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J Appl Physiol 98: 748-752, 2005. First published October 1, 2004; doi:10.1152/japplphysiol.00820.2004
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HIGHLIGHTED TOPICS
Pulmonary Circulation and Hypoxia

NOS3 deficiency augments hypoxic pulmonary vasoconstriction and enhances systemic oxygenation during one-lung ventilation in mice

Rong Liu,1 Oleg V. Evgenov,1 and Fumito Ichinose1,2

1Department of Anesthesia and Critical Care and the 2Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

Submitted 2 August 2004 ; accepted in final form 30 September 2004


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Nitric oxide (NO), synthesized by NO synthases (NOS), plays a pivotal role in regulation of pulmonary vascular tone. To examine the role of endothelial NOS (NOS3) in hypoxic pulmonary vasoconstriction (HPV), we measured left lung pulmonary vascular resistance (LPVR), intrapulmonary shunting, and arterial PO2 (PaO2) before and during left mainstem bronchus occlusion (LMBO) in mice with and without a deletion of the gene encoding NOS3. The increase of LPVR induced by LMBO was greater in NOS3-deficient mice than in wild-type mice (151 ± 39% vs. 109 ± 36%, mean ± SD; P < 0.05). NOS3-deficient mice had a lower intrapulmonary shunt fraction than wild-type mice (17.1 ± 3.6% vs. 21.7 ± 2.4%, P < 0.05) during LMBO. Both real-time PaO2 monitoring with an intra-arterial probe and arterial blood-gas analysis during LMBO showed higher PaO2 in NOS3-deficient mice than in wild-type mice (P < 0.05). Inhibition of all three NOS isoforms with N{omega}-nitro-L-arginine methyl ester (L-NAME) augmented the increase of LPVR induced by LMBO in wild-type mice (183 ± 67% in L-NAME treated vs. 109 ± 36% in saline treated, P < 0.01) but not in NOS3-deficient mice. Similarly, systemic oxygenation during one-lung ventilation was augmented by L-NAME in wild-type mice but not in NOS3-deficient mice. These findings indicate that NO derived from NOS3 modulates HPV in vivo and that inhibition of NOS3 improves systemic oxygenation during acute unilateral lung hypoxia.

hypoxia; shunt; ventilation-perfusion matching

THE INTRAPULMONARY DISTRIBUTION of blood flow and ventilation (ventilation-perfusion distribution) is a major determinant of the efficiency of transpulmonary oxygenation and determines arterial PO2 (PaO2). Hypoxic pulmonary vasoconstriction (HPV) preserves systemic oxygenation by constricting pulmonary vessels in poorly ventilated or atelectatic hypoxic lung regions, thus optimizing the matching of ventilation and perfusion. Although the precise mechanisms that mediate HPV remain incompletely understood, a number of vasoactive mediators, such as arachidonic acid metabolites and endothelin, are known to modulate HPV (1, 25).

Nitric oxide (NO), synthesized by NO synthases (NOS1, NOS2, and NOS3), plays a pivotal role in regulation of vascular tone. Although all three NOS isoforms are found in the lung (5, 18, 26), the principal isoform expressed in the normal pulmonary vasculature is NOS3 (18, 23). We and others have previously reported that NOS3 contributes to the low pulmonary vascular resistance in mice (7, 20). Studies have suggested an important modulatory role of NO on HPV in a variety of species (4, 10, 23). For instance, inhaled NO reverses human HPV (9), whereas an acute, nonselective inhibition of NOS enhances HPV in isolated, perfused rabbit lungs (23). Using buffer-perfused isolated lungs from genetically modified mice, Fagan et al. (8) observed that NOS3 attenuated HPV to a greater extent than did NOS1 or NOS2. Although these studies support a prominent modulatory role of NOS3 on HPV, there is little information as to whether NO derived from NOS3 affects intrapulmonary blood shunting and systemic oxygenation in intact animals.

