Departments of Pediatrics and Neurology, Medical College of Wisconsin and Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin 53226
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ABSTRACT |
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We
previously found that alkalosis-induced vasodilation was mediated by
endothelium-derived nitric oxide (EDNO) in newborn piglet pulmonary
artery and vein rings precontracted with the thromboxane mimetic
U-46619. In contrast, prostacyclin or K+ channel activation
contributed to the response in other preparations. This study was
undertaken to determine whether EDNO alone also mediates
alkalosis-induced pulmonary vasodilation in piglet lungs vasoconstricted with hypoxia and, if not, to identify the mediator(s) involved. Responses to alkalosis were measured during hypoxia under
control conditions after blocking nitric oxide synthase (N-nitro-L-arginine),
cyclooxygenase (meclofenamate), or both endothelium-derived modulators (Dual); after blocking voltage-dependent (4-aminopyridine), ATP- dependent (glibenclamide), or Ca2+-dependent
K+ (KCa; tetraethylammonium) K+
channels; and after blocking both endothelium-derived modulators and
KCa channels (Triple). Vasodilator responses measured after 20 min of alkalosis were blunted in Dual and tetraethylammonium lungs
and abolished in Triple lungs. Thus alkalosis-induced vasodilation in
hypoxic lungs appeared to be mediated by three
Ca2+-dependent modulators: EDNO, prostacyclin, and
KCa channels. In addition, a transient, unidentified
modulator contributed to the nadir of the vasodilator response measured
at 10 min of alkalosis. Future studies are needed to identify factors
that contribute to the discordance between isolated vessels and whole lungs.
isolated lungs; hypoxia; nitric oxide; prostacyclin; potassium channels
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INTRODUCTION |
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IT HAS LONG BEEN ESTABLISHED that alkalosis causes acute pulmonary vasodilation in animal models (8, 10, 13, 16, 18, 22, 27, 35, 41, 42) and children (5, 28, 30) with increased pulmonary vascular tone. However, the mechanism of this response remains unknown. The Ca2+-dependent, endothelium-derived modulators nitric oxide (EDNO) and prostacyclin (PGI2) appeared to mediate alkalosis-induced pulmonary vasodilation in some studies (13, 16, 18, 27, 41) but not in others (8, 10, 42). Vascular smooth muscle K+ channel activation leading to hyperpolarization may also contribute to the response (2, 39). In addition, it has been postulated that increased Ca2+ binding to albumin during alkalosis (26) may reduce extracellular Ca2+ sufficiently to impair vascular smooth muscle contractility, thus leading to vasodilation (35). Although the discordance among these studies may reflect interspecies (4) or maturational (1, 6, 14) differences in modulators of pulmonary vasomotor tone, preparation differences in vascular responses (23, 37) may also play a role.
Previous work in our laboratory showed that alkalosis-induced relaxation of 500-µm-diameter newborn piglet pulmonary artery (13) and vein (16) rings precontracted with the thromboxane mimetic U-46619 was mediated by EDNO alone and not by PGI2 or K+ channel activation. However, the reported heterogeneity of endothelial (11, 38) and smooth muscle (3, 12) modulator activity along the pulmonary vascular tree and other preparation differences led us to hypothesize that the mediator(s) of alkalosis-induced pulmonary vasodilation may differ between isolated vessels and whole lungs. The current study sought to determine whether EDNO alone also mediates alkalosis-induced pulmonary vasodilation in newborn piglet lungs with hypoxia-induced pulmonary vasoconstriction and, if not, to identify the mediator(s) involved.
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METHODS |
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This study conforms with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health [DHHS Publication No. (NIH) 85-23, revised 1985] and was approved by the Institutional Animal Care and Use Committees of the Medical College of Wisconsin and the Zablocki Veterans Affairs Medical Center (Milwaukee, WI). Isolated lungs from 1- to 2-wk-old piglets (n = 50) were prepared as previously described for lambs (14, 27). Briefly, piglets were anesthetized with ketamine (40 mg/kg im), acepromazine (1.5 mg/kg im), and pentobarbital sodium (25 mg/kg ip). A tracheostomy tube was inserted, and the internal carotid artery was catheterized. Heparin (5,000 U iv) was administered, and the piglets were exsanguinated. A midline sternotomy was performed, the ductus arteriosus was ligated, and cannulas were placed in the pulmonary artery and left atrium. The lungs were removed and attached to a recirculating perfusion system and ventilator.
