PROSTAGLANDIN E 1 INHIBITS THE PULMONARY VASCULAR PRESSOR RESPONSE TO HYPOXIA AND PROSTAGLANDIN F2~ E.K. Weir, M.R.C.P. J.T. Reeves, M.D. R.F. Grover, M.D. Cardiovascular Pulmonary Research Laboratory Division of Cardiology, Department of Medicine University of Colorado Medical Center

(Abs ira ct) In the anesthetised dog an infusion of exogenous prostaglandin E1 (100~G/min) inhibits the pulmonary vascular pressor response to hypoxia. Both 25 and 1 0 0 ~ C ~ m i n PGE 1 can reduce the transient pulmonary hypertension caused by a bolus of prostaglandin F2~. This suggests that hypoxia and P G F 2 ~ m a y share a final common pathway in producing pulmonary vasoconstriction. These results may help to explain the mechanism by which endotoxin inhibits the pulmonary vascular response to hypoxia. This effect is probably achieved by stimulating the production of an endogenous dilator prostaglandin. Exogenous PGE 1 can mimic this effect.

This work was supported by grants #HL 14985 and HL 05973 from the National Institutes of Health. Dr. Weir is the recipient of a Fulbright Scholarship. Dr. Grover is the recipient of an NIH Research Career Development Award #HL 29237. We are grateful for the assistance of R. Glas, B. Kaplan, M. Munroe, D. Smith, E. Toyos, S. Hofmeister and D. Jackson. Prostaglandins E1 and F2~ were kindly provided by the Upjohn Company. Address for mailing proofs:

Dr. E.K. Weir Cardiovascular Pulmonary Research La bora tory University of Colorado Medical Center 4200 East Ninth Avenue Denver, Colorado 80220

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INTRODUCTION A minute intravenous dose of endotoxin (15~G/Kg) will abolish the pulmooary arterial pressor response to hypoxis in the anesthetised dog. ± This effect can be completely prevented b~ prior administration of either indomethaein or meclofenamate. The fact that these two chemically dissimilar inhihitors of prostaglandin synthesis achieve the same result suggests that endotoxin might oppose the pressop response to hypoxia by stimulating the production of a dilator prostaglandin. Larger doses of endotoxin, sufficient to cause shock in dogs, lead to the appearance of prostaglandin A1 in the plasma and probably increase prostaglandin E 1 (PGEI)3 Degradation of PGE 1 is reduced during endotoxin shoek.q PGEI is known to lower normoxic pulmonary vascular resistance in man,5 dogs,6,7 cattle,8 swine, 9 and fetal goats.10 It seemed possible, therefore, that endogenous production of a dilator prostaglandin, such as PGEI, might be the mechanism initiated by endotoxin. We wished to determine if an exogenous infusion of PGEI would mimic the effect of endotoxin by reducing the pressor response to hypoxia.

METHODS Ten mongrel dogs of either sex (mean weight 19 + 1 Kg) were anesthetised with sodium pentobarbital (30 mgs/Kg) a~d allowed to breathe 30~ oxygen in nitrogen spontaneously. Two polyethylene catheters (PE 200) were advanced from the femoral arteries to the descending aorta. Two catheters (PE 160) were placed in the superior vena cava via the right jugular vein and another was placed in the pulmonary artery. A Swan-Ganz balloon-tipped catheter was also introduced from the right jugular vein and advanced to a peripheral branch of the pulmonary artery. Pulmonary arterial, wedge and aortic pressures were measured using Statham P23 Db pressure transducers and a Nova 1200 digital computer, which records on demand the average mean pressures for 20 heartbeats. Cardiac output was determined by injecting 1.25 mg of indocyanine green dye into the superior vena cava and withdrawing blood from the aorta, at 20 ml/minute, through a Waters cuvette densitometer. The cardiac output was computed on-line by the Nova computer which uses a semi-logarithmic replot of the displayed dye curve. Pulmonary resistance was calculated as mean pulmonary arterial pressure minus mean wedge pressure (mmHg) divided by cardiac output (L/minute). Systemic arterial oxygen, carbon dioxide and pH were measured by Radiometer electrodes and corrected to the oesophageal temperature. The changes in these variables in response to ten minutes of isocapnic hypoxia were recorded. Pressures were measured every minute, cardiac outputs at five and ten minutes, and blood gases at ten minutes of hypoxia. The inspired oxygen percentage (PIO2 9 ~ , was determined by a fuel-cell oxygen analyzer 0~eil, Sodal and Speck, 1967). Barometric pressure at Denver (1600 m)

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is 630 mmHg. The end-expiratory carbon dioxide was monitored by a Beckman gas analyzer and maintained constant by the addition of carbon dioxide during hypoxie hyperventilation. After return to control values while breathing the normoxic mixture, the pulmonary arterial pressure response to an intravenous bolus of prostaglandin F2~ (PGF2~) 2~G/Kg, was recorded. Following return to baseline pressures an infusion of ~5 ug/min PGE 1 was commenced in five dogs and 100 ug/min in the remaining five dogs. Fifteen minutes after the start of the infusion the hypoxic challenge was repeated. The infusion was continued throughout the hypoxia, a recovery period of about ten minutes and a further challenge with PGF2~. Thirty minutes after the end of the infusion the hypoxic challenge was repeated again. Thus the sequence was hypoxia, PGF2 ~, hypoxia and PGF2~ during PGE 1 infusion, and hypoxia. The two doses used were chosen from pilot experiments because they reduced (25N G/min) or totally inhibited (100 m G/min) the presser response to hypoxia.

