Importance of Transmural Pressure and Lung Volume in
Evaluating Drug Effect on Pulmonary Vascular Tone
By DALI J. PATEL, M.D., PH.D., ALEXANDER J. MAM-OS, B.S.,
AXD FLAVIO M. DE FREITAS, M.D.
M
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EASUREMENT of pulmonary vascular
resistance has frequently been used in
the study of vasoactive drugs to indicate
changes in pulmonary vascular tone.1'2 However, as pointed out by Borst et al.3> 4 and
Fowler,1 it is not possible in many of these
studies to separate vasoactive drug effects
from purely mechanical effects resulting from
changes in transmural pressure,* and lung
volume. It is the purpose of this study to separate these two effects by using a method applicable to intact animals and man.
Pulmonary vascular resistance (PVR) is
defined as the ratio of the mean pressure drop
across the pulmonary vascular bed to the
mean blood flow through the bed. PVR depends on the geometry of the vascular bed and
the physical properties of the blood. The geometry of the vascular bed is related to the
volume of the lung as well as to the distribution of transmural pressure along the vessels,
the number of parallel vessels that are open,
and the physical properties of the vessel
walls.5"9 Most vasoactive drugs will affect the
intravascular pressure, the blood flow, and the
properties of the vessel walls. Assuming the
physical properties of the blood to remain
constant, it should be possible to infer the
vasoactive effect of a drug on the pulmonary
vasculatnre from measurement of PVR, provided the lung volume and transmural pressures are held constant.
The vasoactive effect of a drug on PVR can
be separated from the mechanical effects in
thoracotomized animals with intact circulations as follows: If the airway pressure is held
constant, then the transmural stress tending
to dilate the blood vessels would vary only
with intravascular pressure. Now, if the average intravascular pressure (AIP) is varied
by some means so as not to vary vessel tone,
then a "control" AIP-vs.-PVR curve could
be plotted. The test drug could then be given
and the course of ATP vs. PVR for the test
curve plotted on the same graph. The ordinatc
differences between these two curves may be
interpreted, to a first approximation, as the
change in vascular wall tone induced by the
drug.
Methods
Eleven dogs were studied under intravenous
pentobarbital anesthesia (approximately 26 rag./
Kg.). A sternal-splitting thoraeotomy was performed and the chest wall retracted so that the
lungs were free to expand. The surface of the
lung was kept moist by spraying it with normal
saline. The dog was ventilated with a constantstroke-volume, positive-pressure respiratory pump
(approximately +3 to +12 mm. Hg) that was
momentarily interrupted at a pressure of 3 mm.
Hg during periods of data collection. Thus, there
was essentially no air flow in lungs during periods
of data collection. In such a static system, the
intratracheal pressure would deflect the intraalveolar pressure as long as the channels connecting the two were patent. Pressures in the main
pulmonary artery (PA), left atrium (LA), and
trachea were measured simultaneously using
Statham strain gauges (P23D) connected to a
Sanborn direct-writing recorder. Flow in the main
PA was monitoi-ed continuously by a Kolin electromagnetic flowmeter.10 Since both LA and PA
pressures influence PVR,3 the average intravascular pressure (AIP) was estimated as:
mean PA pressure + mean LA pressure
~
2
It can be readily seen that the passive effect of
any change in pulmonary blood flow, pulmonary
Prom the Section on Clinical Biophysics, Cardiology Branch, National Heart Institute, Bethesda,
Maryland.
This investigation was carried out during Dr.
Freitas' tenure of a Postdoctoral Research Fellowship from the National Heart Institute, United
States Public Health Service.
Received for publication June 29, 1961.
*Transmural pressure is defined as the difference
in pressure between the intravascular pressure and
the pressure exerted on the outside of the vessel wall.
