Effect of prostaglandin E2 on pulmonary vascular resistance in intact dog, swine and lamb

European Journal of Pharmacology, 31 ( 1975 ) 72--80 © North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands

E F F E C T O F P R O S T A G L A N D I N E2 O N P U L M O N A R Y V A S C U L A R R E S I S T A N C E I N I N T A C T D O G , SWINE A N D L A M B 1 PHILIP J. KADOWITZ2, PAUL D. JOINER and ALBERT L. HYMAN Cardiopulmonary Laboratory, Departments of Pharmacology and Surgery, Tulane University, School of Medicine, New Orleans, Louisiana 70112, U.S.A. Received 5 November 1973, revised MS received 16 September 1974, accepted 6 December 1974

P.J. KADOWITZ, P.D. JOINER and A.L. HYMAN, Effect of prostaglandin E2 on pulmonary vascular resistance in intact dog, swine and lamb, European J. Pharmacol. 31 (1975) 72--80. The effects of prostaglandin E2 (PGE2) on pulmonary vascular resistance in the intact dog, swine and lamb were studied using a right heart catheterization technique to isolate and perfuse the left lower lung lobe at controlled blood flow. Infusion of PGE2 into the lobar artery increased lobar arterial perfusion pressure but did not alter pressure in the left atrium in all 3 species. The increase in lobar arterial pressure was associated with a rise in pressure in the small intrapulmonary lobar vein in the dog but no change in pressure in these veins in the swine and lamb. Infusion of PGE2 into the iliac artery produced a marked decrease in perfusion pressure in the hindlimb of the dog. The effects of PGE2 on the canine lung occurred in the absence of any significant change in arterial blood gases, pH, hematocrit or rate and volume of respiration, and this substance increased pulmonary vascular resistance when the lung was perfused with dextran instead of blood. These results show that in dog, swine and lamb, PGE2 increases pulmonary vascular resistance; however, the site of vasoconstriction is different in the dog and swine or lamb. In the swine and lamb vasoconstriction occurred primarily in vessels upstream to the small veins, presumably small arteries, whereas in the dog lung, the pre- and postcapillary vessels were actively constricted by this naturally occurring substance. Pulmonary vascular resistance Right heart catheterization

Swine Lamb

Venoconstriction Vasoconstriction

1. I n t r o d u c t i o n P r o s t a g l a n d i n E~ is a n a t u r a l l y o c c u r r i n g acidic lipid w h i c h is s y n t h e s i z e d in the lung f r o m essential f a t t y acid p r e c u r s o r s b y the enz y m e p r o s t a g l a n d i n s y n t h e t a s e (.;imgg~rd and Samuelsson, 1 9 6 5 ; N u g t e r e n et al., 1 9 6 6 ; van D o r p , 1 9 6 6 ) . Prostaglandins E2 and F2~ are released f r o m the lung b y a variety o f stimuli i n c l u d i n g h y p e r i n f l a t i o n , a n a p h y l a x i s and emb o l i z a t i o n ( L i n d s e y and Wyllie, 1 9 7 0 ; Palmer 1 Supported by U.S. Public Health Service Grants HL 11802 and HL 15580 and a grant from the American Heart Association. 2 This work was done during the tenure of an established investigatorship of the American Heart Association.

