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1 Department of Medicine and 2 Division of Applied Physiology, School of Nursing, Asahikawa Medical College, Asahikawa 078-8510, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after NG-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 ± 3 (SE) to 83 ± 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 ± 2 to 73 ± 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.
pulmonary endothelium; shear stress; recruitment
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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BLOOD
FLOW-DEPENDENT vasodilation has been confirmed in the large
conduit arteries of systemic circulation such as femoral (22) and coronary arteries (24). This
response of increased flow is mainly caused by nitric oxide (NO), which
is produced by an increase in shear stress of vascular endothelium
(6, 17). In the pulmonary circulation, it has been
suggested that NO is released from arterial and venous
endothelial cells (12) and contributes to the maintenance
of the physiologically low basal pulmonary vascular tone (10, 19,
20). In addition, the pulmonary vascular bed has a large
capacity to adapt to changes in blood flow. However, the role of NO in
the mechanism underlying the accommodation to flow changes in the
pulmonary circulation is unknown. In humans, it has been demonstrated
that changes in pulmonary blood flow with head-out water immersion or
increased gravity did not alter exhaled NO output (21). In
contrast, in patients with atrial septal defects, acute changes in
pulmonary blood flow with atrial septal defect closure reduced exhaled
NO (26). Controversy remains over the issue of whether
exhaled NO reflects endothelial NO production (
NO)
under physiological conditions. Furthermore, no direct evidence for
flow-induced release of NO has been reported in "in vivo" studies,
because NO produced intrinsically in the lung is easily cleared and
quickly inactivated by hemoglobin (5). Therefore, the aim
of the present study was to clarify the effects of hemoglobin on lung
NO and to determine the role of NO in the mechanism responsible for the
adaptability of the pulmonary circulation to changes in blood flow.
Isolated lung perfusion models allow convenient assessment of pulmonary
hemodynamics and total NO by analysis of exhaled NO
and perfusate NO metabolites (NOx) during selected experimental conditions (7, 11, 18, 25). We hypothesized that changes in pulmonary flow would affect both exhaled NO and perfusate NOx during
buffer perfusion but not during blood perfusion. In the present study,
we measured exhaled NO, perfusate NO metabolites, and pulmonary
arterial pressure (Ppa) with stepwise changes in perfusate flow
during normoxia (20% O2) and hypoxia (3% O2)
and after treatment with
NG-monomethyl-L-arginine
(L-NMMA), a NO synthase (NOS) inhibitor, during normoxia
in buffer-perfused rabbit lungs. In addition, we examined the
effect of changing flow on exhaled NO in blood-perfused lungs.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation of the Isolated Lung Model
The experimental protocol was approved by the Institutional Animal Care and Use Committee of Asahikawa Medical College. Male Japanese albino rabbits weighing between 2.5 and 3.0 kg were anesthetized with pentobarbital sodium (30 mg/kg iv), intubated, and ventilated by a respirator (model 683, Harvard Apparatus) with NO-free room air. The animals underwent cannulation of the right common carotid artery, which was immediately used for heparinization (1,000 U/kg) and phlebotomy (100-150 ml of blood letting). Subsequently, the chest of the animal was opened, and heart and great vessels were exposed. After the main pulmonary artery was cannulated via the apex of the right ventricle and the left atrium via the left ventricle, the lungs with the heart and the trachea were quickly excised en bloc and placed in a humidified chamber kept at 37°C. The isolated lungs were then connected to the circuit, consisting of a roller pump (Master Flex, Cole-Parmer Instrument) and a reservoir, in which circulatory volume was ~200 ml. After the lungs were rinsed thoroughly with a buffer solution of Krebs-Henseleit buffer containing (in mM) 119.2 NaCl, 4.7 KCl, 1.2 KH2PO4, 1.2 MgSO4, 25 NaHCO3, 3.2 CaCl2, and 15 glucose, the perfusion system was closed (buffer-perfused lungs), or, after 150 ml of buffer solution were taken away, autologous blood was added into a reservoir, and hematocrit was adjusted to ~15% (blood-perfused lungs). Initially, the pump rate (flow rate) was adjusted to 100 ml/min for stabilization. The pH and PCO2 of the buffer were adjusted to 7.4 and 40 Torr, respectively, by ventilating the isolated lungs at 0.9 l/min (30 ml of tidal volume × 30 breaths/min) of minute ventilation (E) with the use
of a gas mixture of 20% O2-5% CO2-balance
N2 (normoxic gas).
