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Ductus arteriosus: Developmental response to oxygen and indomethacin
PROSTAGLANDlNS
DUCTIJSARTERIOSUS:DEVELOPMENTALRESPONSE TO OXYGEN AND INDOMETRACIN Ronald I. Clyman,Franyoise Mauray, Michael A. Heymann and Abraham M. Rudolph The CardiovascularResearch Instituteand the Departmentsof Pediatrics,.Obstetrics, Gynecology,and ReproductiveSciences,University of California,San Francisco,California94143, and the Departmentof Pediatrics,Mt. Zion Medical Center, San Francisco, California94115. ABSTRACT It has been suggested that ineffectiveconstrictionin response to an increase in PO2 is the primary cause for delayed closure of the ductus arteriosusin preterm infants. We studied the isometriccontractileeffects of increasedPO2 and indomethatin on isolated rings of lamb ductus arteriosusfrom animals of different gestationalages (87 to 147 days, term is 150 days). Rings from animals less than 110 days have a significantlysmaller oxygen-inducedcontraction (2.53 + .30 g/mm2, n = 16) when compared with rings from animals near term (4.59 + .69 g/mm2, n = 9). Oxygen contractedrings from all gestationalages contract further upon addition of 1 ug/ml indomethacin. Rings from animals less than 110 days have a significantlylarger indomethacininduced contraction(1.10 f .17 g/mm2, n = 16) than vessels near term (0.52 + .12 g/nm2, n - 9). Inhibitionof prostaglandinproduction in rings less than 110 days results in a total combined oxygen and indomethacininduced tension that is not significantlydifferent from the oxygen or oxygen and indomethacininduced tension developed in rings from animals near term. This is consistentwith the hypothesis that, early during gestation,endogenousprostaglandins inhibit the vessel's ability to contract in response to oxygen. These observationsare also consistentwith the ability of indomethacinto constrict the patent ductus arteriosusin preterm infants. INTRODUCTION There is now convincingevidence that prostaglandinsmaintain the patency of the ductus arteriosusin the fetus near term. ProstaglendinsEl (PGIQ) and E2 (PGE2) relax the isolated calf and lamb ductus arteriosusin a low oxygen environment(1,2). Pretreatmentof isolated lamb ductus arteriosuswith prostaglandin synthesisinhibitors (indomethacinand eicosa-5,8,11,14-tetraynoic acid) also contracts the hypoxic vessel (3). Blockers of prostaglandin synthesis,when given to pregnant mothers near term, constrict the ductus arteriosusof fetal rats, rabbits, and lambs in vivo (4-6). An increasingsensitivityto indomethacinhas beendemonstratedas fetal rats approach term gestation (6).
JUNE
1978 VOL. 15 NO. 6
993
PROSTAGLANDINS
Recently we have observed (7) that the isolated lamb ductus arteriosus exposed to high oxygen tension is as sensitive to PGEl and PGE2 as it is in a low oxygen environment. In the experiments reported herein, the contracting effects of indomethacin on the isolated lamb ductus arteriosus from different gestational age groups were examined at high oxygen tensions. Indomethacin caused further contraction of the ductus arteriosus already constricted by elevated P02. This is consistent with the hypothesis that endogenous prostaglandins inhibit the tendency of the vessel to contract in response to oxygen. In contrast with studies in the rat, we found a more intense response to indomethacin in the youngest fetuses indicating that the prostaglandin mechanism develops early during gestation. MFTHODS AND MATERIALS Time dated fetal lambs, between 87 and 147 days gestational age (term is 150 days), were delivered by cesarean section and rapidly killed by exsanguination. The ductus arteriosus was dissected free from adventitial tissue and divided into 3 to 4 1 mm thick rings which were placed into separate 150 ml lucite plastic organ baths (fluid removed by draining) enclosed in a box excluding light. The rings were suspended between 2 stainless steel hooks in a solution containing 127 mM NaCl, 5 mM KCl, 2.5 mM CaC12, 1.27 mM MgCl2*6H2O, 5.5 mM glucose, and 50 mM Tris*HCl, pH 7.39 at 37OC. Isometric responses of circumferential tension were measured by a Grass FT03C force transducer and recorded on a Grass polygraph. Small samples of the bathing solution were withdrawn and pH and PO2 were measured using Radiometer electrodes and blood gas meter. Each of the rings from a single vessel was stretched to an initial length that would result in a maximal contractile response to increases in oxygen tension for rings in that age group. Rings from animals between 87 and 110 days were stretched to initial lengths of 6, 7, or 8 mm; rings from animals between 111 and 130 days were stretched to 8 or 9 mm; rings from animals between 136 and 147 days were stretched to 9 or 10 mm (unpublished results). The bathing solution in each bath was bubbled with 100% nitrogen (to a PO2 of 16 to 20 torr) and the