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Prostacyclin (PGI2) generation in lungs of fetal and newborn rabbit
PROSTAGLANDINS
PROSTACYCLIN (PGI2) GENERATION IN LUNGS OF FETAL AND NEWBORN RABBIT C. Omini, G. Brunelli, G.C. Folco, A. Marini, R. Pasargiklian and F. Berti Institute of Pharmacology and Pharmacognosy University of Milan 20129 Milan, Italy Newborn Unit and II Clinic, Dept. Obst. and Gynec. University of Milan, 20122 Milan, Italy Abstract Perfused lungs from fetal (26-28 days of gestation) and newborn rabbits preferentially transform arachidonic acid into a substance which,mimics PG12 activity on different isolated tissues in cascase. These data support the hypothesis that antiplatelet and vasodilating activity of PG12 generated in the lungs may contribute to the characteristics of the fetal circulation. Introduction Biosynthesis of prostaglandins by fetal tissues has been reported, and the maturational state of animals has been also tentativelv correlated with' the activity of various enzymes involved in prostaglandin catabolism (1,2). Arachidonic acid metabolism in adult rabbit lunos differs from that of other animal species: for instance, whereas rabbit l;ngs generate preferentially PGE2, guinea-pig lungs have a greater capacity to form thromboxane A2 (TXA 1 (3). Furthermore, Powell and Solomon (2) demonstrated that lungs of feta? rabbits, obtained between days 26 and 28 of gestation convert arachidonic acid to PGE2 while only small amounts of PGFz,, TXB2 and particularly of the PG12 metabolite, 6-oxo-PGFl, are formed. These data and the observation that after 28 days of gestation the PGE2 synthetizing capacity of the pulmonary tissue diminishes, suggests that PGE2 may play a role in fetal lung maturation and development (4,2). However, more recently, Moncada et al. (5), by the use of an anti-serum which crossreacts with PG12 and neutralizes its antiaggregatory activity, reported that adult rabbit lungs release PG12 in the circulation. These findings, which support the previous hypothesis of Gryglewski et al. (6) regarding PGI as a circulating-hormone, prompted us to investigate the ability of isolate 8 and perfused lungs from fetal and newborn rabbits to generate and release PG12 from arachidonic acid. Methods In these experiments, lungs obtained from 12 fetal New Zealand rabbits (between 26 and 28 days of gestation) and lungs taken from newborn rabbits (at days 1,3,4,10,15 from birth) of the same strain were utilized (16 experiments). The lungs were perfused with a Krebs-bicarbonate solution (5 ml min-') at 37OC through the pulmonary artery as previously described (7).
FEBRUARY
1981 VOL. 21 NO. 2
345
PROSTAGLANDINS
In order to eliminate the circulatory shunt through the ductus arteriosus in the heart, the aorta was lisated above and below the ductus before to insertion of-the catheter via the right ventricle into the pulmonary artery. To validate the perfusion procedure of the fetal lunas, the Krebs solution was mixed with Evan's blue dye and used in the same preparation at the end of the experiment. The pulmonary outflow was used to superfuse a bank of isolated tissues in cascade includin spirally cut strips of rabbit coeliac (RbCA) and mesenteric arteries (RbMA4 , rabbit aorta (RbA) and bovine coronary artery (BCA); rat stomach strip (RSS) and rat colon (RC) were also present in the cascade system. The bioassay tissues were treated with a as suggested by Gilmore et al (8) and with indomethacin in order to increase their sensitivity to arachidonate metabothe tonus of the tissues were measured using isotonic transducers connected to a multichannel pen-recorder (Watanabe Mark IV). The lungs from fetal and newborn rabbit were challen ed with bolus injections of arachidonic acid (5 and 10 ug), histamine (10 ug4 , bradykinin (10 