Measurements of Physiological Parameters and Exhaled NO
Ppa and pulmonary venous pressure (Ppv) were measured with pressure transducers (AP-601G, Nihon Koden). Airway pressure (Paw) was also measured with a low-pressure transducer (TP-603T, Nihon Koden). An electromagnetic flowmeter (MFV-1100, Nihon Koden) was placed in line proximal to the pulmonary artery to measure perfusate flow rate. Exhaled NO was continuously measured by a chemiluminescence analyzer (NOA 270B, Sievers) from the outlet limb of the tracheal tube. Signals from these probes were continuously recorded via a data-acquisition system (MacLab, AD Instruments) for real-time recording and later analysis.A quantitative measurement of exhaled NO can be
obtained by measuring both exhaled NO and E
![<A><AC>V</AC><AC>˙</AC></A><SC>no</SC> (nl<IT>/</IT>min)<IT>=</IT>[NO]<IT>×</IT><A><AC>V</AC><AC>˙</AC></A><SC>e</SC>](/content/vol91/issue1/fulltext/363/img001.gif)
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E is expressed in
liters per minute.
Measurements of NOx in the Perfusate
The method for the measurement of NOx [nitrite (NO
11-109 mol).
Experimental Protocols
Protocol 1. Isolated blood-perfused lungs (n = 5) were used to measure levels of exhaled NO at various flow rates. In this protocol, the circuit was closed under normoxic conditions, and the flow rate of perfusate was increased at 25, 50, 75, 100, and 150 ml/min at 4-min intervals.
Protocol 2. Isolated buffer-perfused lungs (n = 6) were used to examine the effect of ACh on Ppa, exhaled NO, and perfusate NOx. To avoid the effect of recirculation of ACh, the lungs were perfused by using an open circuit. During the 20- to 30-min stabilization period, the isolated lungs were perfused with 10 mM of indomethacin to prevent production of prostaglandins. After the stabilization period, the protocol started with perfusion of U-46619 for 15 min, a thromboxane analog (Sigma Chemical) for preconstriction of pulmonary vessels, followed by an opening of the circuit to negate the effect of reperfused ACh. We administered 0.2 ml of 1 µM ACh into the pulmonary artery as a bolus, while the exhaled NO and Ppa were continuously measured, and aliquots of the postlung perfusate were sampled at 5-s intervals to measure perfusate NOx concentrations.
Protocol 3.
Another group of isolated, buffer-perfused lungs (n = 15) was used to measure levels of exhaled NO and perfusate NOx at
various flow rates. In this protocol, the circuit was closed under
normoxic conditions, and the flow rate of the perfusate was adjusted to 25, 50, 75, 100, and 150 ml/min at 4-min intervals (normoxia group). In
8 of the 15 lungs, after measurements in normoxia, the ventilating gas
was switched to 3% O2-5% CO2-balance
N2 (hypoxic gas), and the same procedure of varying flow
rate was repeated (hypoxia group). In the remaining seven lungs, after
measurement during normoxia, the same procedure was repeated 30 min
after the administration of L-NMMA, a competitive inhibitor
of NOS, into the reservoir. The final concentration of
L-NMMA in the perfusate was estimated to be 1 × 104 M (normoxia with L-NMMA group).
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is flow rate of perfusate.
