Mediators of alkalosis-induced relaxation of piglet pulmonary
veins
Ted R.
Halla,
Jane A.
Madden, and
John B.
Gordon
Departments of Pediatrics and Neurology, Medical College of
Wisconsin and Zablocki Veterans Affairs Medical Center, Milwaukee,
Wisconsin 53226
 |
ABSTRACT |
Pulmonary venous
constriction leads to significant pulmonary hypertension and increased
edema formation in several models using newborns. Although alkalosis is
widely used in treating neonatal and pediatric pulmonary hypertension,
its effects on pulmonary venous tone have not previously been directly
measured. This study sought to determine whether alkalosis caused
pulmonary venous relaxation and, if so, to identify the mediator(s)
involved. Pulmonary venous rings (500-µm external diameter) were
isolated from 1-wk-old piglets and precontracted with the thromboxane
mimetic U-46619. Responses to hypocapnic alkalosis were then measured under control conditions after inhibition of endothelium-derived modulator activity or K+ channels. In control rings,
alkalosis caused a 34.4 ± 4.8% decrease in the U-46619-induced
contraction. This relaxation was significantly blunted in rings without
functional endothelium and in rings treated with nitric oxide synthase
or guanylate cyclase inhibitors. However, neither cyclooxygenase
inhibition nor voltage-dependent, calcium-dependent, or ATP-dependent
K+-channel inhibitors altered alkalosis-induced relaxation.
These data suggest that alkalosis caused significant dilation of piglet pulmonary veins that was mediated by the nitric oxide-cGMP pathway.
nitric oxide; guanosine 3',5'-cyclic monophosphate; isolated vessels; U-46619
 |
INTRODUCTION |
ALKALOSIS IS WIDELY USED in treating neonatal and
pediatric pulmonary hypertension (3, 26). This practice is based on clinical (8, 27) and laboratory (10, 12, 18, 19, 25, 30, 34, 35)
studies showing that both hypocapnic and metabolic alkalosis acutely
reduced pulmonary vasoconstriction due to hypoxia, thromboxane, and
other stimuli in newborns of several species. In isolated pulmonary
arteries, alkalosis caused relaxation (17), and in isolated lamb (18)
and rat lungs (14), vascular occlusion studies suggested that the
alkalosis-induced reduction in total pulmonary vascular resistance
(PVR) was due predominantly to arterial vasodilation. However,
responses to alkalosis have not previously been directly measured in
pulmonary veins. Because pulmonary venous constriction due to hypoxia
or thromboxane contributes significantly to pulmonary hypertension and
edema formation (6, 11, 29, 41), we sought to determine whether
alkalosis causes pulmonary venous dilation and, if so, to identify the
mediator(s) involved.
Although alkalosis-induced pulmonary vasodilation is well described,
the mechanism of the response remains unknown and the mediator(s)
uncertain (1, 12, 14, 17, 19, 25, 37, 39, 40). Gordon et al.
(17) previously found that alkalosis-induced relaxation of
500-µm-diameter piglet pulmonary artery rings was blocked by
inhibitors of the nitric oxide (NO)-cGMP pathway. In contrast,
alkalosis-induced pulmonary vasodilation in intact piglets (19) seemed
to be mediated by PGI2. This discordance between preparations could reflect heterogeneity in modulator synthesis and/or
activity between arteries and veins within the pulmonary vasculature
(15, 16, 36). Therefore, we hypothesized that, unlike pulmonary
arteries (17), alkalosis-induced relaxation of piglet pulmonary veins
is not mediated by the NO-cGMP pathway. To test this hypothesis and
identify the contribution of other putative mediators of the response,
the effects of alkalosis were measured in precontracted pulmonary
venous rings under control conditions and after inhibition of the
NO-cGMP pathway, dilator PG synthesis, or K+-channel activation.
 |
METHODS |
Preparation.
This study 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). As in the previous study by Gordon et al. (17) on pulmonary artery rings, 1-wk-old piglets
(n = 24) were anesthetized with ketamine (40 mg/kg im), acepromazine (1.5 mg/kg im), and pentobarbital sodium (25 mg/kg ip).
Heparin (5,000 U iv) was administered through a carotid
artery catheter and the piglets were killed by exsanguination.