tissues allowed to equilibrate for 45 min until a steady tension was developed. The tissues then were exposed to 100% oxygen (to a PO2 of 680 to 720 torr) for 1 hour allowing the tension to achieve a new plateau. The oxygen-induced contraction was considered as the difference in the tensions at high and low PO2. After the rings reached a new steady tension in the high PO2 environment, indomethacin was added to the bath in a final concentration of 1 ug/ml (2.8 x 10-6 M) and the rings were allowed to achieve a new increase in tension over the next hour. Additional doses of indomethacin to a final concentration of 5 pg/ml or 10 pgfml produced no further increase in tension. The indomethacin-induced contraction was considered as the difference in the steady tensions at high PO2 and high PO2
994
JUNE
1978 VOL. 15 NO. 6
PROSTAGLANDINS
plus indomethacin (1 ug/ml). Following the experiment the tissues were removed from the baths and blotted dry before weighing (wet weight). The tension developed in the tissue was expressed as force/ unit area (g/mm2). This area was the surface of the tissue which was perpendicular to the direction of the force. Since the ring samples assume a flattened shape when stretched to their initial length, the cross-sectional area was computed as the area of a rectangle whose length was the initial length of the stretched tissue. In order to calculate the cross-sectional area of this rectangle the tissue density was assumed to be 1. Therefore, a tissue with a wet weight of 1 mg was assumed to have a volume of 1 mm3 and the surface area perpendicular to the force was calculated by dividing this volume by the initial length of stretch. Indomethacin (Sigma) was prepared in ethanol (16 mg/ml) and aliquots were added to the bath solution. The maximal concentration of ethanol in the bath (0.06%) had no effect on tissue contractility. RESULTS The response of the ductus arteriosus to an increase in PO2 was similar to that reported previously(7) . Figure 1 shows the oxygen induced contraction in rings (from 3 different gestational age groups) which were stretched to initial lengths that result in maximal contractile responses for rings in that age group. Vessels from 111 to 130 days gestation develop the same tension (4.26 + .46 g/mm2 , 2 SEM) as vessels near term (4.59 f .69 g/mm2>. Only vessels from animals less than 110 days gestation have a significantly smaller oxygen induced contraction (2.53 + .30 g/mm2, p < .005 unpaired t-test) when compared with vessels near term. The oxygen induced response of animals less than 110 days is about 55% of the response in animals near term. As can be seen from Figure 1, oxygen contracted rings (from all gestational ages tested) contract further upon addition of indomethacin (1 pg/ml). Vessels from animals less than 110 days gestation have a significantly larger indomethacin induced contraction (1.10 f .17 g/mm2, p < .025 unpaired t-test) than vessels near term (0.52 t .12 g/mm2). In addition, the indomethacin induced contraction in animals less than 110 days gestation represents a significantly larger proportion of the combined oxygen plus indomethacin induced contraction than it does in animals near term (p < ,001 unpaired t-test). DISCUSSION Vessels less than 110 days gestational age have a significantly reduced response to oxygen in comparison with those from older animals; however, inhibition of prostaglandin production in rings less than 110 days results in a total combined oxygen and indomethacin induced tension that is not significantly different
JUNE
1978 VOL. 15 NO. 6
995
6A
Tension 4-
n=/6
H
(g/mm* 1
lndomethocin findomethacin
lndomethocin Totol
O-
Gestotionol Age (days)
JO-+ .03
87- 110
f 02 /
,I6 t .02
111-130
Fig. 1. Comparisonof oxygen and indomethacininduced contraction in lamb ductus arteriosusat different gestationalages. Rings of the ductus arteriosusfrom fetal lambs (87-110days, 111-130 days, and 135-150 days) were suspendedin a low PO2 (16 to 20 torr) solution. The rings were stretched to an initial length which has been shown to produce a maximal contractileresponse for rings in that age group. The bars represent the mean (A SEM) increase in tension produced by the oxygen induced contraction,the indomethacin induced contractionand the combined total oxygen and indomethacininduced contraction. Only the oxygen induced contraction in the 87-110 days group is significantlysmaller than the oxygen induced contractionin the 135-150 days group. However, the combined total oxygen and indomethacininduced contraction in the 87-110 days group is not significantlydifferent from the oxygen-inducedor total combined oxygen and indomethacininduced contractionin the 135-150 days group. The number under each histogram is the ratio of the indomethatin induced contractionto the combined total oxygen and indomethacin induced contractionin that age group.