Statistical Analysis
The effect of ACh on exhaled NO and perfusate NOx in protocol 2 was analyzed by an ANOVA with repeated measurements. The difference between data obtained in protocols 1 and 3 was also analyzed by use of an ANOVA. When significance was indicated, a post hoc t-test with Bonferroni's correction for multiple comparisons was used. In all cases, a P value < 0.05 was considered statistically significant. All data presented represent means ± SE.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of Changing Flow on Exhaled NO in Blood-perfused Lungs
Figure 1 represents the effect of changing perfusate flow on exhaled NO in a blood-perfused lung. Exhaled NO was unaltered by stepwise increments of perfusate flow. The mean values of exhaledNO at various flow rates were
28 ± 5 nl/min at 25 ml/min, 27 ± 6 nl/min at 50 ml/min,
26 ± 5 nl/min at 75 ml/min, 25 ± 5 nl/min at 100 ml/min,
and 26 ± 6 nl/min at 150 ml/min. There were no statistically
significant differences in the mean values of exhaled NO among various
flow rates.
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Effects of ACh on Exhaled NO and Perfusate NOx
Administration of ACh into the pulmonary artery increased exhaled NO, whereas it decreased Ppa. Paw was not affected by ACh (Fig. 2). The mean exhaled NO significantly rose from 67 ± 3 ppb of control value up to 83 ± 7 ppb in 10 s (P < 0.01), followed by a gradual decrease toward the control level in the next 40 s (Fig. 3). Unlike the exhaled NO, which diffused rapidly to the airway, the NOx of the perfusate remained unchanged after ACh (Fig. 3). The mean Ppa was significantly decreased from 20 ± 2 to 16 ± 2 mmHg after ACh injection (P < 0.01).
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Effects of Changing Flow on Exhaled NO and Perfusate NOx
Figure 4 illustrates that stepwise elevations of perfusate flow caused corresponding increments of both exhaled NO and Ppa during normoxia. Subsequently, an abrupt reduction in flow elicited a rapid decrease in exhaled NO (Fig. 4A). Although hypoxia reduced the baseline level of exhaled NO and increased that of Ppa, a flow-dependent increase in exhaled NO was still observed (Fig. 4B). The administration of L-NMMA into the reservoir caused a rapid fall in exhaled NO and a moderate rise in Ppa (Fig. 5A). After a stabilization period of ~20 min, the stepwise elevations in flow rate did not change exhaled NO but did cause corresponding elevations in Ppa (Fig. 5B).
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Figure 6 summarizes the relationship
between NO and flow rate during normoxia and hypoxia
and after L-NMMA treatment during normoxia. Stepwise
elevations in flow (25, 50, 75, 100, and 150 ml/min) caused
corresponding elevations in exhaled NO (46 ± 2, 59 ± 2, 66 ± 3, 68 ± 4, and 73 ± 3 nl/min,
respectively) during normoxia. The NO rose
curvilinearly along with the increase in the perfusate flow during
normoxia and hypoxia. However, the administration of L-NMMA
elicited a marked drop in NO and abolished the
flow-dependent increase in NO. In contrast to the
exhaled NO responses, no relationship was detected between the
perfusate NOx accumulation and flow rate under each experimental
condition (Table 1). The level of
perfusate NOx accumulation tended to decrease during hypoxia compared
with normoxia (hypoxia: 6.3-7.1 nmol/min; normoxia: 8.3-9.2
nmol/min; not significant), whereas the administration of
L-NMMA significantly decreased the perfusate NOx
accumulation at all flow rates compared with control values (Table 1).