Lungs were perfused with a mixture of autologous blood and 3% dextran
(Sigma, St. Louis, MO) in Ringer lactate (hematocrit 12%).
Perfusate exited the lungs from the left atrium to a reservoir and was
pumped (Masterflex model 7523-20, Cole Parmer, Vernon Hills, IL) at a
constant flow of 100 ml · kg
1 · min
1 through a
heat exchanger (Sci Med Pediatric, Sci Med Life Systems, Minneapolis,
MN) to the pulmonary artery. Pulmonary arterial pressure (Ppa), airway
pressure (Paw), and left atrial pressure (Pla) were constantly measured
(model P23XL, Ohmeda Medical Devices, Madison, WI) and recorded on a
polygraph (model 7, Grass Instruments, Quincy, MA). Because the flow
was constant, any change in Ppa reflected a change in pulmonary
vascular resistance (PVR).
The lungs were ventilated (model 613, Harvard Apparatus, South Natick,
MA) with a normoxic, normocapnic gas mixture (94% air-6% CO2) at a rate of 15 breaths/min and a tidal volume of
15 ml/kg body wt (initial Paw of 8-11 mmHg). End-expiratory
pressure was set at 3 mmHg. The ventilator settings were maintained
constant throughout each experiment to obviate any effects of changes
in Paw or volume on PVR. The desired perfusate
PO2, PCO2, and pH were
achieved by altering inspired gases (air, CO2, and
N2).
Experimental protocol: mediators of alkalosis-induced
vasodilation.
Lungs were assigned to a single treatment group (Table
1) to obviate the potentially confounding
effects of repeated alkalotic challenges (27). After 30 min of normoxic, normocapnic ventilation, inhibitors were added to the
perfusate (Table 1). Lungs were then allowed to stabilize for a further
30 min under the same normoxic, normocapnic conditions. After 60 min of
perfusion, the stable baseline normoxic, normocapnic Ppa was measured
(henceforth termed "normoxic Ppa"). The inspired O2 was
then reduced to 5-6% to induce hypoxic pulmonary
vasoconstriction, and the stable hypoxic, normocapnic Ppa was measured
after 20 min (henceforth termed "hypoxic Ppa"). The inspired
CO2 was then lowered from 6 to 3% to induce hypocapnic
alkalosis (target PCO2 = 23-27 Torr,
pH 7.55-7.60) for 20 min in all groups except the time control
lungs, which were maintained normocapnic. Ppa was reported at the nadir
of the response, which occurred after ~10 min of alkalosis (termed "alk-nadir") and after 20 min of alkalosis (termed "alk-20
min").
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Experimental protocol: role of extracellular Ca2+.
To determine whether the reported decrease in Ca2+
concentration during alkalosis (26) contributes to
alkalosis-induced pulmonary vasodilation as previously suggested
(35), responses to alkalosis were also measured in lungs
(n = 5) after the Ca2+ concentration was
increased. Briefly, lungs were prepared as described in
Experimental protocol: mediators of alkalosis-induced vasodilation, but after 30 min of perfusion, Ca2+ was
added to the perfusate to achieve a target Ca2+
concentration of 2.5 mM rather than the
1.0 mM seen in control (Con) lungs. Normoxic, hypoxic, alk-nadir, and alk-20 min Ppa values
were then measured as described in Experimental protocol: mediators of alkalosis-induced vasodilation. Blood was collected in lithium-heparin tubes, and Ca2+ concentrations were also
measured (model 865, CIBA-Corning) during normoxia and alk-20 min.
Drugs and solutions.
