496
Pulmonary Venous Responses to
Thromboxane A2 Analogue and Atrial
Natriuretic Peptide in Lambs
J. Usha Raj and J. Anderson
To characterize pulmonary venous vasoactivity and the factors that modulate it, we determined
venous responses to a vasoconstrictor agent, thromboxane A2 (TXA2) analogue U46619, and to
a vasodilator agent, atrial natriuretic peptide (ANP), in 28 isolated blood-perfused lamb lungs
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under conditions of varying vascular tone and intraluminal pressures. TXA2 was given in a 5
,ug/kg bolus followed by a steady infusion of 1 ,ug/kg/min to three groups of lungs: group 1,
n = 4, with low vasomotor tone; group 2, n = 8, with moderate vasomotor tone; and group 3, n = 7,
with moderate vasomotor tone and high venous intraluminal pressures. Group 3 lungs were
reverse-perfused to obtain high venous pressures. ANP was given as two 10 ,ug/kg bolus
injections, 5 minutes apart, to three groups of lungs: group 4, n =4, with low vasomotor tone;
group 5, n=5, with moderate vasomotor tone; and group 6, n=8, with high vasomotor tone.
Group 6 lungs were vasoconstricted with TXA2 infusion. In all lungs, we measured blood flow
and pressures in the pulmonary artery and left atrium and partitioned the venous segment by
measuring pressures in 20-80-,um venules by micropuncture. We found that the venous
constrictor response to TXA2 was greatest in lungs with moderate basal vasomotor tone and low
venous intraluminal pressures. In lungs with low vasomotor tone or high venous intraluminal
pressures, the venous response to TXA2 was attenuated. The vasodilator response to ANP was
negligible in lungs with low vasomotor tone, probably because they were already maximally
vasodilated, but similar in lungs with moderate and high vasomotor tone. We conclude that
pulmonary venous response to TXA2 is dependent on the degree of basal vasomotor tone and
on venous intraluminal pressures but that the response to ANP is independent of the degree of
vasomotor tone. (Circulation Research 1990;66:496-502)
In the lungs, veins exhibit considerable vasomotion1-4 and greatly influence microvascular
pressures and fluid filtration.3,4 A small change
in venous resistance will significantly affect the
hydrostatic pressures in filtering vessels upstream
from the veins, even if there is no change in arterial
resistance. Thus, microvascular pressures and fluid
and protein flux are very sensitive to changes in
venous resistance. We have previously reported that
in newborn lambs pulmonary arteries and veins constrict during hypoxia3 and that thromboxane A2
(TXA2) mediates the venous constriction during
hypoxia.5 Also, there is some evidence that during
hypoxia there is a greater release into the circulation
From the Department of Pediatrics, Harbor-UCLA Medical
Center, UCLA School of Medicine, Torrance, California.
Supported by grant HL-34606 from the National Heart, Lung,
Blood Institute and by a grant from the American Lung Association of Los Angeles County.
Address for reprints: J. Usha Raj, MD, A-17 Annex, HarborUCLA Medical Center, 1000 West Carson Street, Torrance, CA
90509.
Received March 27, 1989; accepted September 1, 1989.
of atrial natriuretic peptide (ANP), a powerful
vasodilator,6 which may be a protective phenomenon.
Because of these observations, we chose to study the
response of the pulmonary veins to TXA2 and ANP
and to investigate some of the factors that modulate
the venous response to these two vasoactive agents.
We used isolated blood-perfused lungs of neonatal
lambs for our studies and partitioned the venous
segment by measuring pressures in 40-80-,um diameter venules by micropuncture.
Materials and Methods
Isolated Perfused Lung Preparation
We isolated and perfused lungs of 28 neonatal
lambs, aged 6.5 + 1.7 days and weighing 4.7+ 1.4 kg, as
described previously.7 Briefly, the lamb was anesthetized intramuscularly with ketamine (25 mg/kg body
wt). Catheters were placed in the carotid artery and
internal jugular vein, and an endotracheal tube was
tied into the trachea. After intravenous infusion of
1,000 IU heparin sodium/kg body wt, we rapidly
exsanguinated the lamb via the carotid artery cathe-
Raj and Anderson Pulmonary Venous Responses to Vasoactive Agents
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ter and collected the blood. Heart and lungs were
removed, and fluid-filled cannulas were tied into the
pulmonary artery and left atrium with care being
taken that no air bubbles entered the pulmonary
artery. The ductus arteriosus, aortic root, and both
venae cavae were ligated, and a ligature was tied
around the ventricles to occlude their lumen.
