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_ Copyright, 1968, by the Society for Experimental Biology and Medicine.
Reprinted from PRocesDINGS oF THE Soctery Yor ExPERIMENTAL BioLogy AND MEDICINE,
1963, v113, 18-20

Effect of Glyceryl Trinitrate on Pulmonary Vasculature of
Anesthetized Dogs.* (28263)

ALAN L. PInKERSON, PETER A. Kor AND Donatp M. KNowLan
(Introduced by John C, Rose)

Department of Physiology and Biophysics, Georgetown University School of Medicine, and F.A.A.
Clinical Research Institute, Washington, D. C.

Following administration of glyceryl trihi-
trate (GTN) pulmonary artery pressure has
been observed to increase, decrease, or re-
main unchanged. Since GTN is a smooth
muscle relaxant, like the nitrites, the expected.
response is a decrease in vessel tone with re-
duction of pulmonary artery pressure. The
variation from this expected result has been
attributed to effects on the heart or systemic
circulation(1) or to an anomalous action of
vasoconstriction on pulmonary blood vessels
(2). In the present study, 2 types of cardiac
by-pass experiments were used to demonstrate
the direct effect of GIN on the pulmonary
blood vessels and to clarify the effects of ex-
trapulmonary factors in the pulmonary vascu-
lar response.

Methods. Eighteen mongrel dogs weigh-
ing 10 to. 20 kg were studied under pentobarbi-
tal (25 mg/kg) or chloralose (80 mg/kg)
anesthesia. A left thoracotomy was performed
and all animals were studied with chest open
and on positive pressure respiration. Poly-
ethylene catheters were placed in the pulmon-
ary artery, left atrium, distal aorta and endo-
tracheal tube. Pressures were recorded with
strain gauge transducers and a multichannel
direct writing oscillograph. A Walton-Brodie
strain gauge arch was sutured to the surface
of the right ventricle for observation of
changes in myocardial contractile force. Single
injections of GTN (25 or 50 pg/kg) were
given into the right ventricle or main pulmon-
ary artery.

After control injections with instantaneous
and mean pressure recordings, the right or
left ventricle was by-passed using a mechani-
cal pump previously described(3). The pump
maintains a constant preset output against re-
sistances up to 700 mm Hg and delivers puls-

+ Supported in part by a grant from Nat. Heart
Inst., U.S.P.HS.

atile flow at a preselected stroke volume and
rate which can be varied over a wide range.
The pump inlet was connected to the left or
right atrium and output to the descending
thoracic aorta or main pulmonary artery re-
spectively. The left or right ventricle was
thus eliminated from the general circulation.
With the mechanical pump in place, similar
injections and recordings were performed as
in the control animals. In selected cases flow
was measured with an ultrasonic flowmeter
connected into the tube leading from the left
atrium to the ventricular by-pass pump.
Results. In 12 control animals with intact
circulations, following injection of GTN into
the right ventricle or main pulmonary artery,
there was a delay of 6 to 12 seconds before
the onset of systemic hypotension. During
this time there was no change or a slight fall
in pulmonary artery pressure. As systemic
pressure declined, however, pulmonary artery
mean pressure rose an average of 2 mm Hg
above baseline values in 11 of the 12 animals
(Table I) with a simultaneous increase in
myocardial contractile force and heart rate
(Fig. 1). After the systemic pressure

TABLE I, Effect of GTN on Mean Pulmonary
Artery Pressure in 12 Dogs Before and After Left
Ventricular By-Pass.

With L. V. by-pass

Before L, V. by-pass

MaxAP, % MaxAP, %
DogNo. mmHg’ change mmHg change
1 +4 +18 6 -19
2 +2 +11 5 -17
3 +2 +33 -3 23
4 +2 +29 -2 -
5 +2 +40 2 12
6 +2 422 a -7
T +2 +40 2 15
8g +2 +14 6
9 +1 5 2
10 +3 +16 6
11 0 0 4
12 +1 +6 2
+241 342



GLyceryL TRINITRATE ON PULMONARY VASCULATURE

. .
ee |

FIG. 1. Representative tracings of myocardial

contractile force, pulmonary artery pressure, and

femoral artery pressure taken before (top 3 trac-

ings) and after (lower 3 tracings) left ventricular

by-pass. Arrows mark time of injection of-GTN
25 ug/kg into right ventricle.