The lungs were removed, immersed in cold modified Krebs solution (MKS), and refrigerated at 4°C. At the time of study,
500-µm-external-diameter veins were gently dissected out and cut into
2-mm-long rings. The veins were identified by 1) tracing them
back from extrapulmonary veins through four or five generations and
2) their relatively translucent walls and lesser
muscularization compared with similar-sized arteries (20, 23, 31).
Stainless steel hooks were inserted through the lumen of each venous
ring, and the lower hook was attached to the base of a 10-ml organ bath
(Harvard Apparatus, South Natick, MA) that was filled with MKS
maintained at 37.5°C and bubbled with 6% CO2-21%
O2-balance N2 to achieve a pH of
7.40. The
top hook was suspended from an isometric force transducer (model
52-9529, Harvard Apparatus) mounted on a micromanipulator (model 55020, Stoelting, Chicago, IL) with which vessel tension could be
adjusted as needed. Tension was constantly recorded on flatbed
recorders during the experiment (model L6514-4, Linseis, Princeton
Junction, NJ).
Protocol.
In preliminary KCl length-tension experiments (data not shown), we
found that the optimal resting tension of 500-µm-diameter piglet
pulmonary veins was 500 mg. Therefore, resting tension was set at 500 mg in all subsequent alkalosis experiments. Veins were allowed to
equilibrate at this resting tension for 60-90 min before any
interventions. Vascular smooth muscle integrity was then assessed by
measuring the responses to three successive challenges with 40 mM KCl.
The veins were washed with fresh MKS and allowed to stabilize at
resting tension for 20 min between each KCl challenge. After the final
wash, the veins were submaximally contracted with
10
8 M U-46619 (termed U-46619 challenge
1), a concentration found to induce 70% of maximal contraction in
preliminary experiments (data not shown). Veins that failed to exhibit
an increase in tension of at least 200 mg/mg vein wt in response to the
third KCl challenge or to U-46619 challenge 1 were excluded
from further study.
After a stable response to U-46619 challenge 1 (
20 min),
endothelial integrity was assessed by measuring the responses to 10
7 M ACh. If ACh caused >35% reduction in the
U-46619 challenge 1 response, endothelial function was
considered intact and the veins were assigned to either control (Con)
or one of the inhibitor-treated groups (Table
1). If ACh caused <15% reduction in the
U-46619 challenge 1 response, the veins were considered to have
nonfunctional endothelium and were assigned to the Endo
group.
After the ACh response was measured, all veins were washed with fresh
MKS and returned to resting tension. Inhibitors were added (Table 1), and baseline tension was measured after 30 min. Submaximal contraction was again induced with U-46619 (termed U-46619 challenge 2),
and the stable increase in tension was measured (after
20 min). Then CO2 was reduced from 6 to 2%, resulting in a rapid (<5
min) increase in pH to
7.60, and the stable alkalotic vein tension
was measured after 15 min. The gas mixture was then returned to 21%
O2-6% CO2-balance N2, resulting in
a rapid return to control pH of
7.40, and vessel tension was
measured again. A final response to the endothelium-dependent vasodilators ACh or the calcium ionophore A-23187 was then measured in
control veins and veins treated with NO-cGMP pathway inhibitors. At the
end of each experiment, rings were blotted dry and weighed, and all
tension measurements were normalized to vessel weight (in mg tension/mg
vein wt).
Study groups.
Each vein was assigned to only one of the study groups indicated in
Table 1. Inhibitors were not added to Con or Endo
veins. Concentrations of the different inhibitors used in this study were
based on those previously reported (7, 9, 17, 21, 22, 28, 36).