The lungs were perfused with the blood drained
from the lamb. If the volume of blood was insufficient, a solution of 5% dextran 70 in Ringer's lactate
was added to the blood. Blood was warmed (38°390 C), filtered (40-,um filters), and degassed before
entering the lungs. A calibrated roller pump (Integral
Variable Drive, Cole-Parmer Instrument, Chicago,
Illinois) circulated the blood through the lungs. We
continuously measured pulmonary artery and left
atrial pressures with Statham pressure transducers
(model P23, Gould, Cleveland, Ohio). Zero reference level for vascular pressures was the top surface
of the lung (site of all micropunctures). Pulmonary
artery pressure was varied by altering blood flow, and
left atrial pressure was varied by adjusting the height
of the venous reservoir. All lungs were perfused in zone
3. Airway pressure was kept constant at 7 cm H20 with
a gas mixture of 30% 02, 6% C02, and 74% N2; left
atrial pressure was 8 cm H20, relative to the top of the
lung. At the beginning of the experiment, blood flow
was adjusted so that pulmonary artery pressure was
about 30 cm H20, and thereafter, blood flow was kept
constant until the end of the experiment.
Blood pH, 02, and CO2 tensions were measured at
10-minute intervals (Radiometer BMS 3M1C2,
Copenhagen, Denmark). Hematocrit and blood glucose concentrations were monitored every 20 minutes.
Venous Pressure Measurement
We partitioned the pulmonary veins by measuring
venular and left atrial pressures and by determining
the pressure drop across the venous segment. We
measured pressures in 20-80-,um diameter subpleural venules with glass micropipettes and the servonull
pressure-measuring system.7,8 Glass micropipettes
with a tip diameter of 2-4 ,um were filled with 1.2 M
NaCl colored with green dye and were connected
electrically and hydraulically to a servonull pressuremeasuring system (model 4A, Instruments for Physiology and Medicine, San Diego, California). The
lung surface was stabilized with a metal ring that also
held a pool of normal saline for obtaining the zero
reference pressure. Subpleural vessels were viewed
through a stereomicroscope (Carl Zeiss, Thornwood,
New York) at x 80 and x 120 magnification with
illumination from a cold light source (Intralux 5000,
Volpi, Auburn, New Jersey). Venules were identified
by observing the direction of blood flow from small to
larger vessels. We accepted microvascular pressure
measurements that fulfilled the following criteria:
1) reproducible zero reference pressure obtained
both before and after the pressure measurement,
2) an immediate response in the microvascular pres-
497
sure tracing when either the pulmonary artery or left
atrial pressure was perturbed, 3) immediate washout
of injected dye from the pipette by the flowing blood,
indicating that the pipette tip was lying freely in the
vessel lumen, and 4) a pressure measurement that
was independent of small changes in the optimal
servonull gain setting, indicating that the pipette tip
was in liquid.
Experimental Protocols
The response of the entire pulmonary circulation
and the pulmonary veins to a vasoconstrictor agent,
TXA2 analogue U46619, was studied under three
conditions: 1) low vasomotor tone, 2) moderate vasomotor tone, and 3) moderate tone and high venous
intraluminal pressures.