Prostaglandin E2 Hindlimb

Dog

et al., 1 9 7 0 ; Piper and Vane, 1 9 6 9 ; Berry et al., 1 9 7 1 ; a n d Said, 1973). In a d d i t i o n to synthesis a n d release, the lung is a m a j o r organ f o r t h e m e t a b o l i s m o f these lipids and prostaglandins o f the E a n d F t y p e are a l m o s t completely inactivated d u r i n g a single passage t h r o u g h the p u l m o n a r y c i r c u l a t i o n (Ferreira and Vane, 1 9 6 7 ; Piper et al., 1 9 7 0 ; McGiff et al., 1 9 6 9 ) . A l t h o u g h t h e effects o f PGE2 on the s y s t e m i c c i r c u l a t i o n have been s t u d i e d extensively, t h e effects o f this lipid on the pulm o n a r y c i r c u l a t i o n have been t h e o b j e c t o f f e w studies and these results are inconclusive since p u l m o n a r y b l o o d f l o w was n o t c o n s t a n t (BergstrSm et al., 1 9 6 8 ; H o r t o n , 1 9 6 9 ; Nakano, 1 9 7 3 ; Said, 1 9 6 8 ; Alpert et al., 1973). In a d d i t i o n , t o the best o f o u r k n o w l e d g e no-

PGE2 AND PULMONARY VASCULAR RESISTANCE

thing is known about the effects of PGE2 on the pulmonary veins. The purpose of the present investigation was to study the effects of PGE2 on the pulmonary circulation with emphasis on the pulmonary veins since endogenously released prostaglandins have been detected in the pulmonary venous effluent (Lindsey and Wyllie, 1970; Palmer et al., 1970). The effects of PGE2 on pulmonary vascular resistance were evaluated in the intact dog, swine and lamb under conditions of controlled blood flow using a new right heart catheterization technique. In addition, the effects of this substance were contrasted in the pulmonary and hindlimb vascular beds in the dog.

2. Materials and methods For studies on the pulmonary circulation, mongrel dogs weighing 15--22 kg, swine weighing 48--80 kg, and lambs weighing 26-32 kg, were anesthetized with pentobarbital sodium 30--45 mg/kg i.v. and were strapped

Pu~P~

Fig. 1. Diagram showing the right heart catheterization procedure in the intact dog, swine and lamb. The lobar arterial perfusion catheter is introduced from the external jugular vein into the artery of the left lower lobe and the lobe is perfused at controlled flow with blood withdrawn from the right atrium. Pressure in the lobar vein is measured with a small teflon catheter placed transseptally into an intrapulmonary lobar vein 2--3 mm in diameter.

73

to a fluoroscopic table. Supplementary doses of anesthetic were given when needed to maintain a uniform level of anesthesia. A spec i a l l y designed double lumen 20F balloon c a t h e t e r was introduced from the external jugular vein into the arterial branch of the left lower lung lobe under fluoroscopic guidance. A 0.9 mm teflon cathether with its tip positioned about 2 cm from the tip of the balloon catheter was used to measure pressure in the perfused lobar artery. Catheters with side holes were passed into the main pulmonary artery and femoral artery and into a small lobar vein and the left atrium transseptally. Special precautions were used to ensure that pressure measurements were made in lobar veins 2--3 mm in diameter without wedging. Briefly, a 0.9 mm teflon catheter having side holes near its tip was passed through a 3 mm catheter that had been previously wedged in a small intrapulmonary lobar vein. The 0.9 mm catheter was then withdrawn 1--3 cm from the wedge position until pressure dropped abruptly. It was then fixed in place with a cope adaptor after the 3 mm catheter had been withdrawn to the left atrium. When contrast media was injected into the 0.9 mm catheter it returned rapidly to the left atrium showing t h a t the vein was not obstructed. The position of these catheters is shown in fig. 1 and the methods have been described previously (Hyman, 1969a; Hyman et al., 1971). All pulmonary vascular pressures were measured with Statham P23D transducers zeroed at the level of the right atrium and recorded on an oscilloscopic recorder model DR-8 (Electronics for Medicine, Inc., White Plains, N.Y.}. Mean pressures were obtained from the pulsatile signal by electrical averaging. The trachea was intubated with a cuffed endotracheal tube and the animals spontaneously breathed room air enriched with oxygen. The rate and volume of respiration were measured with a Wrights Respirometer. After all catheters were positioned and the animals heparinized (500--1000 units/kg), the balloon on the perfusion catheter was distended with 2--4 ml Hypaque ® (sodium diatrizoate, 50%