Inhibition of NO synthase by 10
4 M
N
-nitro-L-arginine
(L-NNA) was confirmed in the L-NNA group by comparing endothelium-dependent relaxation to ACh or A-23187 before and
after addition of the inhibitor to the bath. ACh caused a 78.8 ± 2.8% decrease in the U-46619 challenge 1 response (i.e., before addition of the inhibitor) and a 4.2 ± 1.0% after
10
4 M L-NNA. A-23817 caused a 42.5 ± 5.4% decrease in U-46619-induced constriction in preliminary studies
of control veins (data not shown) and a 6.6 ± 8.5% decrease after
addition of 10
4 M L-NNA in this study.
Similarly, ACh- and A23187-induced relaxation was significantly blunted
in a group treated with 10
5 M
1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one
(ODQ; data not shown). In addition, relaxation to
10
6 M sodium nitroprusside was reduced from 43.7 ± 6.5% under control conditions to 6.6 ± 5.9% after addition of
10
5 M ODQ in preliminary experiments. Previous
studies (17, 28, 36) found that 10
5 M meclofenamate
and 10
5 M indomethacin both effectively inhibit
cyclooxygenase (Cyclo). Because the effects of these inhibitors were
similar in the current study, they were combined into a single
Cyclo-inhibited group.
Although ATP-dependent K+ (KATP)-channel
activation was effectively blocked by 10
5 M
glibenclamide (Glib) in piglet pulmonary arteries (17) and in another
study (9), we found that full inhibition of 10
8 to
10
7 M cromakalim-induced relaxation of piglet veins
required 10
4 M Glib. Therefore, this higher
concentration was used in the Glib group in this study. Iberiotoxin
(IbTX) has previously been used in concentrations ranging from
10
9 to 10
7 M to inhibit
Ca2+-dependent K+
(KCa)-channel activation (17, 22). We used the
higher concentration to block KCa-channel activation
in the IbTX group in this study. Voltage-dependent K+
(KV)-channel inhibition has been described with
concentrations of 4-aminopyridine (4-AP) between 10
3
and 10
2 M in previous studies of pulmonary vessels
(5, 43). However, in patch-clamp studies, 10
3 M 4-AP
was sufficient to block KV-channel opening (1, 5), and
higher concentrations caused smooth muscle depolarization through
non-KV-dependent mechanisms (21). Therefore, we measured the responses to alkalosis after adding 10
3 M 4-AP
in the 4-AP group.
Drugs and solutions.
MKS consisted of (in mM) 120 NaCl, 4.7 KCl, 1.7 NaH2PO4, 0.2 MgSO4 · H2O, 2.5 CaCl2 · 2H2O, 20 NaHCO3, and 10 glucose. For the KCl challenges, the MKS
NaCl and KCl concentrations were changed to 80 and 40 mM, respectively,
to maintain isosmolar conditions. ACh, IbTX, sodium nitroprusside (all
from Sigma, St. Louis, MO), and meclofenamate (BIOMOL Research
Laboratories, Plymouth Meeting, PA) were prepared in normal saline.
Stock solutions of indomethacin (Sigma) and U-46619 (BIOMOL) were
prepared in ethanol and added to normal saline. Glib, ODQ (Sigma), and
A-23187 (BIOMOL) were prepared in DMSO. L-NNA (Sigma) was
dissolved with a small amount of HCl in saline. 4-AP (Sigma) was
dissolved in water, and the pH was then titrated back to 7.40 with HCl.
Neither addition of the different inhibitors nor their vehicles in the
volumes (10-100 µl) used in this study altered the pH of the
MKS. All drug concentrations are expressed as final molar
concentrations in the organ bath.
Data analysis.
Data are expressed as means ± SE. The number of veins and piglets in
each group are indicated in Figs. 1-4 and Tables 1 and 2. In no
case were more than two veins from a single piglet assigned to a
particular study group. Absolute tension and changes in tension in
response to various interventions are expressed in milligrams per
milligram of vessel weight. To facilitate comparisons among different
groups, the percent reduction in the U-46619 challenge 2 response by alkalosis was also calculated and shown. Data were analyzed
by t-test or one-way or two-way repeated-measures ANOVA as
appropriate with SigmaStat version 2.03 statistical software (SPSS,
Chicago, IL). Data were considered significant at P < 0.05, and Fisher's least significant difference test was used to identify differences between or within groups when the ANOVA was significant.
 |
RESULTS |
There were no differences in piglet weight (2.96 ± 0.07 kg) or age
(6-9 days) among the different groups. Vein weight and diameter,
eucapnic and hypocapnic pH and PCO2,
and tension in response to 40 mM KCl and U-46619 challenge 1 were also similar among the groups (mean values for all veins are shown
in Table 2). ACh caused a 78.7 ± 2.8%
decrease in the U-46619 challenge 1 response of the 67 veins
with intact endothelium compared with a 5.0 ± 2.7% decrease in the
six Endo
veins (P < 0.05). Resting tension increased
significantly with the addition of L-NNA and ODQ in the
L-NNA and ODQ groups, respectively, but was unchanged in
the Con and Endo
veins or after addition of other inhibitors (Fig. 1).