Circulation Research, Volume IX, November 1901
1217
1218
PATEL, MALLOS, FREITAS
12
• CONTROL
o
10
NOR-EPI
86420
8
10
12
14
16
18
20
22
24
26
28
AIP (mm Hg)
1210-
I
8-
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(6)
I
e
a:
o-H
,
0
8
—i
10
1
1
1
1
T
12
14
16
18
20
1
1
1
r
22
24
26
28
AIP (mm Hg)
Figure 1
(Top)—Pulmonary vascttlar resistance (PVR)
at various average intravascnlar pressures (AIP)
during the control state and during norepinephrine
(Nor-Epi) administration. Airway pressure was
held constant at 3 mm. Kg. The time sequence
of control and test values of PVR is shown by
the solid-line arrows. The points on the norepinephrine curve are numbered in order of increasing dosage. The broken-line arrow indicates the
value of PVB, obtained soon after the drug was
discontinued. (Bottom)—The experiment shown
in the top figure teas repeated in the same dog
after hexamethonirnn teas administered.
blood volume, or a change in PA or LA pressure
would be reflected in the measurement of AIP.
Therefore, if the comparison of PVR between
the control and the test state were made at the
same AIP, the result Avould be relatively free
of any passive effect. The PVR was calculated as:
_ mean PA pressure — mean LA pressure
PVxt —
^
•
•
mean flow
Just prior to thoraeotomy, the dog was infused
with approximately 500 cc. of dextran and then
bled of the same volume of blood. This blood was
later reinfused to establish the control AIP-vs.PVR curve. For test studies, Z-norepinephrine
bitartrate* was administered at a constant rate,
by intravenous drip. Dosage varying from 0.6 to
*Levophed.
4.3 /xg./Kg./min. of Levophed base were employed. In order to make random the effects of
spontaneous changes in PVR that may occur
following thoraeotomy, the order of test and
control procedures was varied in different dogs.
Even though the same airway pressure was
maintained during each period of data collection,
the lung volume could have varied between the
control and the test states due to a change in
pulmonary compliance. However, any change in
PVR due to such a change in lung volume would
have been small in these experiments. It has been
shown-"'"8 that an increase in PVR secondary to
n. change in lung volume per se occurs at extremes
of lung inflation, i.e., at collapse and when the
lungs are markedly inflated. The control and
test data for calculation of PVR in this study
were collected at a moderate degree of lung
inflation and, therefore, would be relatively insensitive to small changes in lung volume.
Results and Discussion
Figure 1 (top) illustrates one dog experiment in which A'alues of PVR at Ararious A I P ' s
during the control state and during norepinephrine (NE) administration are shown in
their proper time sequence as indicated by
arrows. The airway pressure was held constant
at 3 mm. Hg. A complete course of the drug
effect is thus traced out as the NE dosage is increased from 1.1 fig./Kg./min. to 3.2 ju.g./Kg./
inin.; the points on the NE curve are numbered in the order of increasing dosage. Note
that the absolute value of PVR decreases with
an increasing dose of NE, since the increase
in A I P has produced vascular distention. In
spite of this decrease of PVR, the increase in
vascular wall tone caused by the drug is evident from comparison of the two curves. The
Arasomotor effect of the drug can be obtained
by subtracting the control values of PVR
from test values at corresponding A I P .
Figure 1 (bottom) shows the experiment
repeated in the same dog after the initial tone
in the pulmonary blood vessels was abolished
by means of hexamethonium* (4 mg./Kg.).
It can be seen that the control curve is now
relatively flat, indicating that the vascular bed
is apparently distended to some rigid limit
(which may include newly opened parallel
*Bistrium, E. E. Squibb & Sons, New York, New
York.
Circulation Research, Volume IX, November 1961
PULMONARY VASCULAR TONE
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vascular channels) and does not dilate with
further increase in AIP. The dose of NE was
increased from 0.65 /xg./Kg./min. to 3.1 ^.g./
Kg./min. in this experiment; the points on
the NE curve are numbered in the order of
increasing dosage.
