAA = 99mTc macroaggregated albumin.

 
For NOS inhibition, NG-monomethyl-L-arginine (L-NMMA; ClinAlfa, Läufelfingen, Switzerland) was infused intravenously at 2.4 mg kg–1 · body weight min–1 during 5 minutes, followed by 0.1 mg kg–1 · body weight min–1 during 60 minutes.

Perfusion distribution was analyzed using rectangular volumes of interest (VOI)—width 18 mm and length = lung dimension in ventral–dorsal direction. Volumes were defined on the interface between the apical and mid and the mid and basal third of the right lung (Figure 1B). They were divided in two equal parts (ventral/dorsal) and their perfusion was expressed in percent of that in the entire VOI.

Exhaled NO was measured by chemiluminescence according to American Thoracic Society guidelines (21), but at an exhalation rate of 25 ml/second using a Sievers 280 B Analyzer (Aerocrine, Solna, Sweden).

Statistical significance was tested with repeated-measures analysis of variance or Student's t test or Wilcoxon rank sum test for paired and unpaired variables. Experimental data are presented as mean values ± SD; p values less than 0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Regional Lung Distribution of NOS
The eNOS mRNA expression was significantly higher in dorsal than in ventral lung tissue biopsies (p < 0.05; Figure 2A) . Furthermore, Ca2+-dependent NOS activity was higher in dorsal than in ventral lung regions (p < 0.05). Ca2+-independent NOS activity was similar in the two regions (p = NS; Figure 2B).




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  		Figure 2. (A) Expression of mRNA for endothelial NOS (eNOS) in ventral and dorsal lung tissue. Human lung eNOS mRNA levels are illustrated as relative units between the expression of eNOS mRNA and the housekeeping gene ß-actin. Differences between the eNOS expression levels in dorsal and ventral parts of the lung were evaluated by Wilcoxon rank sum test for paired groups (*p < 0.05, n = 13). (B) NOS activity in ventral and dorsal lung tissue. Activity of nitric oxide synthase in human lung specimens obtained at surgery. The activity was determined in ventral (filled bars) and dorsal (open bars) specimens from the lower lobe in the presence and absence of 1.8-mM Ca2+ (*p < 0.05, n = 21).

 
Lung Perfusion Activity
A typical example of a transaxial SPECT section in a human volunteer is depicted in Figure 3 , showing a marked change in activity during NOS inhibition, suggesting a redistribution of pulmonary perfusion. Activities over apical and basal lung regions are presented in Figure 4 . A description of results listed later here is based on analysis of basal regions only, which receive the greater part of lung perfusion and are the more important regions for gas exchange as a whole.



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  		Figure 3. SPECT image of pulmonary perfusion before and after NOS inhibition. SPECT acquisition in a healthy human volunteer is illustrated before (a) and after (b) administration of the NO synthase inhibitor L-NMMA intravenously. A horizontal projection is shown with the ventral lung regions facing upward and the dorsal downward. The subject was placed in the supine position throughout the procedure, and the basal parts of the lungs are shown. R = right lung.

 


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  		Figure 4. Regional pulmonary perfusion in supine and prone positions. Distribution of pulmonary blood flow is determined by SPECT in healthy human volunteers, studied at two different occasions in prone (n = 8) and supine positions (n = 9), respectively. The relative distribution was determined for the ventral (filled bars) and dorsal (open bars) regions of the lungs before and during intravenous infusion of the NO synthase inhibitor L-NMMA. At the first row, relative blood flow distribution in apical sections is shown and at the second row in basal sections. In the left column, data from supine positions are demonstrated, and in the right column, data from prone positions are shown. (Statistical significance in the figure is indicated for differences between control conditions and in the presence of L-NMMA for ventral and dorsal VOIs, respectively; *p < 0.05, **p < 0.01.)