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Fig. 1.
Resting tension increased after addition of either
N -nitro-L-arginine
(L-NNA) or
1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one
(ODQ) to bath. Con, control; Endo , nonfunctional endothelium;
Cyclo, cyclooxygenase; Glib, glibenclamide; IbTX, iberiotoxin; 4-AP,
4-aminopyridine. Nos. in parentheses, no. of veins, piglets/group.
* Significantly greater than Con.
|
|
Alkalosis caused a significant decrease in absolute U-46619
challenge 2 tension in Con and Cyclo veins but not in the
L-NNA, ODQ, or Endo
groups (Fig.
2A). In addition, the percent
reduction in the U-46619 challenge 2 response was significantly
greater in the Con and Cyclo groups than in the others (Fig.
2B). Neither absolute tension measured during alkalosis (Fig.
3A) nor the percent decrease in the
U-46619 challenge 2 response differed among the Con and
K+ channel-inhibited groups (Fig. 3B).

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Fig. 2.
A: resting tension and tension measured after 2nd submaximal
contraction induced by U-46619 (U-46619 challenge 2; #2) were
higher in L-NNA, Endo , and ODQ groups compared with
Con group (*). Alkalosis decreased U-46619 challenge 2 tension
in Con and Cyclo groups (**). B: percent decrease in U-46619
challenge 2 response during alkalosis was significantly blunted
in L-NNA, Endo , and ODQ groups ( ). Nos. in
parentheses, no. of veins, piglets/group. All differences were
significant at P < 0.05.
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Fig. 3.
A: K+-channel inhibition had no effect on absolute
tension under any study condition. B: percent decrease in
U-46619 challenge 2 response during alkalosis did not differ
between groups. Nos. in parentheses, no. of veins, piglets/group.
|
|
Resting tension and tension measured during U-46619 challenge 2 were significantly higher in L-NNA, ODQ, and Endo
groups compared with those in the other groups (Fig. 2), raising the possibility that their blunted alkalosis-induced responses were simply
due to their greater baseline tone. To address this question, Con veins
were divided into high-tension and low-tension subgroups based on
whether their responses to U-46619 challenge 2 were above or
below the median U-46619 challenge 2 tension achieved in all Con veins (2,348.2 mg/mg vein wt). Although all tension measurements were higher in the Con high-tension than in the Con low-tension groups
(Fig. 4A), the absolute decrease in
tension during alkalosis was actually greater in the Con high-tension
veins. However, the percent decrease in U-46619 challenge 2 response was similar in both groups (Fig. 4B). Thus higher
baseline tension did not appear to contribute to the blunted
alkalosis-induced responses of the Endo
, L-NNA, and
ODQ veins.

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Fig. 4.
A: tension was greater under all study conditions in Con
high-tension compared with Con low-tension veins (*). Alkalosis caused
a greater absolute decrease in tension in Con high-tension veins.
B: percent decrease in U-46619 challenge 2 response
during alkalosis was similar in both groups. Nos. in parentheses, no.
of veins, piglets/group.
|
|
 |
DISCUSSION |
Pulmonary veins are thin walled and have relatively little smooth
muscle compared with pulmonary arteries in human (20), porcine (31),
and ovine (23) newborns. However, veins from newborn lambs and piglets
constricted to hypoxia and thromboxane, contributing to pulmonary
hypertension and increased edema formation (6, 11, 29, 41). Our finding
in this study that alkalosis relaxed Con piglet pulmonary venous rings
after preconstriction with the thromboxane analog U-46619 (Figs.