ug), SRS-A (1 U), norepinephrine (1 ug) and acetylcholine (5 ug). SRS-A was prepared according to the procedure described by Blackwell et al. (9). Results When perfused fetal lungs were treated with arachidonic acid (5 and 10 a dose dependent relaxation of BCA, RbCA and RbMA was observed, indicating the presence of PGI2-like activity in the pulmonary outflow (Fig. 1). The concomitant loss of spontaneous motility of RC and the small contraction of RSS speak in favour of the above suggestion. In fact, injection of reference standard PGI2 over the bioassay tissues induces a similar modification of their tonus. Since during pulmonary challenge with arachidonic acid the RbA contraction did not occur, it is 1ikel.v that fetal lunqs do not qenerate TXA,,. Manipulation of fetal-and newborn lungs leads to a sustaineh relaxation of BCA and RbCA indicating production of PGI -like activity from pulmonary tissues. However, inflation of fetal lungs 8. ld not modify the pattern of arachidonic acid products. Furthermore, when fetal lungs were challenged with histamine (5 ug), SRS-A (1 U), bradykinin (5 ug), no modification of the tonus of the tissues in cascade was recorded, indicating that activation of arachidonic acid metabolism did not take olace: treatment of the fetal lunas with noreoineohrine and acetylcholine was also ineffective. When 1 day aid rabbit lung were given bolus injections of arachidonic acid (5-10 us), a metabolic pattern similar to that observed in fetal lungs was evident. As-shown in Fig. 2, which represents a typical experiment of the 12 performed, 5 ug of arachidonic acid is preferentially transformed to PGI,-like material. Conversion of arachiaonic acid has been investigated also in lungs obtained from newborn rabbits sacrificed between days 3 and 15 from birth. In the 16 lungs examined the bolus injections of arachidonic acid (5-10 ug) caused a dose dependent relaxation of BCA and RbCA and a sustained contraction of RC and RSS without modification of RbA. The response of the bioassay system suggested the appearance in the pulmonary outflow of PGI2-like material mixed with a biologica activity similar to that induced by PGE and PGFaa. In our experimental conditions the conversion of arachidonic acl4 in 3 days old rabbit lungs was quantitatively similar to that observed with 15 day rabbit lungs. Fig. 3 represents an experiment performed with lungs of a 5 day rabbit.
w)
346
FEBRUARY
1981 VOL. 21 NO. 2
PROSTAGLANDINS
Fig.
1 -
Metabolic ed
conversion
fetal
flow
rabbit
bovine and (BK)
a
FEBRUARY
colon
bolus and
Prostacyclin in
aorta
of (HCR),
The
CRC).
the
reacting was
acid
27
rabbit
(RbA), artery
(12)
day
bank
through slow
arachidonic
on
a
coronary ‘rat
of
lung
super-fused
of:
as
rabbit
of assay
lungs:
coeliac
injected
histamine
artery
(RbCA), strip
were (HI, over
out-
consisting (RSS) injected
bradykinin
anaphylaxis
directly
perfus-
Lung
stomach agonists
of
in
tissues
rat
following substance
(AA)
gestation.
(SRS-A). the
ttssues
cascade.
1981 VOL. 21 NO. 2
347
PROSTAGLANDINS
Fig.
2
-
Metabolic ed a
of
bank
of
1 assay
artery
(RbMA),
(RbA), artery
bovine
and in
348
conversion
lung
(RbCA), PGE
casca
(E2)
of
day
arachidonic
old tissues
rat and
Lung
consisting
stomach artery
coronary were
acid
rabbit.
rat
colon
injected
(AA)
of:
strip
(BCA), CRC).
mesenteric rabbit
rabbit Prostacyclin over
perfus-
superfused
rabbit
(RSS),
directly
in
outflow
the
aorta coeliac (1
)
tlssugs
2 e.
FEBRUARY
1981 VOL. 21 NO. 2
PROSTAGLANDINS
‘2 25
Fig.
3 -
FEBRUARY
Metabolic conversion of arachidonic acid (AA) in perfused lung of 5 days old rabbit. Lung outflow superfused a bank of assay tissues consisting of: rat stomach strip (RSS), bovine coronary artery (BCA) and rat colofl (RRC). Prostacyclin (12) .and PGE2 (E2) were injected directly over the tissues in cascade.