In the present study, we hypothesized that reduced endogenous production of NO due to a congenital deficiency of NOS3 or pharmacological inhibition of NOS would augment HPV in a mouse model of acute unilateral lung hypoxia. This model enabled us to examine the in vivo effects of regional hypoxia on pulmonary vascular tone, intrapulmonary shunt, as well as systemic oxygenation. We report that NOS3 deficiency augments HPV and systemic oxygenation during acute unilateral lung hypoxia in mice.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
This investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health and was approved by the Subcommittee on Research Animal Care of the Massachusetts General Hospital. We studied male wild-type mice (C57BL/6) and NOS3-deficient mice (B6129P2-NOS3tml/Unc; NOS3–/–) that were backcrossed onto C57BL/6 background more than 10 generations; mice were 6 to 12 wk old and weighed 21–30 g. Animals in each experimental group were matched for body weight. All mice were obtained from the Jackson Laboratory (Bar Harbor, ME) and maintained in the hospital's animal resource facility.

Experiments were performed in wild-type and NOS3–/– mice treated with and without N{omega}-nitro-L-arginine methyl ester (L-NAME), an inhibitor of all three NOS isoforms. Mice that were not treated with L-NAME received the same volume of vehicle (normal saline) as control.

Anesthesia and surgical preparation.   Mice were anesthetized by intraperitoneal injection of ketamine (0.1 mg/g body wt) and fentanyl (0.25 µg/g). Muscle relaxation was obtained by intraperitoneal injection of pancuronium (5 µg/g) after tracheostomy. Volume-controlled ventilation was initiated at a respiratory rate of 100 breaths/min with a tidal volume of 11 ml/kg (model 687; Harvard Apparatus, Holliston, MA) at inspired O2 fraction = 1.0 and a positive end-expiratory pressure of 1 cmH2O. Systemic arterial pressure (SAP) was monitored via a PE-10 catheter placed in the right carotid artery. Lactated Ringer solution was infused via the carotid arterial catheter at 0.06–0.09 ml·h–1·g–1 with the use of a syringe pump (Kent Scientific, Torrington, CT). L-NAME (0.1 mg/g) or the same volume of saline (0.01 ml/g) was administered intraperitoneally immediately after tracheotomy (30 min before hemodynamic measurements). The dose of L-NAME was selected on the basis of previous studies (12, 20). All physiological signals were displayed and recorded with a digital data acquisition system (DI720; Dataq Instruments, Akron, OH).

Measurement of HPV.   Magnitude of HPV was assessed in 14 saline-treated wild-type mice, 13 saline-treated NOS3–/– mice, 12 L-NAME-treated wild-type mice, and 10 L-NAME-treated NOS3–/– mice. After thoracotomy, a small-vessel ultrasonic flow probe (0.5VB; Transonic Systems, Ithaca, NY) was placed around the left pulmonary artery to obtain left pulmonary artery blood flow (lpa). A catheter (a 30-gauge needle connected to PE-10 tubing) was placed by direct puncture of the main pulmonary artery to measure pulmonary arterial pressure (PAP). The inferior vena cava (IVC) was partially occluded with a circumferential 5-0 silk ligature to transiently reduce cardiac output until lpa was reduced by ~50%. The slope, derived by linear regression between mean lpa and mean PAP during IVC occlusion, represents left lung pulmonary vascular resistance (LPVR) (13, 14, 21). Unilateral alveolar hypoxia was induced by left mainstem bronchus occlusion (LMBO) with a microvascular clip. Transient IVC occlusion was repeated three times before LMBO and 5 min after the microvascular clip was placed (during LMBO). The percentage of increase in LPVR induced by LMBO was calculated as (LPVRduringLMBO – LPVRbeforeLMBO)/LPVRbeforeLMBO x 100.

Measurements of intrapulmonary shunt fraction.   Intrapulmonary shunt fraction (QS/QT) was determined in four additional groups of mice (n = 6 in each group): NOS3–/– and wild-type mice that had one-lung ventilation with LMBO and NOS3–/– and wild-type mice that had two-lung ventilation without LMBO. Blood samples were simultaneously withdrawn from the carotid and pulmonary arteries and analyzed for pH, PO2, and PCO2 by a blood-gas analyzer (Rapidlab 840; Chiron Diagnostics, Medfield, MA). Oxygen saturation and the concentration of total hemoglobin were measured with a hemoximeter (OSM3; Radiometer, Copenhagen, Denmark). Barometric pressure was noted daily to calculate alveolar PO2. Oxygen content of arterial blood, pulmonary end-capillary blood, and mixed venous blood was calculated assuming a hemoglobin oxygen binding capacity of 1.31 ml/g and pulmonary end-capillary blood oxygen saturation of 1.0. QS/QT was calculated with a standard equation (17).