Acetylcholine, bradykinin, tetraethylammonium (TEA), calcium chloride
(all from Sigma), and meclofenamate (Mec; BIOMOL Research Laboratories,
Plymouth Meeting, PA) were dissolved in normal saline to achieve the
desired concentration. Glibenclamide (Glib) was dissolved in dimethyl
sulfoxide. N-nitro-L-arginine
(L-NNA; Sigma) was dissolved in saline to which a few drops
of 12 N HCl were added. 4-Aminopyridine (4-AP; Sigma) was dissolved in
saline, and HCl was added to titrate the pH to 7.40. All drug
concentrations are expressed as final molar concentrations in the
reservoir unless otherwise indicated. The total volume of all drugs was
<3 ml, which was insignificant compared with the volume of perfusate
(275-350 ml) or the circulating blood volume of intact piglets.
Baseline normoxic, normocapnic pH was measured after the addition of
the study drugs in all groups.
Statistical analysis.
All comparisons of data within and between groups were made by one- or
two-way repeated- measures ANOVA with SigmaStat version 2.03 statistical software (SPSS, Chicago, IL). When significance was
achieved at P < 0.05, post hoc testing was performed
with Fisher's least significant difference test to identify between- and within-group differences. Data are expressed as means ± SE. Because baseline Ppa differed under the different inhibitor conditions, both absolute Ppa and the percent decrease in the hypoxic response during alkalosis (calculated as hypoxic Ppa Ppa alk/hypoxic Ppa
normoxic Ppa) are shown.
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RESULTS |
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There were no differences among treatment groups in
terms of hematocrit (mean 11.8 ± 0.3%), age (mean 8.4 ± 0.3 days), weight (mean 3.0 ± 0.1 kg), or blood gas results under
the different study conditions (Table 2).
There was a small but significant increase in peak Paw over time in the
4-AP-inhibited (2.3 ± 0.8 mmHg), NOS- and
cyclooxygenase-inhibited (Dual; 2.5 ± 0.9 mmHg), and NOS-,
cyclooxygenase-, and KCa channel-inhibited (Triple; 2.8 ± 0.6 mmHg) groups but not in other groups. The ratio
of wet-to-dry lung weight (mean 6.3 ± 0.1) did not differ among
groups.
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Hypoxia caused a significant increase in Ppa in Con (Fig.
1A) and time control
(Fig. 1B) lungs. Hypocapnic alkalosis caused a significant
decrease in hypoxic Ppa in Con lungs (Fig. 1A), but there
was no change in Ppa during sustained normocapnic hypoxia in the time
control lungs (Fig. 1B). The alk-nadir occurred in Con lungs
after about 10 min of alkalosis. At alk-20 min, the Ppa remained
significantly decreased compared with normocapnic hypoxic lungs but was
significantly greater than that in alk-nadir lungs. The hypoxic
responses decreased by 94.1 ± 7.1% at alk-nadir and 71.4 ± 10.5% at alk-20 min. A pattern of maximal alkalosis-induced vasodilation at 10 min of alkalosis followed by an increase in Ppa was
seen in all treatment groups (see Figs. 1-5).
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Normoxic and hypoxic Ppa values were greater in lungs treated with 1 mM
L-NNA compared with Ppa in Con lungs (Fig.
2A), and bradykinin-induced vasodilation decreased from 80.7 ± 12% in Con to 30.5 ± 2.4% in L-NNA lungs, indicating effective
NOS inhibition (data not shown). However, there was no difference in
alkalosis-induced vasodilation between Con and L-NNA lungs
during either alk-nadir or alk-20 min (Fig. 2). Mec (104
M) significantly decreased normoxic and hypoxic Ppa compared with that
in Con lungs. However, treatment with this cyclooxygenase inhibitor
alone also had no effect on the vasodilator response to alkalosis (Fig.
2). In contrast, the Dual group showed increased normoxic and hypoxic
Ppa and significantly blunted pulmonary vasodilation during alk-nadir
and alk-20 min (Fig. 2).
KV channel inhibition with 3 mM 4-AP increased normoxic Ppa
compared with that in Con lungs but did not change hypoxic Ppa or the
vasodilator response to alkalosis (Fig.
3). KATP channel inhibition
with 105 M Glib reduced hypoxic Ppa compared with that in
Con lungs but again did not alter the response to alkalosis (Fig. 3).