996
JUNE
1978 VOL. 15 NO, 6
PROSTAGLANDINS
from the oxygen-inducedor total combined oxygen and indomethacin induced tension developed in rings from animals near term. This is consistentWith the hypothesis that, early during gestation, endogenousprostaglandinsinhibit the vessel's ability to contract in response to oxygen. In addition, indomethacinprwed to be more effective in producing contractionin the more immaturevessels. Although the differencein effectivenessmay reflect a change in the sensitivityof the prostaglandinbiosyntheticsystem to indomethacin,it may also represent a change in the sensitivity of the vessel to, or a change in the synthesisand degradationof, locally produced prostaglandinsduring development. This question will require further elucidation. It is unlikely that the action of indomethacinon the ductus arteriosus,in the above studies, occurs by a nonspecificaction of the drug (8). Few of the other enzymes known to be susceptible to indomethacinare inhibitedby the concentrationsused here (8, 9). Prostaglandinsynthetaseinhibitorsbehave similarlyon the ductus arteriosusdespite their structuraldiversity (3,lO).Furthermore,nonspecificeffects of indomethacin(e.g., inhibitionof phosphodiesteraseand prostaglandin15-dehydrogenaseactivity, or uncouplingof oxidativephosphorylation)would have led to relaxation rather than contraction. The current findings support the concept of the continued sensitivityof the ductus arteriosusto prostaglandsin the oxygen environmentof postnatal,as well as prenatal, existence. If the tone of the vessel representsa balance between contracting (e.g., oxygen) and relaxing (e.g., prostaglandins)influences,then it is possible that patency of the ductus arteriosusin premature infants is due to an alterationin the metabolism of endogenous prostaglandins,and not to a lack of responsivenessto oxygen. The use of indomethacinto constrict the patent ductus arteriosus in preterm infants supports this hypothesis(11,12). ACKNOWTZUGEMWTS This work was supportedby USPHS Program Project Grant HL06285 and WL-21409-01from the National Heart, Lung, and Blood Institute. We wish to thank Ms. ChristineRoman for her helpful assistance, and Ms. Anne Marsh for her skillful help in the preparation of this manuscript. Correspondenceshould be sent to Ronald I. Clyman, 1403-E%, Universityof California-SanFrancisco,San Francisco,California 94143.
JUNE
1978 VOL. 15 NO. 6
997
PROSTAGLANDINS
REFERENCES 1.
Starling, MB., and R.B. Elliott. The Effects of Prostaglandins, prostaglandin inhibitors, and oxygen on the closure of the ductus arteriosus, pulmonary arteries and umbilical vessels in vitro. Prostaglandins 8:187, 1974.
2.
Coceani, F., and P.M. Olley. The response of the ductus arteriosus to prostaglandins. Can. J. Physiol. Pharmacol. -51:220, 1973.
3.