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Effects of Hypoxia and L-NMMA on the Pulmonary Hemodynamics
Figure 7 illustrates pressure-flow relationships (Fig. 7A) and pulmonary vascular conductance-flow curves (Fig. 7B) for the three conditions. In normoxia, there was a linear relationship between Ppa and flow over the range of flows investigated. Hypoxia caused a parallel upward shift in the pressure-flow relationship, and L-NMMA increased the slope of this relation. Pulmonary conductance spontaneously increased progressively along with flow in both normoxia and hypoxia. However, there were no statistically significant differences in conductance after L-NMMA treatment during normoxia among the various flow rates (50, 75, 100, and 150 ml/min). Thus L-NMMA abolished the flow-mediated increase in conductance over the range of 50-150 ml/min.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Difference in NO Diffusion Between Buffer- and Blood-perfused Lungs
The major source of lung NO is considered to be the airway epithelium and the pulmonary endothelium, because NOS immunoactivity is localized in both tissues (1, 15). During blood perfusion, NO produced from the vascular endothelium would be bound by hemoglobin and, therefore, not able to diffuse through the alveoli because of the high affinity of hemoglobin for NO (5). Furthermore, NO produced from the airway epithelium is continuously cleared into the pulmonary blood via the alveoli during the inspiratory period, whereas the NO remaining in the airway is expired into the exhaled gas (13). In the present study, we found that the baseline level of exhaled NO in buffer-perfused lungs was several times higher than that in blood-perfused lungs, and the flow-mediated changes in exhaled NO observed in buffer-perfused lungs were totally eliminated during blood perfusion. These differences between the two conditions are due to the presence of hemoglobin in the pulmonary circulation. Our basic experimental findings using blood-perfused lungs support previous findings that, in humans, changes in pulmonary blood flow with head-out water immersion or increased gravity failed to alter the output of NO exhaled from the lungs at rest or during exercise (21). We conclude that exhaled NO does not reflect NO produced from the pulmonary endothelium under physiological conditions of blood perfusion.During buffer perfusion, because NO is a lipid-soluble and highly diffusible gas (27), NO produced from the endothelium would either be dissolved into the perfusate to become NOx, or simply diffuse out through the alveoli and appear in the exhaled gas. By measuring these fractions, the kinetics of NO from the endothelium, on stimulation with ACh or changing flow, can be estimated. Therefore, for estimating diffusion kinetics of NO, the lung model with buffer perfusion is of critical importance for determining the role of NO in the regulation of the pulmonary circulation.
Effect of ACh on NO
NO to result in vasodilation, whereas it
constricts vascular smooth muscle by stimulating muscarinic receptors
(4). Furthermore, it stimulates the release of
vasoconstrictor prostanoids in rabbit lungs (2). To
eliminate the effects of prostanoids in our experiment, we pretreated
the perfusate with indomethacin, an inhibitor of cyclooxygenase. A
bolus injection of ACh elicited a decrease in Ppa and a transient
increase in exhaled NO concentration, whereas perfusate NOx did not
change (Figs. 2 and 3). These results indicate that NO produced from
the precapillary arterial endothelium evoked pulmonary vasodilation and
then quickly diffused out through the alveoli. This diffusion response
of NO is possibly pronounced because NO is a lipid-soluble gas and has
a very low buffer-gas partition coefficient (27). This
behavior of NO is consistent with observations of a previous study that
showed that NO aerated in the prelung perfusate completely escaped into
the exhaled air within a single lung passage, whereas only trace
amounts of NO were recovered in the postlung perfusate
(25). Thus a pharmacological stimulus such as ACh can
release NO from the endothelium and potentially evoke pulmonary
vasodilation. The buffer-perfused lung model reveals the production of
endothelial NO as changes in exhaled NO by eliminating the normal in
vivo masking effects of hemoglobin.