Measurements of left atrial pressure and systemic oxygenation.   In another subset of mice (9 saline-treated wild-type mice, 9 saline-treated NOS3–/– mice, 5 L-NAME-treated wild-type mice, and 5 L-NAME-treated NOS3–/– mice), a catheter (a 30-gauge needle connected to PE-10 tubing) was placed in the left atrium to measure left atrial pressure (LAP) before and 5 min after the left mainstem bronchus was occluded. To allow insertion of the left atrial catheter, the flow probe on the left pulmonary artery was omitted in these experiments. Arterial blood sample was obtained during LMBO by direct withdrawal from left ventricle with a 27-gauge needle for blood-gas analysis. To further assess the impact of NOS3 deficiency on systemic oxygenation during LMBO in four wild-type and four NOS3–/– mice, a flexible polarographic Clark-type oxygen micro probe (0.5 mm OD; LICOX CC1.R, GMS, Kiel-Mielkendorf, Germany) was advanced into the abdominal aorta via the left femoral artery. PaO2 was measured in real time and recorded continuously. The PaO2 electrodes were calibrated before and after each experiment in air at ambient pressure according to the manufacturer's instructions.

Statistical analysis.   All data are expressed as means ± SD. For results of HPV and QS/QT measurements, a two-way ANOVA with a post hoc Student-Newman-Keuls test was used for evaluating differences between genotypes and treatments. Measurements made with the intra-aortic PaO2 probe were compared by unpaired t-test in wild-type and NOS3–/– mice. Measurements within the same experimental group before and during LMBO were compared by a paired t-test. If the normality test failed, Mann-Whitney rank sum test was applied. A SigmaStat 3.0 software package (Systat Software, Richmond, CA) was used for statistical analysis. A value of P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
Effect of NOS3 deficiency on the magnitude of HPV.   Before thoracotomy, SAP was higher in NOS3–/– mice than in wild-type mice (112 ± 28 vs. 92 ± 20 mmHg, P < 0.05). After thoracotomy and before LMBO, hemodynamic parameters did not differ between the two genotypes after saline treatment (Table 1). LMBO increased PAP, decreased lpa, and increased LPVR compared with baseline values in both wild-type and NOS3–/– mice (Table 1, P < 0.001 for all comparisons by paired t-test). Although LMBO more than doubled LPVR in both wild-type and NOS3–/– mice, NOS3–/– mice had a higher LPVR during LMBO than did wild-type mice (287 ± 69 vs. 205 ± 81 mmHg·ml–1·min·g body wt, P < 0.05). Similarly, the percent increase in LPVR induced by LMBO was greater in NOS3–/– mice than in wild-type mice (151 ± 39% vs. 109 ± 36%, P < 0.05, Fig. 1), suggesting that HPV was augmented in NOS3–/– mice.


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  		Table 1. Hemodynamic variables before and during LMBO

 


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  		Fig. 1. Percent increase of left lung pulmonary vascular resistance (LPVR) in response to left mainstem bronchus occlusion (LMBO) in wild-type and NOS3-deficient (NOS3–/–) mice, treated with saline or N{omega}-nitro-L-arginine methyl ester (L-NAME). Data are means ± SD.

 
To ascertain whether the increased LPVR in NOS3–/– mice during LMBO was not due to an increased LAP, LAP was measured in additional wild-type and NOS3–/– mice. There were no differences in LAP between NOS3–/– and wild-type mice before LMBO (2.4 ± 0.7 vs. 2.6 ± 0.6 mmHg) or during LMBO (2.9 ± 0.5 vs. 3.1 ± 0.3 mmHg).

Effect of L-NAME on the magnitude of HPV.   Before thoracotomy, L-NAME-treated wild-type mice had a higher SAP than did saline-treated wild-type mice (134 ± 19 vs. 92 ± 20 mmHg, P < 0.001). On the other hand, L-NAME treatment did not change SAP in NOS3–/– mice. Administration of L-NAME increased PAP, decreased lpa, and increased LPVR in both wild-type and NOS3–/– mice before and during LMBO compared with saline-treated mice of corresponding genotypes (Table 1). Administration of L-NAME augmented the percent increase in LPVR induced by LMBO in wild-type mice (P < 0.01, Fig. 1) but not in NOS3–/– mice.