The results from 11 dogs are shown in table
1. Only the control and test values obtained
at the same AIP (within 1 mm. Hg) are included in the table. There was a significant
overall increase of 27 per cent in PVR during
NE administration as compared with the control value (P < 0.01 by statistics of paired
data), which indicates active vasoconstriction
in the pulmonary vascular bed. Since each
value of PVR during NE administration was
compared with its corresponding control value
at the same AIP and the same airway pressure, the mechanical effects would be excluded. The vasoconstriction appears to be due
to a local effect of NE on the pulmonary vascular bed. Since NE produced S3'stemic hypertension in our experiments, this would tend
to produce a primary reflex dilation of the
pulmonary vascular bed.11
In figure 2, all the data from 11 dogs are
shown. A composite control curve was constructed by averaging 38 control values of:
PVR which fell within increments of 3 nun.
Hg in AIP. As noted previously,3 the slope
of: this control curve is steep initially and then
levels off, indicating a distended rigid state
of vessels as AIP increases. All values of PVR
(from 11 dogs) following NE administration
were then related (or normalized) to this composite control curve by means of the following
equation:
.. , -„„
PVRr X PVEco
normalized PVRr =
,
r Vxvoc
where PVKr = test value of PVR obtained
during NE administration, PVROc — original
control value of PVR, and PVR cr — control
value of PVR obtained from the composite
control curve at a corresponding AIP. In this
way, all data can be compared with one control curve. The test values lying above the
composite control curve would indicate active
vasoconstriction; those lying on the curve
would
indicate no effect; and those below the
Circulation Research. Volume IX, November 1961
]219
44• CONTJfOL
° NOR-EPI
403632-
fj
^24
o>
I
£
(T. 161284-
13
15
19
21
23
25
AIP (mm Hg)
Figure 2
Pulmonary vascular resistance (PVR) vs. average intravascular pressure (AIP) obtained from
11 dogs. The ainvay pressure was held constant
at 3 mm. Hg. A composite control curve was
constructed by pooling all control values of PVR.
The test values of PVR during norepinephrine
(Nor-Epi) administration were then compared with
this composite control curve. The figure also
includes 7 additional test points not included
in table 1. The matching control values for these
test points were estimated first from the control
curve of the same dog and then normalized for
comparison with the composite control curve.
control curve would indicate active vasodilation. Since most of the points lie above the
composite control curve, the overall effect during NE administration is active vasoconstriction in the pulmonary vascular bed. For
purposes of this discussion, it would be interesting to consider a test value of PVR lying
above the composite control curve but below
the broken line which indicates the initial
control value* of PVR. Now, if this test value
is compared with the initial control A'alue of
*The initial control value of PVE was cliosen
between 8 iind 9 mm. Hg AIP, since this would he
the approximate value of AIP in a control dog
prior to any infusion. It is important to note tli:it
such a control value would tend to fall on the steep
part of the PVR-vs.-AIP control curve.
PATEL, MALLOS, FEEITAS
1220
Table 1
Besults from Eleven Dogs"
State
AIP
mm. Hg
iP
mm. Hg
Flow
L./min.
C
NE
19
20
23.5
29.4
1.59
1.36
14.8
21.6
+ 6.8
C
NE
13
13
9.7
8.2
0.93
0.84
10.4
9.8
-0.6
3
C
NE
17
17
13.2
15.6
0.97
0.96
13.6
16.3
+2.7
4
C
NE
36
16
14.3
27.0
0.98
1.11
14.6
24.4
+9.8
5
C
NE
9
8
12.3
11.0
0.51
0.42
24.1
26.0
+1.9
6
C
NE
10
10
13.6
13.5
1.19
1.09
11.4
12.4
+1.0
7
C
NE
20
20
19.5
10.7
1.11
0.59
17.5
18.1
+0.6
8
C
NE
11
10
8.1
17.6
1.62
2.12
5.0
8.3
+3.3
9
C
NE
14
14
15.8
18.8
1.51
1.60
14.2
15.9
+1.7
C
C
13
13
13.2
13.2
1.50
1.80
8.8
7.3
NE
NE
13
13
21.3
7.3
1.10
0.97
26.3
7.5
C
C
13
19
21
14
19
21
16.2
16.2
21.7
20.6
24.3
30.9
1.68
2.70
3.17
2.00
2.71
3.86
9.7
6.0
6.8
10.3
9.0
8.0
Dog
no.
1
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.10
11
c
PVR
mm. Hg/L./min.