Effect of Recirculation on Lung NO
Before discussion of the present results, the potential effects of recirculation on the measurement of perfusate NOx and exhaled NO in buffer-perfused lungs should be addressed. As mentioned previously, a fraction of NO produced from the endothelium is dissolved into the well-oxygenated perfusate, after which it is rapidly oxidized to form NOSource of Flow-mediated Release of NO
We found that stepwise elevations in flow increased exhaled NO, whereas the perfusate NOx accumulation remained constant (Fig. 6 and Table 1). To determine the origin of flow-mediated increments of exhaled NO, we examined the effects of hypoxia, which induces pulmonary vasoconstriction with a decrease inNO from the
airway epithelium (11), and a NOS antagonist
(L-NMMA), which inhibits NO produced from both the airway
epithelium and the vascular endothelium. First, during
hypoxia, we observed decreases in exhaled NO with increases in Ppa
compared with normoxia. Despite a reduction in the baseline level of
exhaled NO during hypoxia, we found that the flow-mediated increase in
exhaled NO persisted (Fig. 6), along with the concomitant stepwise
increase in pulmonary conductance (Fig. 7). These findings render it
very unlikely that NO derived from the airway epithelium is responsible
for the flow-mediated increments of exhaled NO and the flow-mediated
increases in pulmonary vascular conductance. Second, we found that
L-NMMA greatly diminished the basal production of both
exhaled NO (Fig. 6) and perfusate NOx accumulation (Table 1) and
abolished the flow-mediated increase in pulmonary conductance (Fig. 7).
These results suggest that the flow-mediated increase in exhaled NO
originates from the vascular endothelium and that this
endothelial-derived NO contributes in a major way to the adaptability
of the pulmonary circulation to increases in flow. In addition, the
source of flow-mediated exhaled NO appears to be the precapillary
arterial segment, as opposed to the postcapillary venous segment,
because anatomic considerations indicate that only NO produced from the
arterial endothelium could contribute to exhaled NO. In support of this
view, it has been demonstrated that the major loci of pulmonary
vascular resistance are the arterial and precapillary segments and that
endothelial NO release from these segments contributes to low
resistance of pulmonary circulation (3).
On the other hand, perfusate NOx accumulation in the steady state has
been attributed mainly to the NO produced from the endothelium of both
pulmonary arteries and veins (11, 25). However, if perfusate flow is altered, subsequent changes in perfusate NOx accumulation would likely reflect venous NO, because
most of NO from precapillary endothelium will diffuse out through
alveoli as described above.
Role of NO in Flow-mediated Increase in Conductance
In canine femoral arteries, it has been demonstrated that vessel wall shear stress is involved in flow-mediated vasodilation (24). NO is considered to be a major mediator of shear stress-induced vasodilation in the systemic resistance vessels (6). In contrast to the systemic circulation, the pulmonary artery rapidly subdivides into terminal branches that have thinner walls, less smooth muscle, and greater internal diameters than corresponding branches of the systemic arterial tree. These structural properties of the pulmonary vessels offer much less resistance to blood flow than do the systemic arterial vessels. In addition, the pulmonary vascular bed has a regulating system that allows vascular resistance to decrease in response to increased blood flow and/or increases in perfusion pressure (16). However, the role of NO in the mechanism underlying regulation of the pulmonary circulation in response to increasing flow has not been fully understood. Hakim (8) demonstrated that the reduction in precapillary resistance as flow increased was attenuated after N G-nitro-L-arginine under the condition of pulsatile flow and hypoxia, suggesting that shear stress-induced NO release is present in the pulmonary vascular bed in isolated canine lungs. On the other hand, Cremona et al. (3) reported that NG-nitro-L-arginine did not change the flow-mediated reduction in resistance in pig, suggesting that NO release is not fundamental to the mechanism underlying the flow-mediated decreases in pulmonary vascular resistance. Although we have to consider the differences among animal species in basal release of NO in the lung, to our knowledge, the present study is the first to demonstrate flow-mediated increases in NO release in the pulmonary vascular bed.Two mechanisms have been postulated to account for the decrease in pulmonary vascular resistance in response to elevated blood flow and perfusion pressure: recruitment and dilation. The term recruitment means that the previously unperfused capillaries are recruited (opened) by the increased flow or perfusion pressure, and the term dilation means that the increased perfusion pressure has dilated those vessels already open (16). To discuss the role of NO in these flow-mediated hemodynamic changes, the changes in pulmonary vascular conductance (reciprocal of resistance) are illustrated in Fig. 7B. Here, conductance progressively increases along with flow during both normoxia and hypoxia. In our experimental setting, the mean Paw was ~6 cmH2O, and Ppv ranged from 1 to 2 mmHg (1.3-2.6 cmH2O). Under these conditions, it is likely that the perfusion of the isolated lung tends to exhibit the zone II condition in a large part of the lung (9). Thus, under normoxic and hypoxic conditions, increases in conductance in response to elevated flow indicate that the capillary recruitment and/or dilation are occurring along with the increases in flow or perfusion pressure.