74 Winthrop Labs) until pressure in the lobar art e ry and lobar vein decreased to near left atrial pressure. The lower left lung lobe was then perfused with a Sarns roller p u m p (model 3500) with blood withdrawn f r om the right atrium. The o u t p u t of the p u m p was adjusted so t h at pressure in the lobar artery approximated pressure in the main p u l m o n a r y artery. The pumping rate averaged 150 ml/min in the lamb, (mean +S.E.) 268 -+ 31 ml/min in the dog, and 279 ± 80 ml/min in the swine and was n o t changed during the experiment. Blood gases and p H were measured with a Rad i o m e t e r Analyzer. Control arterial blood gases, p H and h e m a t o c r i t {mean -+ S.E.) were pO2, 101 + 9 mm Hg; pCO2, 44 + 4 mm Hg; pH 7.36 + 0.03; h e m a t o c r i t 44 -+ 2 in the dog. A standard lead II electrocardiogram was monitored on the DR-8 recorder. Blood flow in the normally perfused lung lobes was determined by the dye-dilution technique. CardioGreen ® (indocyanine green Hynson, Westcott and Dunning, Inc.) was injected into the main p u l m o n a r y artery and the dye c o n c e n t r a t i o n in aortic b lo o d was measured with a Gilford Densitometer. The dye curves were recorded on the DR-8. For hindlimb studies, a second group of 8 mongrel dogs weighing 11--19 kg were anesthetized with pentobarbital sodium 30 mg/kg i.v. Systemic arterial pressure was measured through a cath eter inserted in the carotid artery. Drugs were injected through a catheter in the jugular vein. After administration of heparin, 500 units/kg i.v., the left iliac artery was perfused by a Sigmamotor p u m p with blood withdrawn f r o m the abdominal aorta. The pumping rate was adjusted so that iliac arterial perfusion pressure a p p r o x i m a t e d systemic arterial pressure. The flow rate averaged 110 ml/min in these experiments. Systemic arterial and iliac arterial pressures were measured with Statham transducers (P23AC) and recorded on a Grass polygraph. Prostaglandin E2, The Upjohn Company, Kalamazoo, Mich., was dissolved in 95% ethyl alcohol, 2 mg/ml, and stored in a freezer. On the day o f use, an aliquot of the stock solu-

P.J. KADOWITZ ET AL. tion was diluted with saline and infused into the lobar artery at 20 gg/min or iliac artery at 5 pg/min at a volume of 0.1 ml/min for a period of 10 min with a Harvard infusion pump. The h e m o d y n a m i c data were evaluated using methods described by Snedecor (1956) for paired and group comparisons. A p-value of less than 0.05 was considered significant.

3. Results The effects of PGE2 on the p u l m o n a r y circulation in the intact spontaneously breathing dog are shown in figs. 2 and 3. Infusion of PGE2, 20 pg/min, into the lobar artery increased lobar arterial pressure significantly. The onset of the rise in pressure was rapid (30--60 sec) and pressure rose sharply during 25

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Fig. 2. Effect of infusion of PGE2, 20 pg/min, into lobar artery on lobar arterial pressure, lobar venous pressure and left atrial pressure in the dog. PGE2 was infused for a 10 min period, n indicates number of dogs tested and refers to all parameters.

PGE2 AND PULMONARY VASCULAR RESISTANCE

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Fig. 3. Effect of infusion of PGE2, 20 pg/min into the lobar artery on aortic pressure, main pulmonary arterial pressure, pulmonary blood flow and calculated pulmonary vascular resistance in the dog. n indicates number of dogs tested and refers to all parameters.

the first 2 min after which steady state was reached and pressure was well maintained or increased slowly during the rest of the 10 min infusion period. Pressure was increased from a preinfusion value of (mean + S.E.) 18.0 + 1.9 to 22.5 +- 1.7 m m Hg at 10 min (fig. 2). The rise in lobar arterial pressure was accompanied by a significant increase in pressure in the small intrapulmonary vein but no change in left atrial pressure. Venous pressure increased