1981 VOL. 21 NO. 2
349
PROSTAGLANDINS
Discussion The findings of this study show that fetal lungs (26-28 days of gestation) and lungs of 1 day newborn rabbits generate from arachidonic acid a substance which mimics the biological activity of PG12. However, although the bioassay tissues failed to reveal other cycle-oxygenase products, such as PGs and TXA?. their oresence in the oulmonarv effluent mav not be ruled out. The greater concentration of PGI2llike ac‘tivity may ha\e masked a small yield of PGs. These data are not in aoreement with those previouslv shown bv Powell and Solomon (2), who found only-small amounts of 6-bxo-PGF,&in homo-genates of fetal lungs incubated with labelled arachidonic acid. The discrepancv mav be due to our different exoerimental aooroach. based on isolated and perFused lungs instead of lung homogenate. " . Furthermore, as shown by Sun and McGuire (lo), the quantitative metabolic pattern of arachidonic acid depends on the incubation conditions: thus when trace amounts of radioactive prostaglandin endoperoxides (PGH ) were incubated with hiah concentration of rabbit luna microsomes. the most a$undant Droduct became 6-0x0-PGFla. The ability of rabbit lungs to convert arachidonic acid into PGI -like material is well maintained in newborn animals of 15 days. However, th5 concomitant appearance of prostaglandin-like material in the lung perfusate indicate that with development not only PGIP-synthetase, but other enzymes of the eicosoid system, such as prostaglandinj-reductase and isomerase, may be induced. The preferential formation of PG12 from arachidonic acid in fetal lungs supports the idea of a metabolic function of the pulmonary tissue in producing a circulatory hormone (6). Thus, the antiplatelet and vasodilatino activitv of PGI? circulatina in the fetus mav reinforce PGI:, of maternal origin (uterus-lung] in the maintenance of the c;rculatory regulation. Thus, PG12 may contribute to the resistance of fetal blood to clotting (11) and to the high cardiac output and low vascular resistance which characterize the fetal circulation (12). Also, PG12 may represent an alternative candidate than PGE2 in fetal lung maturation and development (2,4). The previous suggestion of Powell and Solomon (4), that the control of pulmonary surfactant synthesis and release in fetallung, should now be reconsidered. In fact, the rapid rise in surfactant synthesis in the fetal rabbit beginning at 25 days of gestation (13), could fit with the capacity of fetal rabbit lung to preferentially transform arachidonic acid into PG12. Furthermore, the documented ability of PG12 to activate adenyl-cyclase, increasing cyclic-AMP concentration in many tissues (14), is in accord with the evidence that cyclic-AMP stimulates surfactant production in lung of fetal rabbit near to birth (15). Acknowledgement This work was supported by a grant of the C.N.R. (No. 79.01064.83.115).
References 1.
Pace Asciak, C.R. Prostaglandin biosynthesis and catabolism in several organs of developing fetal and neonatal animals. In: "Advances in Prostatlandin and Thromboxane Research", vol. 4 (F. Coceani and P.M. Olley, eds.), Raven Press, N.Y., p. 45-59, 1978
2.
Powell, W.S. and S. Solomon. Biosynthesis of prostaglandins and thromboxane in fetal tissues. In: "Advances in Prostaglandin and Thromboxane Research", vol. 4 (F. Coceani and P.M. Olley, eds.) Raven Press, N.Y., p. 61-74, 1978.
350
FEBRUARY
1981 VOL. 21 NO. 2
PROSTAGLANDINS
3.
Berti F., G.C. Folco, S. Nicosia, C. Omini and R. Pasargiklian. The role of histamine HI and H2 receptors in the generation of thromboxane A2 in the perfused guinea-pig lungs. Brit.J.Pharmac. 65:629-633, 1979. Powell W.S. and S. Solomon. Biosynthesis of prostaqlandins and thromboxane B2 by fetal lung homogenates. Prostaglandins 15:315-364, 1978. Moncada S., R. Korbut, S. Bunting and J.R. Vane. circulating hormone. Nature 273:767-768. 1978.