2-4) suggests that alkalosis may reduce venous constriction, with
a consequent decrease in pulmonary hypertension and edema formation. In
contrast to isolated veins, alkalosis failed to alter venous resistance
in vascular occlusion studies of hypoxic lamb lungs (18) and
U-46619-treated rat lungs (14). This may reflect limitations of the
vascular occlusion technique in identifying responses of
500-µm-diameter pulmonary veins. Alternatively, there may be
interspecies or interpreparation differences in the apparent effects of
different pressor stimuli and alkalosis on venous tone. Further studies
measuring the effects of alkalosis on pulmonary hemodynamics and fluid
filtration in various species will be needed to evaluate the efficacy
of alkalosis in reducing pulmonary venous hypertension and the
resultant pulmonary edema.
Alkalosis-induced relaxation was significantly blunted in veins without
functional endothelium and in those treated with a NO synthase
inhibitor. But it was not blocked in veins treated with Cyclo
inhibitors (Fig. 2). These data suggest that alkalosis-induced pulmonary venous dilation is mediated by endothelium-derived NO. This
conclusion is consistent with the previous study by Gordon et al. (17)
on piglet pulmonary artery rings and is supported by studies showing
that extracellular alkalosis increases cytosolic pH (2) and
Ca2+ concentration (38), two potent stimuli for NO
synthesis (13, 24). Guanylate cyclase inhibition also blocked
alkalosis-induced relaxation in both piglet pulmonary veins (Fig. 2)
and pulmonary arteries (17), suggesting that NO acted through a
cGMP-dependent mechanism. Although NO-cGMP-mediated vasodilation
appeared to involve KV- or KCa-channel
activation in some studies (33, 42, 43), this did not appear to be the
case in the alkalosis-induced response of piglet vessels because
K+-channel inhibition had no effect on alkalosis-induced
relaxation of either pulmonary veins (Fig. 4) or arteries (17).
In contrast to piglet pulmonary vessels, NO did not appear to
contribute to alkalosis-induced vasodilation in rabbit (39) or rat (14)
lungs. PGI2 synthesis, like NO synthesis, is enhanced by
increased endothelial cell cytosolic Ca2+ (32).
Furthermore, Cyclo inhibition blocked alkalosis-induced vasodilation in
rat (40) and lamb (25) lungs. Thus some of the interspecies differences
in the mediator of alkalosis-induced vasodilation may reflect
interspecies differences in dominant endothelium-derived modulator
synthesis (4). Non-endothelium-dependent mechanisms of
alkalosis-induced vasodilation may also contribute (12) because
patch-clamp studies of isolated dog and rat pulmonary artery smooth
muscle cells have shown that alkalosis opened and acidosis closed
KV channels in the absence of endothelium (1, 5).
In addition to interspecies differences, intraspecies differences in
the apparent mediator of alkalosis-induced vasodilation have been
described in studies of lambs (12, 25), piglets (17, 19), and rats (37,
40) with different preparations. We speculated that the discordance
between isolated piglet pulmonary artery rings in which NO synthase
inhibition blocked alkalosis-induced relaxation (17) and intact piglets
in which the PGI2 synthase inhibitor tranylcypromine
inhibited the response (19) was due to heterogeneity in synthesis
and/or activity of endothelium-derived modulators within the pulmonary
circuit (15, 16, 36). However, contrary to our hypothesis,
alkalosis-induced relaxation of piglet pulmonary veins was also
mediated by the NO-cGMP pathway (Fig. 2). Although our findings do not
exclude the possibility that smaller vessels within the whole lung
respond differently to alkalosis than 500-µm-diameter veins and
arteries, several other interpreparation differences such as pressor
stimuli, type and specificity of inhibitors, perfusate, and
neuroendocrine factors may also contribute. Future studies must
determine how species and preparation differences alter the effects of
alkalosis on the pulmonary vasculature if the mechanism of
alkalosis-induced pulmonary vasodilation is to be elucidated.
 |
ACKNOWLEDGEMENTS |
This work was supported by the Children's Hospital Foundation of
the Children's Hospital of Wisconsin and the Department of Pediatrics
of the Medical College of Wisconsin (Milwaukee, WI).
 |
FOOTNOTES |
J. A. Madden was supported by funds from Veterans Affairs Medical Research.
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. §1734 solely to indicate this fact.
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).
Received 18 August 1999; accepted in final form 6 December 1999.
 |
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