In contrast, 3 mM TEA increased hypoxic Ppa and blunted
alkalosis-induced pulmonary vasodilation during alk-nadir and alk-20
min (Fig. 3), suggesting that KCa channels contribute to
alkalosis-induced vasodilation. Although alkalosis-induced pulmonary
vasodilation was blunted to a similar extent in TEA (Fig. 3) and Dual
(Fig. 2) lungs, these inhibitors appeared to act through independent
pathways because the dilator response at alk-20 min was completely
abolished by the combination of NOS, cyclooxygenase, and
KCa channel inhibition in the Triple group (Fig.
4). However, even in the Triple group, significant vasodilation occurred at alk-nadir (Fig. 4).
High blood Ca2+ concentration in isolated lungs. Ionized Ca2+ concentrations measured in three Con lungs (Calcium) during normocapnic hypoxia ranged from 1.02 to 1.10 mM. Ionized Ca2+ concentration in the Calcium lungs was 2.44 ± 0.14 mM during normocapnic hypoxia and 2.33 ± 0.12 mM during hypocapnic hypoxia. Although ionized Ca2+ concentrations were significantly higher in Calcium compared with Con lungs, Ppa measured during normoxia, hypoxia, alk-nadir, and alk-20 min did not differ between groups (Fig. 5A). Thus similar alkalosis-induced vasodilation occurred despite twice normal perfusate ionized Ca2+ concentrations in Calcium lungs (Fig. 5).
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DISCUSSION |
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The major finding in this study of hypoxic newborn piglet lungs was that the vasodilator response measured at alk-20 min appeared to be mediated by EDNO, PGI2, and KCa channel activation. In addition, an apparently transient, unidentified modulator contributed to the nadir of the vasodilator response seen at 10 min of alkalosis. These results contrast with previous studies from our laboratory of newborn piglet pulmonary artery (13) and vein (16) rings preconstricted with U-46619 in which the response to alkalosis was mediated by EDNO alone. Collectively, our data from a single species studied at a single age support the hypothesis that the mechanisms or mediators of alkalosis-induced vasodilation differ significantly between isolated vessels and whole lungs and suggest that preparation differences may contribute to the apparent discordance in previous studies that examined how alkalosis acts on the pulmonary vasculature.
Previous studies have shown that alkalosis enhanced PGI2 (18, 34, 41) and EDNO (25) synthesis, likely by increasing endothelial cytosolic Ca2+ concentration (40) and/or directly promoting NOS activity (9). Our observation that alkalosis-induced pulmonary vasodilation was blunted after inhibition of both cyclooxygenase and NOS but not after inhibition of either modulator individually (Fig. 2) suggests that alkalosis stimulated synthesis of both PGI2 and EDNO in piglet lungs. Moreover, the alkalosis-induced increase in the synthesis of either modulator appeared sufficient to attenuate the hypoxic response even when the other modulator was inhibited. This may explain why NOS inhibition alone failed to block alkalosis-induced pulmonary vasodilation in rat (10) and rabbit (42) lungs. On the other hand, cyclooxygenase inhibition alone did block alkalosis-induced pulmonary vasodilation in newborn lamb (27) and adult rat (41) lungs, suggesting that the endothelium-derived modulator(s) that mediates alkalosis-induced pulmonary vasodilation may differ between species or during development as suggested by other studies describing interspecies (4) or maturational (1, 14) differences in the dominant endothelium-derived modulator of vasomotor tone.
Although dual inhibition of NOS and cyclooxygenase blunted alkalosis-induced pulmonary vasodilation in hypoxic piglet lungs (Fig. 2), it did not abolish the response. This observation and a study of intact lambs in which combined NOS and cyclooxygenase inhibition also failed to block alkalosis-induced pulmonary vasodilation (8) suggest that other modulators contribute to the response. In the current study, we found that 3 mM TEA also blunted alkalosis-induced pulmonary vasodilation (Fig. 3). Although 3 mM TEA is thought to act predominantly on KCa channels, it may have nonspecific effects on other K+ channels. However, neither 4-AP nor Glib altered the response to alkalosis, suggesting that KCa channels but not KV or KATP channels mediated alkalosis-induced pulmonary vasodilation in piglet lungs. This differs from studies of pulmonary artery smooth muscle cells or vessels from mature rats (2, 39) in which KV channels were activated by alkalosis and may reflect interspecies differences or the recently reported maturational shift from KCa to KV channel dominance (6).