Group 1 consisted of lungs with low vasomotor
tone (n=4). At the time of collection of blood,
indomethacin, an inhibitor of cyclooxygenase
enzyme, and Piriprost U60257, a 5'-lipoxygenase
inhibitor (gift of Dr. M. Bach, Upjohn, Kalamazoo,
Michigan) was added to the blood to stop the production of vasoconstrictor prostaglandins and leukotrienes. Indomethacin solution was added to achieve
a blood concentration of 20 ,g/ml,9 and U60257 was
added to achieve a concentration of 200-500 gg/
ml.5,10 We have previously shown that lungs treated
in this manner have lower basal vasomotor tone than
untreated lungs.5
To test that the drugs indomethacin and U60257
did not affect the responsiveness of the pulmonary
vasculature to other vasoactivW agents, we tested the
response of these lungs to a bolus injection of 200 ,ug
angiotensin. In untreated lungs, a bolus injection of
200 ,g angiotensin results in a transient rise in
pulmonary artery pressure of 5-10 cm H20. The
treated lungs demonstrated a similar vascular
response to angiotensin; this occurrence indicated
that the vasoactivity of the vasculature was unaffected by the presence of indomethacin and U60257.
Group 2 consisted of lungs with moderate vasomotor tone (n=8). These lungs were perfused with
untreated blood. Basal pulmonary vasomotor tone
was generally higher in these lungs than in group 1
lungs.
Group 3 consisted of lungs with moderate vasomotor tone and high venous intraluminal pressure
(n=7). These lungs were perfused with untreated
blood as in group 2 lungs. To obtain high distending
pressures in the veins, we reverse-perfused the lungs.
Blood entered the lungs via the left atrium and
drained from the pulmonary artery. At the start of
perfusion, blood flow was adjusted to maintain left
atrial pressure around 30 cm H20; the pulmonary
artery pressure was 8 cm H20.
In all lungs, once blood flow and inflow pressure
were stable, a venular pressure measurement was
obtained. Then a 5 jig/kg body wt bolus of TXA2 was
infused into the inflow cannula followed by a steady
infusion of TXA2 at 1 ,ug/kg body wt/min. Once a
steady-state pulmonary vascular response was
498
Circulation Research Vol 66, No 2, February 1990
TABLE 1. Baseline Pulmonary Vascular Resistance in Three Groups of Isolated Lamb Lungs Before Infusion of Thromboxane A2 Analogue
Pulmonary vascular
Number of
Blood flow
resistance
(cm H20 min/ml kg)
Condition
Group
lungs
(ml/kg body wt/min)
96±+19
0.226+0.5*
4
1
Low vasomotor tone
50±7
Moderate vasomotor tone
0.440+0.07
2
8
0.525±0.26
48±11
3
7
Moderate vasomotor tone with reverse perfusion
*p<0.05 vs. groups 2 and 3.
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obtained, which was usually within 5-10 minutes,
another venular pressure measurement was obtained.
The response of the pulmonary veins to vasodilator
agent ANP was studied under three conditions:
1) low vasomotor tone, 2) moderate vasomotor tone,
and 3) high vasomotor tone.
Group 4 consisted of lungs with low vasomotor
tone (n=4). The lungs were treated as described for
group 1 lungs.
Group 5 consisted of lungs with moderate vasomotor tone (n=5). The lungs were perfused with
untreated blood.
Group 6 consisted of lungs with high vasomotor
tone (n =8). These lungs are the same as in group 2.
After obtaining a steady-state response to the vasoconstrictor agent TXA2, the response to ANP was
studied in the presence of a vasoconstricted pulmonary vascular bed.
In all the lungs, the response to ANP was studied
by observing the response to two 10 ,ug/kg body wt
bolus injections of synthetic rat ANP (MW 3102;
gift of Dr. David Shapiro, Merck Sharp & Dohme,
West Point, Pennsylvania) given 5 minutes apart.
Terminally, in all lungs in groups 4-6, papaverine
hydrochloride in a dose of 100 ,ug/ml perfusate
Low Vasomotor Tone
60-
was added to determine if there was any residual
vasomotor tone.
Data Analysis
In each group of lungs, the response of the
pulmonary vasculature to the vasoactive agent was
statistically tested by a paired t test. Results shown
are mean±SD for each group of lungs. Basal vascular resistance and basal vascular pressure drops
among groups 1-3 and among groups 4-6 were
compared by multiple unpaired t tests with the
Bonferroni correction. The response to TXA2 analogue and ANP in the lungs was compared among
groups by an analysis of variance for multiple
comparisons. We accepted a value of p<0.05 as
indicative of statistical significance.