Effect of NOS3 deficiency on intrapulmonary shunt.   As depicted in Fig. 2, when both lungs were ventilated, there was no difference in QS/QT between NOS3–/– mice and wild-type mice (9.4 ± 3.0 vs. 8.6 ± 1.7%). One-lung ventilation increased QS/QT in both wild-type and NOS3–/– mice, compared with mice of respective genotype that had two-lung ventilation (P < 0.001 for both). However, one-lung ventilation with LMBO induced a larger increase in QS/QT in wild-type than in NOS3–/– mice (21.7 ± 2.4 vs. 17.1 ± 3.6%, P < 0.05).



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  		Fig. 2. Intrapulmonary shunt fraction (QS/QT) in wild-type and NOS3–/– mice during 2-lung ventilation or one-lung ventilation with LMBO. Data are means ± SD; n = 6 in each group. *P < 0.001 vs. mice with respective genotype that had 2-lung ventilation; {dagger}P < 0.05 vs. wild-type mice during 1-lung ventilation with LMBO.

 
Effects of NOS3 deficiency or L-NAME on systemic oxygenation.   To assess the impact of differences in the magnitude of HPV on systemic oxygenation, arterial blood-gas analyses were performed during LMBO in wild-type and NOS3–/– mice. As shown in Table 2, there were no significant differences in arterial hemoglobin concentration, pH, arterial PCO2, and HCO3– between saline-treated wild-type and NOS3–/– mice. However, PaO2 was higher in NOS3–/– mice than in wild-type mice during LMBO (P < 0.05). Administration of L-NAME increased PaO2 further during LMBO in wild-type mice (P < 0.001 vs. saline-treated wild-type mice) but not in NOS3–/– mice. Systemic oxygenation during LMBO was further assessed by using an intra-arterial PaO2 probe in a subset of saline-treated mice of both genotypes. No difference in PaO2 before LMBO was detected between NOS3–/– and wild-type mice (542 ± 60 vs. 558 ± 103 Torr, Fig. 3). With LMBO, PaO2 decreased in both genotypes to its new steady state within 2 min; however, NOS3–/– mice had a higher PaO2 than did wild-type mice during LMBO (324 ± 45 vs. 219 ± 59 Torr, P < 0.05).


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  		Table 2. Arterial blood-gas analysis during LMBO

 


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  		Fig. 3. Tracings of real-time arterial PO2 (PaO2) measurements before and during LMBO in saline-treated wild-type mice (solid line) and NOS3–/– mice (dashed line). Tracings represent the mean values and SD (gray area) of 4 independent experiments in each genotype. LMBO-induced decrement in PaO2 was markedly smaller in NOS3–/– mice than in wild-type mice (P < 0.05; at 5 min after the start of LMBO).

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 
The purpose of this study was to examine the modulatory role of NOS3 on HPV, intrapulmonary shunting, and systemic oxygenation during acute unilateral alveolar hypoxia in vivo. Consistent with previous studies (8, 23), we observed that NOS3 deficiency augments pulmonary vasoconstriction in the hypoxic lung. We demonstrated that the enhancement of HPV in NOS3–/– mice during one-lung ventilation was associated with a decreased intrapulmonary shunt and improved systemic oxygenation. These findings are in contrast to the majority of previous investigations in which HPV was measured as an increase of total pulmonary vascular resistance in isolated buffer-perfused lung models, which ignore the influence of red blood cells (19) and preclude the possibility of examining the influence of HPV on intrapulmonary shunt and systemic oxygenation.

Although NOS3–/– mice had higher SAP than did wild-type mice when measured with intact chest, thoracotomy and surgical instrumentation decreased SAP in both genotypes and abolished the difference in SAP (see Table 1). It is likely that surgical bleeding and mechanical interference of cardiovascular function by instruments (e.g., flow probe on left pulmonary artery and pulmonary artery catheter) decreased cardiac output after thoracotomy. It is also possible that open chest caused left ventricular dysfunction, thereby decreasing SAP and obscuring the hemodynamic differences between the two genotypes (11, 16). On the other hand, it is notable that NOS3 deficiency significantly augmented HPV despite the obscuring effects of thoracotomy on hemodynamic parameters in this model. It is conceivable that NOS3 deficiency may have an even greater impact on the magnitude of HPV in closed-chest animal.