 
Lung Perfusion Activity under Basal Conditions
In the supine position, lung perfusion activity was higher in dorsal than in ventral regions (56% and 44%, respectively, p < 0.001; Figures 3 and 4). In the prone position, the perfusion activity was more homogeneous (53% ventral and 47% dorsal, p = NS; Figure 4). The difference between dorsal and ventral regions was larger in the supine than in the prone position (p < 0.001).

Lung Perfusion Activity during NOS Inhibition
In the supine position, NOS inhibition by L-NMMA caused a ventral shift of lung perfusion (Figure 3); that is, dorsal perfusion decreased (56% before and 52% after NOS inhibition). The ventral perfusion increased correspondingly (44 to 48%, p < 0.05; Figure 4). In the prone position, no significant changes in lung perfusion were detected after NOS inhibition (Figure 4).

Validation of NOS Inhibition
In both supine and prone positions, infusion of L-NMMA caused a prompt increase in mean arterial blood pressure (p < 0.001) and a simultaneous decrease in heart rate (p < 0.01; Figure 5) . In addition, exhaled NO decreased in parallel (p < 0.001; Figure 5). There was no significant difference in effect by L-NMMA on blood pressure, heart rate, or exhaled NO between supine and prone positions.



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  		Figure 5. Effects by L-NMMA on exhaled NO, blood pressure, and pulse rate (healthy human volunteers in prone and supine positions). Summary of effects of intravenous infusion of the NO synthase inhibitor L-NMMA on exhaled nitric oxide (FENO), arterial systolic (Syst) and diastolic (Diast) blood pressures, and heart rate (n = 17).

 
The acid–base balance was unchanged in healthy volunteers throughout the study. Values were as follows: before L-NMMA, supine position PO2 14.3 ± 1.4 kPa, PCO2 5.5 ± 0.6 kPa, pH 7.40 ± 0.12, prone position PO2 14.0 ± 1.0 kPa, PCO2 5.6 ± 0.5 kPa, and pH 7.40 ± 0.02; after L-NMMA, supine position PO2 13.8 ± 1.9 kPa, PCO2 5.2 ± 0.8 kPa, pH 7.42 ± 0.03, prone position PO2 13.8 ± 1.0 kPa, PCO2 5.5 ± 0.6 kPa, pH 7.41 ± 0.02. A reduction of exhaled NO by 75 ± 15% was achieved before the second administration of macroaggregates. Exhaled NO was 19.8 ± 9.0 ppb before and 5.0 ± 3.0 ppb 40 minutes after L-NMMA administration.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The highlights of this study are that endogenous NO formation is involved in regional regulation of pulmonary vascular tone and that NO production is higher in dorsal compared with ventral lung regions in humans. SPECT images in volunteers, before and after NOS inhibition, verify the functional importance of these findings.

The dominant dorsal lung perfusion in the supine position and more uniform perfusion in the prone position are consistent with previous studies in humans and animals during spontaneous respiration (6, 18, 22–24). These earlier findings were obtained with the use of various techniques such as radiospirometry (25) and SPECT in humans (26) and microspheres in animals (23, 24). The agreement between different species using a variety of techniques indicates a true description of physiologic conditions, which is further strengthened in this study. It should be kept in mind that the present SPECT method does not measure perfusion per se but the image produced by radioactive microspheres trapped in capillaries. The tracer technique is, on the other hand, well established and considered to give a true representation of pulmonary blood flow (PBF) (27). The algorithm used for correction of photon interactions with human tissue is not ideal for the chest and does not take photon scattering into account. Hence, accurate assessments of absolute regional activity are precluded. However, the technique allows for relative comparisons, as conditions are stable between the acquisitions.

It was demonstrated in 1986 by in vitro technique with microspheres in dogs that the vascular conductance was higher in dorsocaudal than in ventrocephalad regions of the lung (11). This suggests regional differences in regulation of the pulmonary vascular tone, which was further supported in a study with a series of vasodilators in vitro (28). A more pronounced endothelium-dependent vascular relaxation was shown as a response to a number of substances acting via the NO pathway in the dorsal equine lung. The difference in vascular conductance may also indicate anatomical differences such as number of vessels and branching differences. Gravity may also influence distribution of pulmonary perfusion. Fractal vascular trees and perfusion heterogeneity in isogravitational planes suggest a structural basis for regulation of regional PBF (29).