Coceani, F., P.M. Olley, and E. Bodach. Lamb ductus arteriosus: Effect of prostaglandin synthesis inhibitors on the muscle tone and the response to prostaglandin E2. Prostaglandins 2:299, 1975.
4.
Olley, P.M., E. Bodach, J. Heaton, and F. Coceani. Further evidence implicating E-type prostaglandins in the patency of the lamb ductus arteriosus. Eur. J. Pharmacol. -3.4~247,1975.
5.
Larsson. Studies on cloSharpe, G.L., B. Thalme, and K.S. sure of the ductus arteriosus XI. Prostaglandins 8_:363, 1974.
6.
Sharpe, G.L., K.S. Larsson, and B. Thalme. Studies on closure of the ductus arteriosus XII. Prostaglandins 2:585, 1975.
7.
Clyman, R.I., MA. Heymann, and A.M. Rudolph. Ductus arteriosus responses to prostaglandin El at high and low oxygen concentrations. Prostaglandins =:219, 1977.
8.
Flower, R.J., and J.R. Vane. Inhibition of prostaglandin biosynthesis. Biochem. Pharmacol. -23:1439, 1974.
9.
Manku, M.S., and D.F. Horrobin. Indomethacin inhibits responses to all vasoconstrictors in the rat mesenteric vascular bed: Restoration of responses by prostaglandin E2. Prostaglandins -12:369, 1976.
10.
Olley, P.M., E.P. White, E. Bodach, J. Heaton, and F. Coceani. The contractile response of the developing lamb ductus arteriosus to ibuprofen. Circulation -54(Suppl. 2): 168: 1976 (Abstract)
11.
Heymann, M.A., A.M. Rudolph, and N.H. Silverman. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N. Engl. J. Med. -295:530, 1976.
12.
Friedman, W.F., M.J. Hirschklau, M.P. Printz, P.T. Pitlick, and S.E. Kirkpatrick. Pharmacologic closure of the patent ductus arteriosus in the premature infant. N. Engl. J. Med. -295:526, 1976.
998
JUNE 1978 VOL. 15 NO. 6
DUCTIJSARTERIOSUS:DEVELOPMENTALRESPONSE TO OXYGEN AND INDOMETRACIN Ronald I. Clyman,Franyoise Mauray, Michael A. Heymann and Abraham M. Rudolph The CardiovascularResearch Instituteand the Departmentsof Pediatrics,.Obstetrics, Gynecology,and ReproductiveSciences,University of California,San Francisco,California94143, and the Departmentof Pediatrics,Mt. Zion Medical Center, San Francisco, California94115. ABSTRACT It has been suggested that ineffectiveconstrictionin response to an increase in PO2 is the primary cause for delayed closure of the ductus arteriosusin preterm infants. We studied the isometriccontractileeffects of increasedPO2 and indomethatin on isolated rings of lamb ductus arteriosusfrom animals of different gestationalages (87 to 147 days, term is 150 days). Rings from animals less than 110 days have a significantlysmaller oxygen-inducedcontraction (2.53 + .30 g/mm2, n = 16) when compared with rings from animals near term (4.59 + .69 g/mm2, n = 9). Oxygen contractedrings from all gestationalages contract further upon addition of 1 ug/ml indomethacin. Rings from animals less than 110 days have a significantlylarger indomethacininduced contraction(1.10 f .17 g/mm2, n = 16) than vessels near term (0.52 + .12 g/nm2, n - 9). Inhibitionof prostaglandinproduction in rings less than 110 days results in a total combined oxygen and indomethacininduced tension that is not significantlydifferent from the oxygen or oxygen and indomethacininduced tension developed in rings from animals near term. This is consistentwith the hypothesis that, early during gestation,endogenousprostaglandins inhibit the vessel's ability to contract in response to oxygen. These observationsare also consistentwith the ability of indomethacinto constrict the patent ductus arteriosusin preterm infants. INTRODUCTION There is now convincingevidence that prostaglandinsmaintain the patency of the ductus arteriosusin the fetus near term. ProstaglendinsEl (PGIQ) and E2 (PGE2) relax the isolated calf and lamb ductus arteriosusin a low oxygen environment(1,2). Pretreatmentof isolated lamb ductus arteriosuswith prostaglandin synthesisinhibitors (indomethacinand eicosa-5,8,11,14-tetraynoic acid) also contracts the hypoxic vessel (3). Blockers of prostaglandin synthesis,when given to pregnant mothers near term, constrict the ductus arteriosusof fetal rats, rabbits, and lambs in vivo (4-6). An increasingsensitivityto indomethacinhas beendemonstratedas fetal rats approach term gestation (6).