ED

reached its lowest values (at 15-34 seconds)
all parameters gradually returned to baseline
values. The left atrial pressure followed the
changes in pulmonary artery pressure but
were smaller.

After left ventricular by-pass the initial in-
terval from the time of injection of GTN to
the onset of systemic hypotension was prolong-
ed an additional 9 to 29 seconds. During this
initial interval while the drug was still con-
fined to the pulmonary circuit there was now
a consistent and significant fall in pulmonary
artery pressure (Table I). As systemic pres-
sure fell there was an increase in myocardial
contractile force and a slight rise in pul-
monary artery pressure (Fig. 1). There were
no associated changes in left atrial or endo-

tracheal pressures. When flow was measured
in the left atrial tube as an indication of total
pulmonary blood flow, there was no change or
a minimal increase of up to 50 cc/min.

In 6 animals with right ventricular by-pass
and constant flow into the lungs, pulmonary
artery pressure decreased following the injec-
tion of GIN. There was no rise in pulmonary
artery pressure coincident with the fall in
systemic pressure as seen in the control ani-
mals.

Discussion. The response of the pulmon-
ary circulation to vasodilating agents is, as a
general rule, moderate. Pulmonary vasodila-
tation when present can easily be obscured by
action of the drug on other segments of the
circulation or heart. With the technique of
left ventricular by-pass, due to the prolonged
circulation time from the left atrium to aorta,
the pulmonary circuit can be isolated for a
short interval in time from the systemic cir-
culation without disruption of blood flow or
nerve supply to the lungs. The direct action
of the drug on the pulmonary blood vessels
following injection into the main pulmonary
artery or right ventricle can be seen before it
reaches the systemic circulation or heart(4).

Following GTN injection into the right ven-
trice or main pulmonary artery with the
mechanical pump connected between the left
atrium and aorta there was an interval of 15
to 41 seconds before any evidence of drug ef-
fect was noticeable on the systemic circula-
tion. During this time while GTN action was
confined to the pulmonary circuit there was
a consistent and significant fall in pulmonary
artery pressure without change in left atrial
pressure or change in flow from the left atrial
tube. This decrease in pulmonary artery pres-
sure immediately following GTN administra-
tion indicates a direct effect of the drug to de-
crease pulmonary vascular resistance.

In animals with an intact circulation, the
increase in pulmonary artery pressure after
injection of GTN has been explained on the
basis of increased pulmonary blood flow(5).
To test this hypothesis experimentally the
mechanical pump which was set to deliver a
fixed stroke volume at a fixed rate was sub-
stituted for the right ventricle and baseline


pressures recorded. The remainder of the
circulation was left intact. Following injec-
tion of GTN into the pump outflow, essen-
tially the main pulmonary artery, no rise
above baseline pulmonary artery pressure was
seen. In fact the pulmonary artery pressure,
left atrial pressure and pressure fall across the
lungs decreased. This indicates that the in-
creased pulmonary artery pressure seen with
the intact right ventricle is due to increased
blood flow. At this time, after injection of
the drug, the pulmonary vascular resistance
is in fact decreased. The increased myocar-
dial contractile force and tachycardia seen co-
incident with the increase in pulmonary ar-
tery pressure also are consistent with an as-
sociated increased output from the right ven-
tricle.

Summary. The effect of GTN on tne pul-
monary vasculature was tested in animals

with an intact circulation, with a mechanical
pump substituted for the left ventricle and
with the pump by-passing the right ventricle.
‘The results of the experiments indicate that in
anesthetized dogs the direct effect of GIN in
the pulmonary circuit is to decrease pulmon-
ary vascular resistance. The observed increase
in pulmonary artery pressure in intact dogs
following the injection of GTN is due to in-
creased pulmonary blood flow.

1. Aviado, D. M., Pharm. Rev., 1960, v12, 159.

2. Hefner, L. L., Friedman, B., Reeves, T. Ja
Eddleman, E. E., Harrison, T. R., Circulation, 1987,
v5, 111.

3. Rose, J. C., Broida, H. P., Hufnagel, C. A.
Gillespie, J. F., Rabile, P. J., Freis, E. D., J. Appl.
Physiol., 1958, v7, 580.

4, Rose, J. C., Freis, E. D., Am. J. Physiol., 1957,
v191, 283.

8. Wiggers, C. J., J.A.M.A,, 1918, v70, 508.

Received March 4, 1963. P.S.E.B.M., 1963, v113.

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