Prostacyclin is a
Gryglewski R.J., R. Korbut and A. Ocetkiewicz. Generation of prostacyclin by lungs in vivo and its release into the arterial circulation. Nature 273~765-767. 1978. Piper P.J. and J.R. Vane. Release of additional factors in anaphylaxis and its antagonism by anti-inflammatory drugs. Nature 223:29-35, 1969. Gilmore N., J.R. Vane and J.H. Wyllie. spleen. Nature 278:456-459, 1968.
Prostaqlandins released by the
Blackwell G.J., Burka J.F. and Flower R.J. On the preparation of a highly purified slow-reacting substance of anaphylaxis (SRS-A) from biological extracts. Br. J. Pharmac., 63, 365P, 1978. IO.
Sun F.F. and J.C. McGuire. Metabolism of prostaqlandins and prostaglandin endoperoxides in rabbit tissues during pregnancy: differences in enzyme activities between mother and fetus. In "Advances in Prostaglandin and Thromboxane Research" vol. 4 (F. Coceani and P.M. Olley, eds.), Raven Press, N.Y., p. 75-85, 1978.
11.
Aballi A.J. and S. OeLamerens. Coagulation changes in the neonatal period and in early infancy. Pediatr. Clin. North Am. 9, 785, 1962.
12.
Rodolph A.M. The Course and distribution of the fetal circulation. In: "Fetal Autonomy", Ciba Foundation Symposium, G.E.W. Wolstenholme and M. O'Connor eds., J.A. Churchill Ltd., London 1969, p. 147.
13.
Gluck L., M. Sdribney and M.V. Kulovich. The biochemical development of surface activity in mammalian lunq. II. The biosynthesis of phospholipids in the lung of the developing rabbit fetus and newborn. Pediatr. Res. 1, 247, 1967.
14.
Gorman R.R., S. Bunting and O.V. Miller, Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaqlandins 13, 377-388, 1977.
15.
Barret C.T., A. Sevanian, N. Lavin and S.A. Kaplan. Role of adenosine 3'-5'-Monophosphate in maturation of fetal lungs. Pediatr. Res. 10, 621, 1976.
FEBRUARY
1981 VOL. 21 NO. 2
351
PROSTACYCLIN (PGI2) GENERATION IN LUNGS OF FETAL AND NEWBORN RABBIT C. Omini, G. Brunelli, G.C. Folco, A. Marini, R. Pasargiklian and F. Berti Institute of Pharmacology and Pharmacognosy University of Milan 20129 Milan, Italy Newborn Unit and II Clinic, Dept. Obst. and Gynec. University of Milan, 20122 Milan, Italy Abstract Perfused lungs from fetal (26-28 days of gestation) and newborn rabbits preferentially transform arachidonic acid into a substance which,mimics PG12 activity on different isolated tissues in cascase. These data support the hypothesis that antiplatelet and vasodilating activity of PG12 generated in the lungs may contribute to the characteristics of the fetal circulation. Introduction Biosynthesis of prostaglandins by fetal tissues has been reported, and the maturational state of animals has been also tentativelv correlated with' the activity of various enzymes involved in prostaglandin catabolism (1,2). Arachidonic acid metabolism in adult rabbit lunos differs from that of other animal species: for instance, whereas rabbit l;ngs generate preferentially PGE2, guinea-pig lungs have a greater capacity to form thromboxane A2 (TXA 1 (3). Furthermore, Powell and Solomon (2) demonstrated that lungs of feta? rabbits, obtained between days 26 and 28 of gestation convert arachidonic acid to PGE2 while only small amounts of PGFz,, TXB2 and particularly of the PG12 metabolite, 6-oxo-PGFl, are formed. These data and the observation that after 28 days of gestation the PGE2 synthetizing capacity of the pulmonary tissue diminishes, suggests that PGE2 may play a role in fetal lung maturation and development (4,2). However, more recently, Moncada et al. (5), by the use of an anti-serum which crossreacts with PG12 and neutralizes its antiaggregatory activity, reported that adult rabbit lungs release PG12 in the circulation. These findings, which support the previous hypothesis of Gryglewski et al. (6) regarding PGI as a circulating-hormone, prompted us to investigate the ability of isolate 8 and perfused lungs from fetal and newborn rabbits to generate and release PG12 from arachidonic acid. Methods In these experiments, lungs obtained from 12 fetal New Zealand rabbits (between 26 and 28 days of gestation) and lungs taken from newborn rabbits (at days 1,3,4,10,15 from birth) of the same strain were utilized (16 experiments). The lungs were perfused with a Krebs-bicarbonate solution (5 ml min-') at 37OC through the pulmonary artery as previously described (7).