JUNE
1978 VOL. 15 NO. 6
993
PROSTAGLANDINS
Recently we have observed (7) that the isolated lamb ductus arteriosus exposed to high oxygen tension is as sensitive to PGEl and PGE2 as it is in a low oxygen environment. In the experiments reported herein, the contracting effects of indomethacin on the isolated lamb ductus arteriosus from different gestational age groups were examined at high oxygen tensions. Indomethacin caused further contraction of the ductus arteriosus already constricted by elevated P02. This is consistent with the hypothesis that endogenous prostaglandins inhibit the tendency of the vessel to contract in response to oxygen. In contrast with studies in the rat, we found a more intense response to indomethacin in the youngest fetuses indicating that the prostaglandin mechanism develops early during gestation. MFTHODS AND MATERIALS Time dated fetal lambs, between 87 and 147 days gestational age (term is 150 days), were delivered by cesarean section and rapidly killed by exsanguination. The ductus arteriosus was dissected free from adventitial tissue and divided into 3 to 4 1 mm thick rings which were placed into separate 150 ml lucite plastic organ baths (fluid removed by draining) enclosed in a box excluding light. The rings were suspended between 2 stainless steel hooks in a solution containing 127 mM NaCl, 5 mM KCl, 2.5 mM CaC12, 1.27 mM MgCl2*6H2O, 5.5 mM glucose, and 50 mM Tris*HCl, pH 7.39 at 37OC. Isometric responses of circumferential tension were measured by a Grass FT03C force transducer and recorded on a Grass polygraph. Small samples of the bathing solution were withdrawn and pH and PO2 were measured using Radiometer electrodes and blood gas meter. Each of the rings from a single vessel was stretched to an initial length that would result in a maximal contractile response to increases in oxygen tension for rings in that age group. Rings from animals between 87 and 110 days were stretched to initial lengths of 6, 7, or 8 mm; rings from animals between 111 and 130 days were stretched to 8 or 9 mm; rings from animals between 136 and 147 days were stretched to 9 or 10 mm (unpublished results). The bathing solution in each bath was bubbled with 100% nitrogen (to a PO2 of 16 to 20 torr) and the tissues allowed to equilibrate for 45 min until a steady tension was developed. The tissues then were exposed to 100% oxygen (to a PO2 of 680 to 720 torr) for 1 hour allowing the tension to achieve a new plateau. The oxygen-induced contraction was considered as the difference in the tensions at high and low PO2. After the rings reached a new steady tension in the high PO2 environment, indomethacin was added to the bath in a final concentration of 1 ug/ml (2.8 x 10-6 M) and the rings were allowed to achieve a new increase in tension over the next hour. Additional doses of indomethacin to a final concentration of 5 pg/ml or 10 pgfml produced no further increase in tension. The indomethacin-induced contraction was considered as the difference in the steady tensions at high PO2 and high PO2
994
JUNE
1978 VOL. 15 NO. 6
PROSTAGLANDINS