In the present study, inhibition of all three isoforms of NOS by L-NAME enhanced HPV and systemic oxygenation in wild-type mice, confirming previous results obtained in isolated perfused rabbits lungs (23). L-NAME has also been shown to enhance systemic oxygenation in septic patients (2) and improve ventilation-perfusion distribution matching in anesthetized, mechanically ventilated dogs (3). These results indicate an important negative regulation of HPV by NO. Interestingly, L-NAME did not augment HPV or systemic oxygenation in NOS3–/– mice in the present study. The latter results are in agreement with a recent report by Fagan et al. (8), who found that NG-nitro-L-arginine, another nonselective NOS inhibitor, doubled HPV in perfused lungs isolated from wild-type mice but not from NOS3–/– mice. Together, these findings suggest that the ability of nonselective NOS inhibitors to augment HPV in response to unilateral alveolar hypoxia is predominantly dependent on inhibition of NOS3.

It is of note that the LMBO-induced increase of LPVR tended to be greater and systemic oxygenation was significantly better during LMBO in L-NAME-treated wild-type mice than in L-NAME-treated NOS3–/– mice. It is possible that the vasoconstrictor effects of L-NAME were downregulated in NOS3–/– mice due to chronic hypertension. Alternatively, life-long deficiency of NOS3 may lead to upregulation of an L-NAME-insensitive vasodilator, which serves to inhibit HPV.

Using the unilateral alveolar hypoxia model, our group (13) previously reported that mutation or inhibition of cytosolic phospholipase A2 attenuated HPV, and vasoconstrictors such as indomethacin and L-NAME restored HPV. The present study demonstrated that mutation or inhibition of an enzyme, NOS3, responsible for synthesis of a vasodilator, NO, augmented HPV and improved systemic oxygenation. These findings suggest that HPV is critically dependent on the underlying tone of the pulmonary vasculature. Moreover, these finding provide further support for the hypothesis that genetic mechanisms contribute to the regulation of HPV. It has recently become increasingly appreciated that polymorphisms in the NOS3 gene are associated with a variety of cardiovascular diseases, including essential hypertension, smoking-associated coronary heart disease, and carotid atherosclerosis (15, 22, 24). Droma et al. (6) reported that two polymorphisms in the NOS3 gene were associated with high-altitude pulmonary edema, a disorder characterized by exaggerated pulmonary hypertension. Taken together, these findings suggest that genetic variations in the NOS3 gene may contribute to differences among individuals in the manner in which the pulmonary vasculature responds to hypoxia.

In conclusion, we demonstrated that NOS3 deficiency augments HPV as well as reduces intrapulmonary shunt and improves systemic oxygenation during one-lung ventilation in mice. Inhibition of all three isoforms of NOS by L-NAME also enhances HPV in wild-type mice but exerts little or no effects in NOS3-deficient mice. These results support the hypothesis that NO derived from NOS3 is an important modulator of HPV in vivo, and inhibition of NOS improves oxygenation during regional lung hypoxia.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
ACKNOWLEDGMENTS
 REFERENCES
 
This study was supported in part by National Heart, Lung, and Blood Institute Grant HL-71987 (to F. Ichinose) and Research Council of Norway Grant 161151/V40 (to O. V. Evgenov).


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
REFERENCES
 
The authors thank Drs. Warren M. Zapol and Kenneth D. Bloch for valuable comments.


   FOOTNOTES
 

Address for reprint requests and other correspondence: F. Ichinose, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114 (E-mail: ichinose{at}etherdome.mgh.harvard.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 ACKNOWLEDGMENTS
 REFERENCES
 

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P. Vermeersch, E. Buys, P. Pokreisz, G. Marsboom, F. Ichinose, P. Sips, M. Pellens, H. Gillijns, M. Swinnen, A. Graveline, et al.
Soluble Guanylate Cyclase-{alpha}1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia
Circulation, August 21, 2007; 116(8): 936 - 943.
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