FEBRUARY
1981 VOL. 21 NO. 2
345
PROSTAGLANDINS
In order to eliminate the circulatory shunt through the ductus arteriosus in the heart, the aorta was lisated above and below the ductus before to insertion of-the catheter via the right ventricle into the pulmonary artery. To validate the perfusion procedure of the fetal lunas, the Krebs solution was mixed with Evan's blue dye and used in the same preparation at the end of the experiment. The pulmonary outflow was used to superfuse a bank of isolated tissues in cascade includin spirally cut strips of rabbit coeliac (RbCA) and mesenteric arteries (RbMA4 , rabbit aorta (RbA) and bovine coronary artery (BCA); rat stomach strip (RSS) and rat colon (RC) were also present in the cascade system. The bioassay tissues were treated with a as suggested by Gilmore et al (8) and with indomethacin in order to increase their sensitivity to arachidonate metabothe tonus of the tissues were measured using isotonic transducers connected to a multichannel pen-recorder (Watanabe Mark IV). The lungs from fetal and newborn rabbit were challen ed with bolus injections of arachidonic acid (5 and 10 ug), histamine (10 ug4 , bradykinin (10 ug), SRS-A (1 U), norepinephrine (1 ug) and acetylcholine (5 ug). SRS-A was prepared according to the procedure described by Blackwell et al. (9). Results When perfused fetal lungs were treated with arachidonic acid (5 and 10 a dose dependent relaxation of BCA, RbCA and RbMA was observed, indicating the presence of PGI2-like activity in the pulmonary outflow (Fig. 1). The concomitant loss of spontaneous motility of RC and the small contraction of RSS speak in favour of the above suggestion. In fact, injection of reference standard PGI2 over the bioassay tissues induces a similar modification of their tonus. Since during pulmonary challenge with arachidonic acid the RbA contraction did not occur, it is 1ikel.v that fetal lunqs do not qenerate TXA,,. Manipulation of fetal-and newborn lungs leads to a sustaineh relaxation of BCA and RbCA indicating production of PGI -like activity from pulmonary tissues. However, inflation of fetal lungs 8. ld not modify the pattern of arachidonic acid products. Furthermore, when fetal lungs were challenged with histamine (5 ug), SRS-A (1 U), bradykinin (5 ug), no modification of the tonus of the tissues in cascade was recorded, indicating that activation of arachidonic acid metabolism did not take olace: treatment of the fetal lunas with noreoineohrine and acetylcholine was also ineffective. When 1 day aid rabbit lung were given bolus injections of arachidonic acid (5-10 us), a metabolic pattern similar to that observed in fetal lungs was evident. As-shown in Fig. 2, which represents a typical experiment of the 12 performed, 5 ug of arachidonic acid is preferentially transformed to PGI,-like material. Conversion of arachiaonic acid has been investigated also in lungs obtained from newborn rabbits sacrificed between days 3 and 15 from birth. In the 16 lungs examined the bolus injections of arachidonic acid (5-10 ug) caused a dose dependent relaxation of BCA and RbCA and a sustained contraction of RC and RSS without modification of RbA. The response of the bioassay system suggested the appearance in the pulmonary outflow of PGI2-like material mixed with a biologica activity similar to that induced by PGE and PGFaa. In our experimental conditions the conversion of arachidonic acl4 in 3 days old rabbit lungs was quantitatively similar to that observed with 15 day rabbit lungs. Fig. 3 represents an experiment performed with lungs of a 5 day rabbit.
w)
346
FEBRUARY
1981 VOL. 21 NO. 2
PROSTAGLANDINS
Fig.