plus indomethacin (1 ug/ml). Following the experiment the tissues were removed from the baths and blotted dry before weighing (wet weight). The tension developed in the tissue was expressed as force/ unit area (g/mm2). This area was the surface of the tissue which was perpendicular to the direction of the force. Since the ring samples assume a flattened shape when stretched to their initial length, the cross-sectional area was computed as the area of a rectangle whose length was the initial length of the stretched tissue. In order to calculate the cross-sectional area of this rectangle the tissue density was assumed to be 1. Therefore, a tissue with a wet weight of 1 mg was assumed to have a volume of 1 mm3 and the surface area perpendicular to the force was calculated by dividing this volume by the initial length of stretch. Indomethacin (Sigma) was prepared in ethanol (16 mg/ml) and aliquots were added to the bath solution. The maximal concentration of ethanol in the bath (0.06%) had no effect on tissue contractility. RESULTS The response of the ductus arteriosus to an increase in PO2 was similar to that reported previously(7) . Figure 1 shows the oxygen induced contraction in rings (from 3 different gestational age groups) which were stretched to initial lengths that result in maximal contractile responses for rings in that age group. Vessels from 111 to 130 days gestation develop the same tension (4.26 + .46 g/mm2 , 2 SEM) as vessels near term (4.59 f .69 g/mm2>. Only vessels from animals less than 110 days gestation have a significantly smaller oxygen induced contraction (2.53 + .30 g/mm2, p < .005 unpaired t-test) when compared with vessels near term. The oxygen induced response of animals less than 110 days is about 55% of the response in animals near term. As can be seen from Figure 1, oxygen contracted rings (from all gestational ages tested) contract further upon addition of indomethacin (1 pg/ml). Vessels from animals less than 110 days gestation have a significantly larger indomethacin induced contraction (1.10 f .17 g/mm2, p < .025 unpaired t-test) than vessels near term (0.52 t .12 g/mm2). In addition, the indomethacin induced contraction in animals less than 110 days gestation represents a significantly larger proportion of the combined oxygen plus indomethacin induced contraction than it does in animals near term (p < ,001 unpaired t-test). DISCUSSION Vessels less than 110 days gestational age have a significantly reduced response to oxygen in comparison with those from older animals; however, inhibition of prostaglandin production in rings less than 110 days results in a total combined oxygen and indomethacin induced tension that is not significantly different
JUNE
1978 VOL. 15 NO. 6
995
6A
Tension 4-
n=/6
H
(g/mm* 1
lndomethocin findomethacin
lndomethocin Totol
O-
Gestotionol Age (days)
JO-+ .03
87- 110
f 02 /
,I6 t .02
111-130
Fig. 1. Comparisonof oxygen and indomethacininduced contraction in lamb ductus arteriosusat different gestationalages. Rings of the ductus arteriosusfrom fetal lambs (87-110days, 111-130 days, and 135-150 days) were suspendedin a low PO2 (16 to 20 torr) solution. The rings were stretched to an initial length which has been shown to produce a maximal contractileresponse for rings in that age group. The bars represent the mean (A SEM) increase in tension produced by the oxygen induced contraction,the indomethacin induced contractionand the combined total oxygen and indomethacininduced contraction. Only the oxygen induced contraction in the 87-110 days group is significantlysmaller than the oxygen induced contractionin the 135-150 days group. However, the combined total oxygen and indomethacininduced contraction in the 87-110 days group is not significantlydifferent from the oxygen-inducedor total combined oxygen and indomethacininduced contractionin the 135-150 days group. The number under each histogram is the ratio of the indomethatin induced contractionto the combined total oxygen and indomethacin induced contractionin that age group.