Difference
in PVR NE-C
+8.9
average
+1.6
average
NE
NE
NE
*Only control and test values obtained at the same average intravascular pressure (within
1 mm. Hg) are included in the table.
AIP =: average intravascular pressure; A P = pulmonary artery pressure—left-atrial
pressure; PVE = pulmonary vascular resistance; C = control; NE = norepinephrine.
PVR, as indicated by the broken line, a decrease in PVR will be noted. This could be
erroneously considered as indicative of active
vasodilatation. However, if the corresponding
control value of PVR obtained at the same
AIP is chosen for comparison, the passive effect is excluded and the PVR is shown to increase, indicating active vasoconstriction.
Therefore, it follows that even a qualitative
statement regarding the vasoactive drug effect
cannot be made in studies in which, during
administration of a drug, PVR decreases in
the presence of a rise in transmural pressure,
or vice versa, as compared with the control
value.1- '--15 With the help of figure 2, one
could partly explain the existing discrepancy
in the literature regarding the effect of NE
on PVR. Patel et al.18 showed an increase in
PVR during NE administration in man. Fowler et al13 reported that XE produced a variable effect on PVR in man, i.e., NE increased,
decreased, or did not change PVR. Since both
mean PA and LA pressures increased during
NE administration in Fowler's study, it is
conceivable that an increase in PVR during
NE administration might have been obtained
Circulation Research, Volume IX, November 1961
PULMONARY VASCULAR TONE
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in all their subjects had comparisons been
made with control values obtained at the same
transmural pressure.
Pulmonary vasomotor changes following
drug administration have also been more directly demonstrated by several workers. Patel
and Burton17 demonstrated vasoconstriction
iu small pulmonary arteries of the rabbit by
means of arterial plastic casts made following
administration of large doses of NB. Borst et
al.4 tested the effect of a drug in one lung of
a dog while the other lung served as control.
Vasomotor activity was inferred from redistribution of blood flow to the two lungs rather
than from changes in PVR. The transmural
pressure was allowed to vary in this study.
Neither of these methods,4'17 although, indicative of vasomotor changes in their respective
preparations, is suitable for application to the
intact animal or man. However, the present
technique can easily be modified for human
application, since the LA pressure can now be
conveniently monitored by the transseptal
left-heart catheterization,18 the PA pressure
by right-heart catheterization, and the pulmonary blood flow may be obtained by the indicator-dilution method. The intrapleural pressure may be monitored, and the patient may
hold his breath, at a fixed point in the respiratory cycle (e.g., at quiet end-expiration). The
pulmonary vascular pressures may be raised
by infusion of dextran or blood to establish
the control curve for AIP vs. PVR. It is realized that to raise these pressures significantly,
one may require a large amount of infusion.
However, Werko10 has been able to raise the
mean PA pressure up to 15 mm. Hg in normal
human subjects by means of dextran infusion.
Thus, it appears feasible to obtain complete
control and test curves of AIP vs. PVR in
man, holding the intrapleural pressure, intraalveolar pressure, and the lung volume constant. This could provide a clearer picture of
the vasoactive and mechanical drug effects.
Summary
The effect of norepinephrine (NE) on pulmonary vascular resistance (PVR) was studied in 11 thoracotomized dogs. Comparisons
Circulation Research, Volume IX, November 1961
1221
between the test and control states were made
at corresponding average intravascular pressures in the pulmonary vascular bed and at
the same airway pressure. A significant increase in PVR (P < 0.01) suggesting active
vasoconstriction was found during NE administration.
Acknowledgment
We are thankful to Dr. Donald L. Fry for his
guidance through this research, and to Drs. Donald
P. Schilder and Leon I. Goldberg for their help.
References
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PATEL, MALLOS, FREITAS
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Circulation Research. Volume IX, November 1961
Importance of Transmural Pressure and Lung Volume in Evaluating Drug Effect on
Pulmonary Vascular Tone
DALI J. PATEL, ALEXANDER J. MALLOS and FLAVIO M. DE FREITAS
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Circ Res. 1961;9:1217-1222
doi: 10.1161/01.RES.9.6.1217
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