75 from 11.3 + 0.9 to 15.0 + 1.2 mm Hg 9 min after the onset of PGE 2 infusion (fig. 2). During infusion of PGE2, pressure in the aorta decreased from 110 + 7 in the control period to 81 -+ 8 mm Hg 8 min after the beginning of the infusion (fig. 3) but pressure in the main pulmonary artery was unchanged. Blood flow to the left, middle, and upper lobes and the right lung lobes was decreased from 1.6 + 0.1 to 1.23 + 0.2 1/min at the end of the infusion period (fig. 3). Since pressures in the main pulmonary artery and left atrium were unchanged while pulmonary blood flow decreased, calculated vascular resistance in the lung lobes perfused by the right ventricle increased from 11.4 + 1.5 to 15.3 + 2.1 mm Hg/ml/min at the end of the infusion period (fig. 3). There was no significant change in pO2, pCO2, pH or hematocrit or aortic blood at either 5 or 10 min after onset of the PGE2 infusion. In addition, there was no significant change in the rate or volume of respiration during the 10 min infusion period. Pressures in the perfused lobar artery and lobar vein returned toward control value after the prostaglandin infusion and these pressures were n o t significantly different from control 20 min after the infusion. Pulmonary blood flow in the normally perfused lobes returned toward control value after the infusion and , b l o o d flow and calculated pulmonary vascular resistance were n o t significantly different from control 20 min after the prostaglandin infusion. The effects of PGE 2 on the pulmonary vascular bed were evaluated in 2 other intact spontaneously breathing dogs in which the left lower lobe was perfused with dextran instead of blood. In these experiments the lung was perfused with warm low molecular weight dextran pH 7.4, and the perfused dextran was removed from the lobar vein by way of a transseptally placed 18F withdrawal catheter. During dextran perfusion PGE2 elicited a marked increase in lobar arterial perfusion pressure (table 1). These studies indicate t h a t the effects of PGE2 on the pulmonary vascular bed are n o t due to platelet aggregation or interaction with any formed element

P.J. KADOWITZ ET AL.

76 TABLE 1 Effect of PGE 2 on vascular pressures in the dog during dextran perfusion. Pressure (ram Hg)

Lobar artery Main pulmonary artery Left atrium Aorta

--2 min

--1 rain

0 min

1 min

2 rain

3 min

22 23 3 140

23 23 3 140

23 23 3 140

27 22 3 130

31 23 2 120

33 23 2 115

PGE2 100 pg/min n=2

since t h e s e e l e m e n t s are n o t p r e s e n t in t h e dextran perfusate. T h e e f f e c t s o f PGE2 o n the p e r i p h e r a l circ u l a t i o n were s t u d i e d in t h e h i n d l i m b vascular bed under conditions of controlled blood f l o w in a s e c o n d g r o u p o f 8 dogs. The infusion o f P G E 2 , 5 p g / m i n , i n t o t h e iliac a r t e r y p r o d u c e d a significant decrease in iliac arterial p e r f u s i o n p r e s s u r e (fig. 4). T h e o n s e t o f this e f f e c t was r a p i d a n d p r e s s u r e d e c r e a s e d sharply d u r i n g t h e first 2 m i n o f infusion a f t e r w h i c h a s t e a d y s t a t e was m a i n t a i n e d d u r i n g t h e rest o f t h e P G E : infusion. A f t e r the term i n a t i o n o f t h e infusion, pressure r e t u r n e d t o w a r d c o n t r o l level a n d was n o t significantly d i f f e r e n t f r o m c o n t r o l 20 min later. Administ r a t i o n o f P G E 2 i n t o t h e iliac a r t e r y p r o d u c e d