Results
During the experiments, blood pH was 7.35-7.50,
Pco2 was 30-45 mm Hg, and Po2 was 110-190
mm Hg. Mean hematocrit of blood was 20.8±3.8%.
Basal pulmonary vascular resistance in group 1
lungs with low vasomotor tone was significantly lower
than in group 2 lungs with moderate vasomotor tone
and in group 3 lungs that were reverse-perfused. The
Moderate Vasomotor Tone
60-
n =4
High Venous Intraluminal Pressures
During Reverse Perfusion
60-
n =8
n =7
* p<O.O5
50-I
50 -
AFTER TxA2
50-
* p<0.05
40-
40-
-2CR 30-
30 -
-
0
I
AFTER TxA2
*p<0.05
4030-
W
U
20-
20
20-4
BEFORE TaA2
cr
10-
10-
10-
l
O
PULMONARY
ARTERY
BEFORE TxA2
BEFORE TxA2
VENULE
LEFT
20-80jm ATRIUM
0.
I
PULMONARY
ARTERY
VENULE
LEFT
20-80,um ATRIUM
0-
*
.
VENULE
LEFT
ATRIUM 20-80pm
PULMONARY
ARTERY
FIGURE 1. Graphs showing effect of thromboxaneA2 analogue (TxA2) on pulmonary vascularpressures in three groups of isolated
perfused lamb lungs. In lungs with low and moderate vasomotor tone, infusion of TxA2 resulted in an increase in pulmonary artery
and venular pressures. In lungs that were reverse-perfused, TxA2 infusion resulted in an increase in left atrial and venular pressures.
Raj and Anderson Pulmonary Venous Responses to Vasoactive Agents
a
250-
zo
**
_J
TOTAL VASCULAR RESISTANCE
U) 200M
VENOUS
RESISTANCE
W
~'
150
IHoE
VASOMOTOR
VASOMOTOR
TONE
INTRALUMINAL
TONE
PRESSURE
Bar graphs showing influence of vasomotor tone
FIGURE 2.
and vascular intraluminal pressures on pulmonary vascular
response to thromboxane A2 analogue in isolated perfused
lamb lungs.
The increase in total vascular resistance after
thromboxane A2 analogue infusion was greater in lungs with
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moderate vasomotor tone (whether they were forward-perfused
[group 2] or reverse-perfused [group 3]) than that in lungs
with
low
vasomotor
tone
(group
1).
Pulmonary
venous
response was greatest in lungs with moderate vasomotor tone
that were forward-perfused (group 2). Low vasomotor tone
and high venous intraluminal pressures attenuated the magnitude
of response
of veins to thromboxane A2 analogue.
*Significantly different from low vasomotor tone at p<O.O05.
**Significantly diffierent from low vasomotor tone and high
venous intraluminal pressure at p <0. 05.
basal vascular resistance in group 2 and 3 lungs was
499
with moderate vasomotor tone (groups 2 and 3) than
in the treated lungs with low vasomotor tone (group
1) (Figure 2). The venous constrictor response to
TXA2 was greatest in the lungs with moderate basal
vasomotor tone and low venous intraluminal pressures (group 2). In lungs with low basal vasomotor
tone (group 1) and in lungs with high venous intraluminal pressures (group 3), the venous response to
TXA2 was attenuated.
Basal pulmonary vascular resistances in the three
groups of lungs, before infusion of ANP, were significantly different from one another (Table 2).
The effect of ANP on pulmonary vascular pressures under conditions of different basal vasomotor
tone is shown in Figure 3. In lungs with low vasomotor tone (group 4), ANP infusion had a negligible
effect on vascular pressures. In lungs with moderate
and high vascular tone, ANP infusion resulted in a
fall in both pulmonary artery and venular pressures.
The pressure drop in both the venous segment and
the segment containing microvessels and arteries
decreased significantly, indicating that both arteries
and veins relaxed with ANP. The percent decrease in
total pulmonary vascular resistance and venous resistance after ANP was similar in lungs with moderate
and high vasomotor tone (Figure 4). Addition of
papaverine to group 4 lungs resulted in no decrease
in pulmonary vascular pressures. However, in lungs
of groups 5 and 6, papaverine resulted in a further
decrease in pulmonary artery and venular pressures
to 20+4 and 12+2 cm H20, respectively.
similar (Table 1).