However, this series adds further explanatory evidence to a regulatory role for NO synthase. First, the gene expression of eNOS was higher in dorsal lung as compared with ventral (Figure 2A). Second, citrulline assays of Ca2+-dependent NO production from L-arginine; that is, NOS activity, was higher in dorsal parts (Figure 2B). Finally, NOS inhibition by L-NMMA in the supine position redirected blood from dorsal to ventral lung regions (Figure 4). Most probably this is caused by a relatively larger change in the vascular tone of dorsal pulmonary vessels as compared with ventral vessels while supine. It is surprising that NOS inhibition while prone did not result in a parallel redirection of PBF. Hence, body position may affect the response to L-NMMA. It is not likely that this is due to technical factors concerned with the SPECT technique or the infusion of the NOS inhibitor. This observation may invoke the assumption that the mechanical change, supine to prone, causes a different stretching of the pulmonary vasculature that changes the response to L-NMMA. Increased exhalation of NO during ventilation with positive end-expiratory pressure in rabbits has been suggested to be caused by a stretch-dependent regulation of pulmonary NO formation in animals (30, 31). In supine, we found that there is a preferential PBF to dorsal lung regions, resulting in filled (stretched) blood vessels. In contrast, blood flow distribution was found to be more uniform in the prone position (18). Hence, a smaller relative effect may be expected from NOS inhibition while prone, which may explain the lack of effect on regional blood flow by NOS inhibition in the prone posture.

The effect by NOS inhibition may also be minimized by effects of prone position on pleural pressure, lung volume, and possibly hemodynamics. The vertical pleural pressure gradient is reduced and FRC is increased in prone position. The difference in response to NOS inhibition between supine and prone position cannot be fully explained in this study, and further investigations are needed to confirm and clarify this point.

In a study using a canine model of acute lung injury, responses to inhaled NO were dependent on distribution of PBF before inhalation (32). They found that in animals receiving oleic acid, PBF redistributed from dorsal edematous to nondependent zones. In these animals, inhaled NO did not change oxygenation or PBF. In animals treated with oleic acid and low-dose endotoxin, PBF was not redistributed from dorsal zones, and oxygenation fell dramatically. In these animals, inhaled NO improved oxygenation and restored ventilation/perfusion relationships. These results suggest that the balance between vasodilators and constrictors in lung disease is of importance not only for oxygenation and PBF but also for the response to treatments such as inhaled NO.

Ventilation distributes preferentially to dependent lung regions in supine humans (33). This is believed to be partly caused by a vertical compliance difference arising from a pleural pressure gradient. This vertical pressure gradient is reduced in prone position and may play a role in decreased spatial distribution of ventilation, NO delivery, and responsiveness to NOS inhibition. The pattern of respiratory muscle contraction is strongly affected by posture and lung volume. It influences pleural pressure gradients and is therefore an important determinant of regional ventilation.

Epithelial NO might play a role in regulating PBF. The NO exhaled and measured in this study at end expiration is regarded to originate mainly from peripheral airways of the lung. Inhalation of L-NMMA, which did not have any effect on hemodynamics and on L-NMMA concentration in plasma, decreased exhaled NO by 40% (34). The exhaled NO was regarded as mostly of epithelial rather than endothelial origin. We cannot discriminate between NO derived from epithelial or endothelial cells. This was, however, not the scope of this investigation. The measurement of exhaled NO was made primarily to verify adequate enzymatic inhibition of NO synthesis by L-NMMA. We have shown a redistribution of PBF during NO synthase inhibition indicating a role for endogenous NO in regulation of PBF regardless of the origin of NO. The origin of the NO responsible for regulation of regional pulmonary perfusion is Ca2+-dependent because there was no difference in Ca2+-independent NOS activity. The difference in eNOS mRNA expression also indicates that that it is the endothelial NOS that has a regulatory role.