Because KCa channels may be activated by PGI2 or EDNO (36, 43), the possibility that alkalosis acted indirectly on KCa channels through one of the endothelium-derived modulators must be considered. However, this did not appear to be the mechanism involved in the current study because the combination of NOS, cyclooxygenase, and KCa channel inhibition in the Triple group (Fig. 4) blunted the vasodilator response after alk-20 min more than did either the Dual group (Fig. 2) or TEA (Fig. 3) alone. Studies showing that alkalosis increases pulmonary vascular smooth muscle cytosolic Ca2+ (7) lead us to speculate that the response to alkalosis was mediated by direct KCa channel activation that led to hyperpolarization and relaxation (29).
In previous studies from our laboratory of isolated piglet vessels preconstricted with U-46619 (13, 16), the response to alkalosis developed over 10 min and was stable for at least 20 min. In addition, our laboratory previously reported (27) that alkalosis-induced pulmonary vasodilation was stable for at least 100 min in hypoxic lamb lungs. In contrast, the current study of hypoxic piglet lungs found that the vasodilator response to alkalosis reached a nadir at 10 min, after which PVR began to increase. This early transient vasodilator response occurred in all groups (Figs. 1-5), including the Triple group, suggesting that it was not mediated by either PGI2, EDNO, or KCa channels. In addition, it occurred in the Calcium group, suggesting that it was unrelated to a decrease in extracellular Ca2+ concentration during alkalosis (26). Future studies are needed to determine whether this nadir occurs in other species and preparations and, if so, to identify the transient mediator involved.
Several factors may contribute to the discordant mediators of alkalosis-induced vasodilation between isolated vessels and lungs. In the current study, lungs were perfused with blood and vasoconstricted with hypoxia (Figs. 1-5), but in previous work by Gordon et al. (13) and Halla et al. (16), vessels were bathed in physiological salt solution and constricted with U-46619. However, neither pressor stimulus nor type of perfusate appears to contribute to the discordance because we have recently found that NOS inhibition blocked alkalosis-induced vasodilation in isolated arteries perfused with blood and failed to block alkalosis-induced vasodilation in lungs perfused with physiological salt solution or lungs preconstricted with U-46619 (15, 17). Further studies are required to determine whether the reported heterogeneity in endothelial (11, 12, 38) or smooth muscle (3) modulator activity along the vascular tree contributes to differences in alkalosis-induced EDNO, PGI2, and/or K+ channel activity between 500-µm-diameter isolated vessels and whole lungs. In addition, the potential contribution of flow, parenchyma, airways, other perivascular tissue, or intervessel communication to the discordance between preparations must be examined.
Discordant responses between isolated vessels and whole lungs are not limited to the mechanisms or mediators of alkalosis-induced pulmonary vasodilation. Responses to other vasoactive stimuli also appear to differ. For example, increased flow and pressure caused vasodilation in intact lungs but caused vasoconstriction in cannulated pulmonary arteries (23, 37). Moreover, hypoxia caused a rapid and sustained increase in PVR in whole lungs (14; Fig. 1B) but a biphasic, transient, or slowly developing response in isolated vessels (21, 24). Development of an isolated vessel preparation that mimics responses of in situ vessels within the whole lung may facilitate elucidation of the mechanisms underlying in vivo responses to alkalosis and other physiologically important stimuli.
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ACKNOWLEDGEMENTS |
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This study was supported by the Children's Hospital of Wisconsin Foundation and the Department of Pediatrics of the Medical College of Wisconsin.
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FOOTNOTES |
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M. A. Vander Heyden was supported by the Elaine Kohler Fund for Healing and the Steigleider Fund.
Address for reprint requests and other correspondence: J. B. Gordon, Children's Hospital of Wisconsin, Critical Care Section, MS 681, PO Box 1997, Milwaukee, WI 53201 (E-mail: jgordon{at}mcw.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.
Received 17 August 2000; accepted in final form 4 October 2000.
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