1 -
Metabolic ed
conversion
fetal
flow
rabbit
bovine and (BK)
a
FEBRUARY
colon
bolus and
Prostacyclin in
aorta
of (HCR),
The
CRC).
the
reacting was
acid
27
rabbit
(RbA), artery
(12)
day
bank
through slow
arachidonic
on
a
coronary ‘rat
of
lung
super-fused
of:
as
rabbit
of assay
lungs:
coeliac
injected
histamine
artery
(RbCA), strip
were (HI, over
out-
consisting (RSS) injected
bradykinin
anaphylaxis
directly
perfus-
Lung
stomach agonists
of
in
tissues
rat
following substance
(AA)
gestation.
(SRS-A). the
ttssues
cascade.
1981 VOL. 21 NO. 2
347
PROSTAGLANDINS
Fig.
2
-
Metabolic ed a
of
bank
of
1 assay
artery
(RbMA),
(RbA), artery
bovine
and in
348
conversion
lung
(RbCA), PGE
casca
(E2)
of
day
arachidonic
old tissues
rat and
Lung
consisting
stomach artery
coronary were
acid
rabbit.
rat
colon
injected
(AA)
of:
strip
(BCA), CRC).
mesenteric rabbit
rabbit Prostacyclin over
perfus-
superfused
rabbit
(RSS),
directly
in
outflow
the
aorta coeliac (1
)
tlssugs
2 e.
FEBRUARY
1981 VOL. 21 NO. 2
PROSTAGLANDINS
‘2 25
Fig.
3 -
FEBRUARY
Metabolic conversion of arachidonic acid (AA) in perfused lung of 5 days old rabbit. Lung outflow superfused a bank of assay tissues consisting of: rat stomach strip (RSS), bovine coronary artery (BCA) and rat colofl (RRC). Prostacyclin (12) .and PGE2 (E2) were injected directly over the tissues in cascade.
1981 VOL. 21 NO. 2
349
PROSTAGLANDINS
Discussion The findings of this study show that fetal lungs (26-28 days of gestation) and lungs of 1 day newborn rabbits generate from arachidonic acid a substance which mimics the biological activity of PG12. However, although the bioassay tissues failed to reveal other cycle-oxygenase products, such as PGs and TXA?. their oresence in the oulmonarv effluent mav not be ruled out. The greater concentration of PGI2llike ac‘tivity may ha\e masked a small yield of PGs. These data are not in aoreement with those previouslv shown bv Powell and Solomon (2), who found only-small amounts of 6-bxo-PGF,&in homo-genates of fetal lungs incubated with labelled arachidonic acid. The discrepancv mav be due to our different exoerimental aooroach. based on isolated and perFused lungs instead of lung homogenate. " . Furthermore, as shown by Sun and McGuire (lo), the quantitative metabolic pattern of arachidonic acid depends on the incubation conditions: thus when trace amounts of radioactive prostaglandin endoperoxides (PGH ) were incubated with hiah concentration of rabbit luna microsomes. the most a$undant Droduct became 6-0x0-PGFla. The ability of rabbit lungs to convert arachidonic acid into PGI -like material is well maintained in newborn animals of 15 days. However, th5 concomitant appearance of prostaglandin-like material in the lung perfusate indicate that with development not only PGIP-synthetase, but other enzymes of the eicosoid system, such as prostaglandinj-reductase and isomerase, may be induced. The preferential formation of PG12 from arachidonic acid in fetal lungs supports the idea of a metabolic function of the pulmonary tissue in producing a circulatory hormone (6). Thus, the antiplatelet and vasodilatino activitv of PGI? circulatina in the fetus mav reinforce PGI:, of maternal origin (uterus-lung] in the maintenance of the c;rculatory regulation. Thus, PG12 may contribute to the resistance of fetal blood to clotting (11) and to the high cardiac output and low vascular resistance which characterize the fetal circulation (12). Also, PG12 may represent an alternative candidate than PGE2 in fetal lung maturation and development (2,4). The previous suggestion of Powell and Solomon (4), that the control of pulmonary surfactant synthesis and release in fetallung, should now be reconsidered. In fact, the rapid rise in surfactant synthesis in the fetal rabbit beginning at 25 days of gestation (13), could fit with the capacity of fetal rabbit lung to preferentially transform arachidonic acid into PG12. Furthermore, the documented ability of PG12 to activate adenyl-cyclase, increasing cyclic-AMP concentration in many tissues (14), is in accord with the evidence that cyclic-AMP stimulates surfactant production in lung of fetal rabbit near to birth (15). Acknowledgement This work was supported by a grant of the C.N.R. (No. 79.01064.83.115).