The effects of TXA, analogue infusion on pulmonary vascular pressures in the three groups of lungs
are shown in Figure 1.
In all lungs in groups 1 and 2, pulmonary artery
and venular
lungs,
after
left
pressures
atrial
TXA,
infusion.
obtained within
drug.
increased,
and venular
The
segment
in
maximum
group
3
increased
effect
was
minutes of steady infusion of the
Thus, with TXA,,
venous
and
pressures
as
well
the pressure
as
in
the
drop in the
segment
that
contains the arteries and microvessels increased significantly,
indicating
that TXA,
constricts
arteries
and veins.
When we
compared the
pulmonary vasculature
response
to TXA,
of the entire
among the
three
groups, we found that the percent increase in total
vascular resistance was greater in the untreated lungs
Discussion
The magnitude of lung microvascular pressure is
important in the control of transmicrovascular liquid
and protein flux as well as in the control of flow
through the microcirculation. The pressure in the
microvascular bed is influenced greatly by changes in
vasomotor tone in the arterial and venous segments.
Microvascular filtration is particularly sensitive to
changes in venous resistance because venular constriction will increase not only microvascular pressures but also the surface area for fluid filtration
upstream from the constriction. Recent data have
provided new information that in the lung, arteries
and veins can constrict independently. In adult lungs,
it has been shown that during hypoxia arteries constrict predominantly,11,12 whereas histamine predominantly constricts veins.13,14 The significance of
TABLE 2. Baseline Pulmonary Vascular Resistance in Three Groups of Isolated Lamb Lungs Before Infusion of Atrial
Natriuretic Peptide
Pulmonary vascular
Blood flow
resistance
Number of
(cm H20 *min/ml kg)
Condition
(ml/kg body wt/min)
Group
lungs
0.233±0.043
92±12
4
Low vasomotor tone
4
0.441±0.130*
58±10
5
Moderate vasomotor tone
5
57±12
8
0.796±0.276t
6
High vasomotor tone
*p<0.05 vs. groups 4 and 6.
tp<0.05 vs. groups 4 and 5.
500
Circulation Research Vol 66, No 2, February 1990
Moderate Vasomotor Tone
Low Vasomotor Tone
60-
60-
n = 4
n
High Vasomotor Tone
60-
=5
n =
8
* p
50-
50*
-
0
40-
p<O.05
40-
E
-) 3030 '2
cr
40-
30BEFORE ANP
20-
AFTER ANP
W
,"BEFORE ANP
30-
-BEFORE ANP
Lfi
1)
20co
<0.05
50-
a:
20AFTER ANP
a-
10-
1 0-
10 -
0-
T
0
l
PULMONARY
ARTERY
VENULE
LEFT
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20-80um ATRIUM
PULMONARY
ARTERY
VENULE
LEFT
20-80pm ATRIUM
PULMONARY
ARTERY
l
VENULE
LEFT
20-80pnm ATRIUM
FIGURE 3. Graphs showing effect of atrial natriureticpeptide (ANP) on pulmonary vascular pressures in three groups of isolated
perfused lamb lungs with varying degrees of vasomotor tone. In lungs with moderate and high vasomotor tone, ANP infusion
resulted in a significant decrease in pulmonary artery and venular pressures, but there was no effect of ANP in lungs with low
vasomotor tone.
venous constriction is apparent in the different
response to hypoxia seen in neonatal and adult
sheep. In the neonatal lamb lung, hypoxia causes
constriction of arteries and veins3 with a concomitant
decrease in the ratio of lymph to plasma protein
concentration.15 In contrast, in adult sheep, hypoxia
results primarily in arterial constriction with no
change in lung lymph flow.16
In this study, we wished to characterize the venous
responses to two vasoactive agents, TXA2 (a vasoconTOTAL VASCULAR RESISTANCE
*
S
VENOUS RESISTANCE
wWW
z c-
z 50-
U-J
LLr
z
< 25-
a:
cc >
IL
0
LOW
VASOMOTOR
TONE
*
MODERATE
VASOMOTOR
TONE
p<0.05. different from low vocomotor
HIGH
VASOMOTOR
TONE
tone
FIGURE 4. Bar graphs showing influence of vasomotor tone
on pulmonary vascular responses to atrial natriuretic peptide.