996
JUNE
1978 VOL. 15 NO, 6
PROSTAGLANDINS
from the oxygen-inducedor total combined oxygen and indomethacin induced tension developed in rings from animals near term. This is consistentWith the hypothesis that, early during gestation, endogenousprostaglandinsinhibit the vessel's ability to contract in response to oxygen. In addition, indomethacinprwed to be more effective in producing contractionin the more immaturevessels. Although the differencein effectivenessmay reflect a change in the sensitivityof the prostaglandinbiosyntheticsystem to indomethacin,it may also represent a change in the sensitivity of the vessel to, or a change in the synthesisand degradationof, locally produced prostaglandinsduring development. This question will require further elucidation. It is unlikely that the action of indomethacinon the ductus arteriosus,in the above studies, occurs by a nonspecificaction of the drug (8). Few of the other enzymes known to be susceptible to indomethacinare inhibitedby the concentrationsused here (8, 9). Prostaglandinsynthetaseinhibitorsbehave similarlyon the ductus arteriosusdespite their structuraldiversity (3,lO).Furthermore,nonspecificeffects of indomethacin(e.g., inhibitionof phosphodiesteraseand prostaglandin15-dehydrogenaseactivity, or uncouplingof oxidativephosphorylation)would have led to relaxation rather than contraction. The current findings support the concept of the continued sensitivityof the ductus arteriosusto prostaglandsin the oxygen environmentof postnatal,as well as prenatal, existence. If the tone of the vessel representsa balance between contracting (e.g., oxygen) and relaxing (e.g., prostaglandins)influences,then it is possible that patency of the ductus arteriosusin premature infants is due to an alterationin the metabolism of endogenous prostaglandins,and not to a lack of responsivenessto oxygen. The use of indomethacinto constrict the patent ductus arteriosus in preterm infants supports this hypothesis(11,12). ACKNOWTZUGEMWTS This work was supportedby USPHS Program Project Grant HL06285 and WL-21409-01from the National Heart, Lung, and Blood Institute. We wish to thank Ms. ChristineRoman for her helpful assistance, and Ms. Anne Marsh for her skillful help in the preparation of this manuscript. Correspondenceshould be sent to Ronald I. Clyman, 1403-E%, Universityof California-SanFrancisco,San Francisco,California 94143.
JUNE
1978 VOL. 15 NO. 6
997
PROSTAGLANDINS
REFERENCES 1.
Starling, MB., and R.B. Elliott. The Effects of Prostaglandins, prostaglandin inhibitors, and oxygen on the closure of the ductus arteriosus, pulmonary arteries and umbilical vessels in vitro. Prostaglandins 8:187, 1974.
2.
Coceani, F., and P.M. Olley. The response of the ductus arteriosus to prostaglandins. Can. J. Physiol. Pharmacol. -51:220, 1973.
3.
Coceani, F., P.M. Olley, and E. Bodach. Lamb ductus arteriosus: Effect of prostaglandin synthesis inhibitors on the muscle tone and the response to prostaglandin E2. Prostaglandins 2:299, 1975.
4.
Olley, P.M., E. Bodach, J. Heaton, and F. Coceani. Further evidence implicating E-type prostaglandins in the patency of the lamb ductus arteriosus. Eur. J. Pharmacol. -3.4~247,1975.
5.
Larsson. Studies on cloSharpe, G.L., B. Thalme, and K.S. sure of the ductus arteriosus XI. Prostaglandins 8_:363, 1974.
6.
Sharpe, G.L., K.S. Larsson, and B. Thalme. Studies on closure of the ductus arteriosus XII. Prostaglandins 2:585, 1975.
7.
Clyman, R.I., MA. Heymann, and A.M. Rudolph. Ductus arteriosus responses to prostaglandin El at high and low oxygen concentrations. Prostaglandins =:219, 1977.
8.
Flower, R.J., and J.R. Vane. Inhibition of prostaglandin biosynthesis. Biochem. Pharmacol. -23:1439, 1974.
9.
Manku, M.S., and D.F. Horrobin. Indomethacin inhibits responses to all vasoconstrictors in the rat mesenteric vascular bed: Restoration of responses by prostaglandin E2. Prostaglandins -12:369, 1976.
10.
Olley, P.M., E.P. White, E. Bodach, J. Heaton, and F. Coceani. The contractile response of the developing lamb ductus arteriosus to ibuprofen. Circulation -54(Suppl. 2): 168: 1976 (Abstract)
11.
Heymann, M.A., A.M. Rudolph, and N.H. Silverman. Closure of the ductus arteriosus in premature infants by inhibition of prostaglandin synthesis. N. Engl. J. Med. -295:530, 1976.
12.
Friedman, W.F., M.J. Hirschklau, M.P. Printz, P.T. Pitlick, and S.E. Kirkpatrick. Pharmacologic closure of the patent ductus arteriosus in the premature infant. N. Engl. J. Med. -295:526, 1976.
998
JUNE 1978 VOL. 15 NO. 6