References 1.
Pace Asciak, C.R. Prostaglandin biosynthesis and catabolism in several organs of developing fetal and neonatal animals. In: "Advances in Prostatlandin and Thromboxane Research", vol. 4 (F. Coceani and P.M. Olley, eds.), Raven Press, N.Y., p. 45-59, 1978
2.
Powell, W.S. and S. Solomon. Biosynthesis of prostaglandins and thromboxane in fetal tissues. In: "Advances in Prostaglandin and Thromboxane Research", vol. 4 (F. Coceani and P.M. Olley, eds.) Raven Press, N.Y., p. 61-74, 1978.
350
FEBRUARY
1981 VOL. 21 NO. 2
PROSTAGLANDINS
3.
Berti F., G.C. Folco, S. Nicosia, C. Omini and R. Pasargiklian. The role of histamine HI and H2 receptors in the generation of thromboxane A2 in the perfused guinea-pig lungs. Brit.J.Pharmac. 65:629-633, 1979. Powell W.S. and S. Solomon. Biosynthesis of prostaqlandins and thromboxane B2 by fetal lung homogenates. Prostaglandins 15:315-364, 1978. Moncada S., R. Korbut, S. Bunting and J.R. Vane. circulating hormone. Nature 273:767-768. 1978.
Prostacyclin is a
Gryglewski R.J., R. Korbut and A. Ocetkiewicz. Generation of prostacyclin by lungs in vivo and its release into the arterial circulation. Nature 273~765-767. 1978. Piper P.J. and J.R. Vane. Release of additional factors in anaphylaxis and its antagonism by anti-inflammatory drugs. Nature 223:29-35, 1969. Gilmore N., J.R. Vane and J.H. Wyllie. spleen. Nature 278:456-459, 1968.
Prostaqlandins released by the
Blackwell G.J., Burka J.F. and Flower R.J. On the preparation of a highly purified slow-reacting substance of anaphylaxis (SRS-A) from biological extracts. Br. J. Pharmac., 63, 365P, 1978. IO.
Sun F.F. and J.C. McGuire. Metabolism of prostaqlandins and prostaglandin endoperoxides in rabbit tissues during pregnancy: differences in enzyme activities between mother and fetus. In "Advances in Prostaglandin and Thromboxane Research" vol. 4 (F. Coceani and P.M. Olley, eds.), Raven Press, N.Y., p. 75-85, 1978.
11.
Aballi A.J. and S. OeLamerens. Coagulation changes in the neonatal period and in early infancy. Pediatr. Clin. North Am. 9, 785, 1962.
12.
Rodolph A.M. The Course and distribution of the fetal circulation. In: "Fetal Autonomy", Ciba Foundation Symposium, G.E.W. Wolstenholme and M. O'Connor eds., J.A. Churchill Ltd., London 1969, p. 147.
13.
Gluck L., M. Sdribney and M.V. Kulovich. The biochemical development of surface activity in mammalian lunq. II. The biosynthesis of phospholipids in the lung of the developing rabbit fetus and newborn. Pediatr. Res. 1, 247, 1967.
14.
Gorman R.R., S. Bunting and O.V. Miller, Modulation of human platelet adenylate cyclase by prostacyclin (PGX). Prostaqlandins 13, 377-388, 1977.
15.
Barret C.T., A. Sevanian, N. Lavin and S.A. Kaplan. Role of adenosine 3'-5'-Monophosphate in maturation of fetal lungs. Pediatr. Res. 10, 621, 1976.
FEBRUARY
1981 VOL. 21 NO. 2
351