The decrease in total vascular resistance and in venous
resistance was similar in lungs with moderate and high
vasomotor tone but was negligible in lungs with low vasomotor
tone.
strictor) and ANP (a vasodilator), and to determine
some of the factors that modulate the venous
responses to these agents. In previous experiments,
we found that during hypoxia, TXA2 mediated the
venous constriction in lamb lungs'1; hence, we chose
to study the effect of this agent on pulmonary veins.
And the vasodilator that we chose to study was ANP
because there is some evidence that during hypoxia
the circulating levels of ANP are elevated,6 suggesting a possible role for ANP in modulating hypoxic
vasoconstriction.
Our data show that the amount of venous constriction resulting from an infusion of TXA2 analogue is
in part dependent on the degree of basal vasomotor
tone and on the magnitude of the intraluminal pressures. The concept that pulmonary vascular
responses to vasoactive agents are dependent on the
degree of resting vasomotor tone was first suggested
by Rudolph and coworkers.17 In studying pulmonary
vascular responses to acetylcholine in the dog, they
found that when the underlying vasomotor tone was
low, acetylcholine resulted in vasoconstriction
whereas when tone was elevated, vasodilation
resulted. A marked vasodilator effect of acetylcholine
when resting vasomotor tone was high has also been
shown in the fetal lamb lung18 and cat lung.19Y20
However, other recent studies21-23 have shown that
when tone is high, the vasopressor response to acetylcholine is augmented. This is similar to the effect
of tone on the response of the pulmonary vasculature
to TXA2 in our studies.
The diminished vasoconstrictor response to TXA2
when the lungs were reverse-perfused indicates that
the high intravascular pressures in the veins directly
opposed the ability of the veins to constrict. This is
consistent with studies in lambs24 and sheep16,25 that
Raj and Anderson Pulmonary Venous Responses to Vasoactive Agents
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showed that in the presence of high pulmonary
vascular pressures the hypoxic vasoconstrictor
response was diminished. In adult sheep with elevated left atrial pressures, Bland et al16 did not find
any significant increase in pulmonary vascular resistance with hypoxia, indicating an absence of vasoconstriction. Similarly, Snapper et a125 found that in
adult sheep with a partially obstructed mitral valve
and left atrial hypertension, hypoxia did not result in
any change in pulmonary vascular resistance. In both
these studies, when left atrial pressure was normal,
hypoxia resulted in significant vasoconstriction.
These results suggested that increased vascular
intraluminal pressure opposed any direct vasoconstrictive effects of hypoxia.
From our previous studies, we have found that in
isolated lamb lungs hypoxia results in constriction of
both arteries and veins. We also found that the
venous constriction during hypoxia was probably
mediated by TXA2. Furthermore, in studies with
lambs, we have reported that there was a smaller
increase in pulmonary vascular resistance with
hypoxia in the presence of left atrial hypertension
than when left atrial pressure was normal.24 These
data obtained from lambs in vivo are consistent with
our findings in isolated lamb lungs; in isolated lungs,
the vasoconstrictor response to TXA2 analogue was
attenuated in the presence of elevated pulmonary
venous pressures, and in lungs in vivo, the vasoconstrictor response to hypoxia was similarly attenuated
when pulmonary venous pressures were high.