NO production in vivo is regulated by different factors. Shear stress caused by high blood flow may result in enhanced NO synthesis in dorsal lung regions. This might indicate that the observed higher Ca2+-dependent NOS activity described in this study is a secondary phenomenon and not the cause of higher blood flow in dorsal regions in the supine position. NOS activity was analyzed in vitro under standardized conditions, for example, equal amounts of enzyme substrate, L-arginine, indicating that constitutional enzyme activity was higher in dorsal lung regions. NOS activity analyzed in our study was not influenced by shear stress because the analysis was made in vitro, not in blood vessels in vivo. Ca2+-independent, inducible NOS activity did not differ between ventral and dorsal tissue samples. Furthermore, expression of mRNA for eNOS was higher in dorsal regions. Taken together, our results strongly suggest a difference in eNOS enzyme content and Ca2+-dependent NOS activity under basal conditions in dorsal lung regions. Our results cannot exclude the possibility that the NOS activity measured ex vivo was influenced by higher shear stress and flow in dorsal regions at the time the tissue was harvested. Whether the increased NOS activity is a primary or secondary phenomenon cannot be fully answered by this study, and further investigations are needed.

Cardiac output was not measured in this study. In an earlier investigation, a decrease in cardiac output of 23 ± 3% was noted during infusion of L-NMMA 0.3 mg–1 kg–1 (35). The mean arterial pressure increased by 12 ± 3%, and systemic vascular resistance increased by 46 ± 9%. Mean pulmonary artery increased by 39%, and pulmonary vascular resistance increased by 113%. Pulmonary vascular resistance is influenced by cardiac output. Some of the effects by L-NMMA on regional flow may in part be due to its effect on cardiac output, that is, derecruitment of pulmonary vessels.

The change in relative blood flow may be the consequence of a change in cardiac output, a change in vascular tone, or both. Pulmonary arteries are known to react as a functional unit with systemic arteries via baroreceptor reflexes. Increased pressure in pulmonary arteries causes a reflex pressure drop in the systemic arteries and decreased pulmonary pressure increases systemic pressure. The rise in both pulmonary and systemic vascular pressure indicates that the change in pulmonary vascular tone is not a secondary reflex to the effect by L-NNMA in the systemic circulation but rather a direct effect by L-NMMA in the pulmonary vasculature.

Prone position increases functional residual capacity, which may improve ventilation. This is another possible explanation for improved gas exchange in prone position.

It should be realized that the findings in this study, as well as in previous (11, 28), were made in healthy lungs and are not directly applicable to lung pathology. There are, however, several clinical studies that clearly demonstrate improved oxygenation in patients with acute lung injury and acute respiratory distress syndrome when turned to the prone position (36–39). In mechanically ventilated patients, it is well known that there is a dominant gas distribution to nondependent lung regions, whereas lung perfusion is preferentially dependent (40, 41). This results in /Q mismatch. The improved oxygenation during mechanical ventilation while prone is a result of a more favorable /Q match. It is likely that this could be caused by lower vascular tone in dorsal lung regions based on the higher dorsal NO production demonstrated in this series.

This investigation showed, in humans, a higher eNOS mRNA expression and NOS activity in dorsal lung regions as compared with ventral. NOS inhibition, while supine, redirected blood flow from dorsal to ventral lung regions, resulting in a more uniform lung perfusion. It is concluded that NO is an important factor for regulation of regional lung perfusion.


   FOOTNOTES
 
Supported by the Swedish Research Council K2003–74X-10401–11A and the Heart and Lung Foundation 200,141,470.

D.R. and S.N. contributed equally to this study.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: D.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; N.P.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.R.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; L.E.G. has patents on technology for exhaled NO measurements and is a shareholder in Aerocrine AB where he is also a member of the Board of Directors; S.A.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; H.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.G.E.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; C.U.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form December 8, 2003; accepted in final form April 30, 2004


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