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n o significant c h a n g e in pressure in t h e a o r t a in t h e s e e x p e r i m e n t s (fig. 4). T h e e f f e c t s o f PGE2 o n t h e p u l m o n a r y circ u l a t i o n in t h e i n t a c t swine a n d l a m b were also s t u d i e d u n d e r c o n d i t i o n s o f c o n t r o l l e d b l o o d f l o w using right h e a r t c a t h e t e r i z a t i o n t e c h n i q u e s . I n f u s i o n o f P G E 2 , 20 p g / m i n , int o t h e l o b a r a r t e r y in 4 s p o n t a n e o u s l y breathing swine i n c r e a s e d l o b a r arterial pressure sign i f i c a n t l y (fig. 5). T h e o n s e t o f this e f f e c t in t h e swine was r a p i d a n d l o b a r arterial pressure rose progressively f o r 3 - - 4 m i n a f t e r which a s t e a d y s t a t e was r e a c h e d a n d pressure was m a i n t a i n e d d u r i n g the rest o f t h e infusion. L o b a r pressure rose f r o m 3 0 . 0 +- 5.4 to 38.3 -+ 6.7 m m Hg 3 m i n a f t e r o n s e t o f infusion (fig. 5). T h e rise in l o b a r arterial pressure in this species was a c c o m p a n i e d b y a r e d u c t i o n in aortic pressure f r o m 1 0 3 + 19 t o 84 -+ 16 m m Hg 9 m i n a f t e r t h e b e g i n n i n g o f t h e infusion b u t n o significant c h a n g e in pressures in t h e m a i n p u l m o n a r y a r t e r y , t h e small l o b a r vein or t h e l e f t a t r i u m (fig. 5). A f t e r t e r m i n a t i o n o f t h e p r o s t a g l a n d i n infusion, pressures in t h e l o b a r a r t e r y a n d a o r t a r e t u r n e d t o w a r d c o n t r o l value a n d 20 m i n a f t e r infusion, pressure in t h e l o b a r a r t e r y was n o t significantly d i f f e r e n t f r o m c o n t r o l whereas aortic pressure h a d n o t y e t r e t u r n e d t o c o n t r o l level. T h e effects o f PGE2 on p u l m o n a r y vascular resista n c e were s t u d i e d in 2 s p o n t a n e o u s l y b r e a t h ing l a m b s u n d e r c o n d i t i o n s o f c o n t r o l l e d b l o o d flow. In this species i n f u s i o n o f P G E 2 ,

PGE2 AND PULMONARY VASCULAR RESISTANCE

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77 o n s e t o f i n f u s i o n in t h e 2 animals a n d at t h e s e t i m e s pressure rose b y 5 a n d 6 m m Hg respectively. During i n f u s i o n o f PGE2 i n t o t h e l a m b , t h e r e was a small decrease in pressure in t h e a o r t a b u t little or n o c h a n g e in pressure in t h e m a i n p u l m o n a r y a r t e r y (table 2). Pressures in t h e l o b a r a r t e r y a n d a o r t a r e t u r n e d t o w a r d c o n t r o l value a f t e r t e r m i n a t i o n o f t h e p r o s t a g l a n d i n infusion. T h e m a x i m u m rise in l o b a r arterial pressure was 5 m m Hg in t h e l a m b , 8.5 + 1.3 m m Hg in t h e swine a n d 5.0 -+ 1 m m Hg in t h e dog.

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Fig. 5. Effect of infusion of PGE2 into the lobar artery on pressures in the aorta, lobar artery, main pulmonary artery, small lobar vein and left atrium in the intact swine, n indicates number of swine tested and refers to all parameters. 20 # g / m i n , i n t o t h e l o b a r a r t e r y increased l o b a r arterial p r e s s u r e b u t h a d little or n o eff e c t o n pressures in t h e small l o b a r vein or left a t r i u m (table 2). T h e p e a k increase in l o b a r arterial pressure o c c u r r e d 5 a n d 8 m i n a f t e r