The newly described group of peptide hormones,
atriopeptins or ANPs, have been shown to have
several cardiovascular and renal effects, including
natriuresis, diuresis, vasodilation, and inhibition of
aldosterone secretion.2627 Though ANP has been
previously shown to be a potent vasodilator of large
arteries in vitro,27 its effects in whole animal studies
have been controversial.28 ANP has been shown to
display regional vasorelaxant selectivity in vitro; for
example, it has a greater effect on arteries than on
veins and a greater effect on large vessels than on
smaller ones.29 ANP elicits an endotheliumindependent relaxation of blood vessels by activating
membrane-associated particulate guanylate cyclase,
cyclic GMP synthesis, and cyclic GMP-dependent
protein kinase activation.30
We have demonstrated that pulmonary veins in
lambs are responsive to the vasodilatory effects of
ANP. Other investigators3' have reported a vasodilatory effect of ANP in the pulmonary vascular bed of
the intact-chest cat. However, in that study the
authors did not determine if both pulmonary arteries
and veins dilated in response to ANP. In the bovine
lung, Ignarro et al32 reported that intrapulmonary
arteries, but not intrapulmonary veins, dilated in
response to ANP. This response was not dependent
on endothelium and was associated with an accumulation of cyclic GMP. Clearly, species differences
exist. In isolated lamb lungs, pulmonary veins dilated
in response to ANP. It is possible that pulmonary
501
venous smooth muscle cells in lambs possess particulate guanylate cyclase that is responsive to ANP,
which may not be true for the bovine species.
The response of pulmonary veins to ANP seems to
be independent of the degree of basal vasomotor
tone. In lungs with low vasomotor tone, there was no
response to ANP, possibly because the pulmonary
vasculature was already maximally vasodilated. We
did not see any decrease in pulmonary vascular
pressures with administration of papaverine in this
group of lungs; this finding indicated that the smooth
muscle in the pulmonary vasculature had negligible
vasomotor tone. In lungs with moderate and high
vasomotor tone, ANP resulted in a fixed amount of
vasodilation. The dose of ANP that we used would
have achieved a blood concentration far in excess of
all reported physiological levels of ANP in blood. It is
possible that we had fully saturated all ANP receptors in the pulmonary vasculature at these doses in
both groups of lungs; this situation would explain the
observation of a fixed amount of vasodilation.
In summary, we have demonstrated that TXA2 is a
powerful vasoconstrictor of the pulmonary vasculature including the veins and that ANP is a powerful
vasodilator of pulmonary arteries and veins. The
magnitude of the venous response to TXA2 is modulated by basal vasomotor tone and by the magnitude
of venous intravascular pressures. ANP effect in the
pulmonary veins, when given in pharmacological
doses, seems to be independent of basal vasomotor
tone. One conclusion from our study is that the
factors that determine the magnitude of pulmonary
venous responses to a vasoconstrictor agent are quite
different from those that modulate the response to a
vasodilator agent. The amount of contraction of a
smooth muscle cell to a vasoconstrictor, such as
TXA2, may be, in part, dependent on the receptoragonist interaction with its resultant intracellular
events, as well as on the initial length-tension state of
the smooth muscle cell. However, in the case of a
vasodilator, such as ANP, the amount of relaxation of
the smooth muscle cell is dependent on the interaction of the receptor-agonist alone and is independent
of the initial tension-length state of the cell. Whether
this is true for other vasoconstrictors and dilators has
yet to be studied.
Acknowledgments
We thank P. Chen and R. Ramanathan for help
during these experiments and C. Dowty for typing the
manuscript.
References
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histamine and isoproterenol in intact dogs. J Pharmacol Exp
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2. Noonan TC, Kern DF, Malik AB: Pulmonary microcirculatory
responses to leukotrienes B4, C4 and D4 in sheep. Prostaglandins 1985;30:419-434
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3. Raj JU, Chen P: Micropuncture measurement of microvascular pressures in isolated lamb lungs during hypoxia. Circ Res
1986;59:398-404
4. Selig WM, Burhop KE, Garcia JGN, Malik AB: Substance
P-induced pulmonary vasoreactivity in isolated perfused
guinea pig lung. Circ Res 1988;62:196-203
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KEY WORDS * lung * pulmonary venous vasoactivity * neonatal
lungs * atrial natriuretic peptide * thromboxane A2
Pulmonary venous responses to thromboxane A2 analogue and atrial natriuretic peptide
in lambs.
J U Raj and J Anderson
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Circ Res. 1990;66:496-502
doi: 10.1161/01.RES.66.2.496
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