In the present study, as clearly demonstrated in Fig. 7, the
administration of L-NMMA abolished the rise in conductance
over the range of 50-150 ml/min of flow with a reduction in the
lung NO. With regard to the contribution of NO to
this response, we suggest that endothelial NO may be associated with
the capillary recruitment and/or shear stress-induced vasodilation.
When new parallel pathways for perfusate flow are recruited by the
increased flow, NO will be released from the endothelium of the new
vessels and contribute to maintaining these vessels open. Similarly,
when the increased flow and perfusion pressure distend vessels that are
already open, further NO will be released from the endothelium by
vascular wall shear stress. Although, from our results, whether either
recruitment or shear stress contributes more to flow-mediated increases
in exhaled NO is unclear; it has been speculated that recruitment
probably occurs with small rises in Ppa, whereas dilation occurs at
higher pressures (16). In the present study, the range of
flow rates that we examined was 25-150 ml/min, and the
corresponding Ppa range was 4-10 mmHg during normoxia, owing to
the buffer-perfused condition (Fig. 7). Therefore, these relatively low
and narrow ranges of pressure may be more likely associated with
vascular recruitment contributing to the flow-mediated increases in
exhaled NO rather than shear stress.
On the other hand, we hypothesized that the increased flow would elevate perfusate NOx accumulation because capillary recruitment and/or dilation induced by changing flow should increase the venous surface area and shear stress, leading to a release of venous endothelial NO. However, in the range of flow rates examined, we did not observe any changes in perfusate NOx accumulation. Pulmonary veins are distensible because of the thin fibrous wall structure, and they function as a capacitance for the pulmonary circulation (14). Furthermore, the Ppv is much lower than the arterial pressure. Therefore, in the range of flow rates that we tested, the perfusate might not fully distribute into the widespread capillaries, or the venous pressure might not alter vascular shear stress enough to provoke release of endothelial NO. If flow rates increase severalfold, such as during exercise, perfusate NOx accumulation could conceivably increase. To more precisely define the role of NO in the regulation of the pulmonary circulation in responses to changing flow and pressure, further studies are required.
In summary, we found that the flow-mediated changes in exhaled NO observed in buffer-perfused lungs were totally eliminated in blood-perfused lungs, suggesting that exhaled NO does not reflect NO released from the pulmonary endothelium under physiological conditions of blood perfusion. In the buffer-perfused condition, we were able to detect NO release from the endothelium in response to both ACh as a pharmacological stimulus and changing flow as a physiological stimulus. In the present study, the flow-mediated increments of pulmonary conductance, a regulating system of pulmonary circulation in response to increasing flow, were observed with the flow-dependent elevations in exhaled NO under normoxic and hypoxic conditions. L-NMMA abolished this flow-mediated increase in conductance with a reduction in the lung NO, indicating that the endothelial NO may be associated with the capillary recruitment and/or shear stress-induced vasodilation. To more precisely elucidate the role of NO in the flow-mediated increase in conductance, further study will be necessary.
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ACKNOWLEDGEMENTS |
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This study was supported by Grants 07670077 and 08670643 from Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. Nakano, Dept. of Internal Medicine, Asahikawa Medical College, 1-1, Higashi 2-1, Midorigaoka, Asahikawa 078-8510, Japan (E-mail kin{at}asahikawa-med.ac.jp).
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.
Received 26 October 2000; accepted in final form 21 February 2001.
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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