Results o f t h e p r e s e n t s t u d y s h o w t h a t in t h e i n t a c t dog, swine a n d l a m b , P G E 2 increases l o b a r arterial pressure w h e n infused i n t o t h e l o b a r a r t e r y . Since b l o o d f l o w t o t h e lung l o b e was m a i n t a i n e d c o n s t a n t b y a p u m p a n d left atrial pressure did n o t change, t h e increase in l o b a r arterial pressure reflects an increase in p u l m o n a r y vascular resistance in all 3 species. Results o f studies in t h e d o g s h o w t h a t t h e increase in p u l m o n a r y vascular resista n c e o c c u r r e d in the a b s e n c e o f a c h a n g e in rate a n d v o l u m e o f r e s p i r a t i o n or p H , pO2 or pCO2 or h e m a t o c r i t o f arterial b l o o d . In addit i o n , t h e increase in p u l m o n a r y vascular resista n c e was similar in e x p e r i m e n t s in w h i c h t h e lung was p e r f u s e d with d e x t r a n or with b l o o d .

TABLE 2 Effect of PGE 2 on vascular pressures in the lamb. Pressure (mm Hg)

Lobar artery Main pulmonary artery Small lobar vein Left atrium Aorta

--2 min

0 min

2 rain

4 min

6 min

8 rain

10 min

30 rain

22 27

22 27

25 27

27 28

27 27

27 26

27 26

23 27

11 4 83

12 4 83

12 4 83

11 11 4 4 78 77 PGE2 20 pg/min

11 3 75

10 3 80

12 3 82

n=2

78 Hence, the effects of PGE2 on the pulmonary vascular bed are not due to platelet aggregation or to interaction with other formed elements in blood. The present data are consistent with results of studies in the dog and calf in which PGE2 increased calculated pulmonary vascular resistance (Said, 1968; Anderson et al., 1972). The effects of PGE2 on the pulmonary vascular bed appear to be independent of changes in b r o n c h o m o t o r tone since this substance did not change the compliance of the lung nor did it affect monitored respiratory parameters in the present study {Said, 1968). Furthermore, in preliminary studies the effects of PGE2 on normal non-respiring lung lobes were quite similar in the dog. The increase in lobar arterial pressure in response to PGE2 infusion was accompanied by a rise in pressure in the small intrapulmonary lobar vein in the dog. Analysis of mean pressure gradients across the canine lung indicate that the increase in resistance is due mainly to an increase in pressure gradient from small vein to left atrium although there was a modest increase in gradient from lobar artery to small vein. These data suggest that in the canine lung PGE2 increases vascular resistance by constricting lobar veins and to a lesser extent vessels upstream in the precapillary bed presumed to be small arteries. Support for the concept that the pressor effect of PGE 2 is due predominantly to an effect on the lobar veins is found in isolated vessel studies (Joiner et al., 1973). In isolated helical segments of lobar vein 3--5 mm in diameter, PGE2 increased isometric tension in a dose-related fashion. PGE 2 was about one-half as p o t e n t as norepinephrine in its ability to increase tension in the vein. In contrast, the response of isolated lobar arteries 3--5 mm in diameter to PGE2 was very weak (Joiner et al., 1973). The magnitude of the increase in lobar arterial pressure in the swine and lamb in response to PGE2 was greater than in the dog. However, in these species there was no change in pressure in the small intrapulmonary lobar vein. These data indicate that in the swine and lamb the rise in pulmonary vascular resistance