STATISTICS Each dog was its own control. The response to hypoxia is given as the mean of the data st five and ten minutes. The first response to hypoxia or PGF2m in each group of five dogs is compared with~their response during PGEI infusion by the two-tailed paired T test. Comparison is not made with the control response to hypoxia after the infusions. The data are shown as the mean and standard error of the mean. Differences are considered to be significant when p < . 0 2 .

RESULTS Infusion of PGE I at the rate of i00 ~G/min caused no significant change in the normoxic pulmonary arterial pressure or resistance. However, during hypoxia the absolute levels of pressure and resistance attained (Table I) and the increase in both variables (Figure i) were considerably reduced.

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Infusion of PGE I at the lower rate of 2 5 M G / m i n only caused a reduction in the absolute pulmonary arte@ial pressure reached during hypoxia (Table I). The fall in pulmonary pressure was not signifieant. "

TABLE I PGE 1 reduces the pulmonary vascular pressor response to hypoxia

Co*~trol n=lO

FC].E1 25~G/min n=5

PaCO2

4.6_+.4

45!4

8g+4

42_+2

3.5!.3 8.4-+.7

46+3

32!2

37+2

2.9-+.5

33-+7

79-+5

45-+3

P sys mm]l~_

Normox~a

i7+i

140_+5

3.2+.3

}lypoxia

32!3

158+7

NormoxJa

14!I

Hypoxia

22!3~ 112-+9" 3.2!.5 6.8-+.q 35-+6

28-+2 40!3

15!;

78!8

Normoxia pGE1 10~G/mln n=5 Hypoxia

Control n=lO

TSR mml{~/ PaO2 L/mi,1 mmllq

gq-+7*

C.O. IJmin

FVR .z~IK/ L/rain

Ppa m.~l~

86113* 2.q!.4

4.6-+.6

5.7!.6 37-+5

qg-+6

17-+1" 93-+13" 3.0-+.3 5.0!.2" 32-+4" 26-+4 q6-+3

Normo×ia

17~I

ii~I~2

2.8~.3

5.6Z.4

42_+6

80~2

W5~3

HypoxJa

34~2

134~5

3.8~.4

8.5~.7

35~4

28~2

40~3

The variables measured were pulmonary arterial pressure, Ppa; pulmonary arterial wedge pressure, Pwedge; systemic arterial pressure, Psys; cardiac output, C.O.; pulmonary vascular resistance (Ppa-Pwedge), PVR; total systemic CO resistance, TSR; systemic arterial oxygen tension, PaO2. (Inspired oxygen tension in Denver (1600 m) is 120 mmHg); and systemic arterial carbon dioxide tension PaCO 2. * p 4 0 . 2 for differences from corresponding data in first control.

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FIGURE 1

PGE1 INFUSION REDUCES THE PULMONARY VASCULAR RESPONSE TO HYPOXIA 20, PULMONARY ARTERIAL PRESSURE RISE DURING

15,

1 I

P:NS

HYPOXIA mm Hg

I

10'

I

6~ PULMONARY VASCULAR RESISTANCE CHANGE DURING HYPOXIA mm

Hg/l/min

4,

P:NS

2' P¢.02 0..

-2'

Y CONTROL

PGE;

25~4g/min n:

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PGE I |OO~g/mln

CONTROl,

5

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Both levels of infusion resulted in a fall in normoxic and hypoxic systemic arterial pressures. However cardiac output also showed a tendency ~or~significant) to decrease during the infusions. Consequently the only significant reduction in systemic arterial resistance was observed during the combination of hypoxia and the infusion of PGE 1 i00~ G/min (Table I). The severity of the hypoxic challenge was not significantly different during the control and infusion parts of the experiment, in terms of systemic arterial oxygen, carbon dioxide and pH. However, when the PGE 1 was being given), there was a tendency for the oxygen tension to be lower snd the carbon dioxide tension to be higher during both normoxia and hypoxia. This occurred despite the fact that the normoxie and hypoxic gas mixtures were the same before and during the infusions. Both infusions of PGE 1 reduced the increase in pulmonary

arterial pressure caused by a bolus injection of prostaglandin F2~ (2~ G/Kg). The absolute pressure attained was also lower (Table II).

TABLE II PGE 1 reduces the pulmonary arterial pressor response to PGF2~ (2 ~ G/Kg)

Baseline Ppa n=5

n=5

PGF2z

Increase in Ppa

Control

17 + 2

38 + 2

21 + 3

PGE 1 25~G/min

14 ~ i

22 ~ 2*

Control

15 + 1

30 + 2

15 + 2

PGE 1 100MG/min

IB ~ 1

23 ~ 2-

i0 ~ i*

8 ~ i*

Ppa; pulmonary arterial pressure, mmHg *

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p