P.J. KADOWITZ ET AL. in response to this substance is the result of vasoconstriction in vessels upstream to the small vein presumably small arteries. Therefore, in the dog, the site of vasoconstriction in the pulmonary vascular bed is different from the swine or lamb. In the dog, PGE2 produced a fall in systemic arterial pressure but did not change pressure in the main pulmonary artery. Blood flow to the left upper and right lung lobes as measured by the dye-dilution technique was decreased and since pulmonary arterial pressure was unchanged, calculated pulmonary vascular resistance increased. These results indicate that PGE 2 also increases vascular resistance in the normally perfused canine lung lobes. However, these data do not indicate whether active vasoconstriction occurred in the normally perfused lung lobes since blood flow was not constant. The effects of PGE 2 on the pulmonary and peripheral vascular beds are different in the dog. In the present study, PGE 2 when infused at 5 pg/min, which established a concentration of about 50 ng/ml in iliac arterial blood, produced a marked decrease in vascular resistance in the dog hindlimb. In contrast, this substance when infused at 20 pg/min, which established a concentration of about 70 ng/ml in lobar arterial blood in the dog and swine, increased pulmonary vascular resistance. The reason for the apparent difference in effect in the hindlimb and pulmonary vascular beds is unknown. In preliminary studies we have found that the effects of PGE 2 are dose-related on the pulmonary vascular bed so that the apparent difference is not due to the doses studied. It is also possible that PGE 2 may be converted to PGF2~ in the lung since the enzyme PGE2 ketoreductase has been found in some organs (Leslie and Levine, 1973). Although the reason for the difference in effect in the lung and hindlimb is unknown, several other endogenous substances, including bradykinin, histamine and acetylcholine, are similar to PGE2 in that they cause pulmonary vasoconstriction and systemic vasodilatation (Daly, 1966; Hauge et al., 1966; Hyman,

PGE2 AND PULMONARY VASCULAR RESISTANCE 1 9 6 8 , 1 9 6 9 b ) . It is o f interest t o n o t e t h a t while t h e effects o f prostaglandins E I and E 2 are similar in m o s t peripheral vascular beds, t h e y are diametrically o p p o s i t e in the p u l m o n a r y vascular b e d in which P G E I decreases p u l m o n a r y vascular resistance in t h e dog, swine and l a m b ( H y m a n , 1 9 6 9 c ; K a d o w i t z et al., 1 9 7 4 a a n d 1 9 7 4 b ) . These differences are even m o r e r e m a r k a b l e since PGEL a n d P G E : differ o n l y in o n e d o u b l e b o n d in the side chain. It is n o t k n o w n if the prostaglandins are involved in the regulation o f the p u l m o n a r y vascular bed. However, their natural occurrence and the great c a p a c i t y for synthesis in this organ along with the release and m e t a b o lism m a y suggest such a role. Moreover, results o f t h e p r e s e n t s t u d y d e m o n s t r a t e t h a t PGE2 is a p u l m o n a r y v a s o c o n s t r i c t o r a g e n t a n d it is possible t h a t e n d o g e n o u s l y released P G E : c o u l d play a role in the regulation o f p u l m o n a r y b l o o d v o l u m e b y n a t u r e o f its effect on the p u l m o n a r y l o b a r veins in s o m e species. Acknowledgements Prostaglandin E2 was kindly supplied by Dr. James R. Weeks of the Upjohn Company. References Alpert, J.S., F.W. Hayes, P.A. Knutson, J.E. Dalen and L. Dexter, 1973, Prostaglandins and the pulmonary circulation, Prostaglandins 3, 759. Anderson, F.L., A.C. Kralios, T.J. Tsgaris and H. Kuida, 1972, Effects of prostaglandins F2 a and E2 on the bovine circulation, Proc. Soc. Exptl. Biol. Med. 140, 1049. ~[ngg~rd, E. and B. Samuelsson, 1965, Biosynthesis of prostaglandins from arachidonic acid in guinea pig lung, J. Biol. Chem. 240, 3518. BergstrSm, S., L.A. Carlson and J.R. Weeks, 1968, The prostaglandins: a family of biologically active lipids, Pharmacol. Rev. 20, 1. Berry, E.M., J.F. Edmonds and J.H. Wyllie, 1971, Release of prostaglandin E2 and unidentified factors from ventilated lungs, Brit. J. Surg. 58, 189. Daly, I.DeB., 1966, Pulmonary and Bronchial Vascular Systems (Edward Arnold, Ltd., London).

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