Ductus Arteriosus Rings Research Articles

Ontogeny of chicken ductus arteriosus response to oxygen and vasoconstrictors

The present study aimed to characterize the contractile reactivity of the chicken ductus arteriosus (DA) from the last stage of prenatal development and throughout the perinatal period. Isolated DA rings from 15-day, noninternally-pipped 19-day, and externally-pipped 21-day embryos were studied using myograph techniques. On embryonic day 15, the chicken DA did not respond to O(2) (0 to 21%), norepinephrine (NE), or phenylephrine (Phe) but contracted in response to high-K(+) solution, the inhibitor of voltage-gated channels 4-aminopyridine, U-46619, and endothelin (ET)-1. These responses increased with advancing incubation age. Contractile responses to O(2), NE, and Phe were present in the 19- and 21-day embryo. Oxygen-induced contraction was restricted to the pulmonary side of the DA and was augmented by the nitric oxide synthase inhibitor N(omega)-nitro-l-arginine methyl ester and the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one and reduced by the peptidic ET(A) and ET(B)-receptor antagonist PD-142,893. Transmural electrical stimulation of nerves, the nonselective cyclooxygenase (COX) inhibitor indomethacin, the COX-1 inhibitor valeryl salicylate, the COX-2 inhibitor nimesulide, the inhibitor of ATP-sensitive K(+) channels glibenclamide, and the inhibitor of Ca(2+)-activated K(+) channels tetraethylammonium did not cause contraction of the DA rings at any age. We conclude that transition to ex ovo life is accompanied by dramatic changes in chicken DA reactivity. At 0.7 incubation, excitation-contraction and pharmacomechanical coupling for several contractile agonists are already present, whereas the constrictor effects of O(2) and cathecolamines appear later in development and are located in the pulmonary side of the DA.

Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus.

Oxygen (O2)-sensitive K+ channels mediate acute O2 sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O2-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O2 constriction in preterm DA is reduced expression and function of O2-sensitive, voltage-gated (Kv) channels. Preterm rabbit DA rings have reduced O2 constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O2-sensitive K+ current. This is associated with decreased mRNA and protein expression of certain O2-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O2 responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O2 constriction in human DAs. These data demonstrate a central role for developmentally regulated DASMC O2-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O2 responsiveness, including persistent DA.

Opposite effects of redox status on membrane potential, cytosolic calcium, and tone in pulmonary arteries and ductus arteriosus.

At birth, associated with the rise in oxygen tension, the pulmonary arteries (PA) dilate and the ductus arteriosus (DA) constricts. Both PA and DA constrict with vasoconstrictors and dilate with vasodilators. They respond in a contrary manner only to changes in oxygen tension. We hypothesized that the effects of changes in oxygen are mediated by changes in redox status. Consequently, we tested whether a reducing agent, DTT, and an oxidizing agent, dithionitrobenzoic acid (DTNB), would have opposite effects on a major oxygen signaling pathway in the PA and DA smooth muscle cells (SMCs), the sequence of change in potassium current (IK), membrane potential (Em), cytosolic calcium, and vessel tone. Under normoxic conditions, DTT constricted adult and fetal resistance PA rings, whereas in DA rings DTT acted as a potent vasodilator. In normoxia, voltage-clamp measurements showed inhibition of IK by DTT in PASMCs and, in contrast, activation in DASMCs. Consequently, DTT depolarized fetal and adult PASMCs and hyperpolarized DASMCs. [Ca2+]i was increased by DTT in fetal and adult PASMCs and decreased in DASMCs. Under hypoxic conditions, DTNB constricted DA rings and caused vasodilatation in fetal PA rings. DTNB inhibited IK and depolarized the cell membrane in DASMCs. In contrast, activation of IK and hyperpolarization was seen in PASMCs. Thus the same redox signal can elicit opposite effects on IK, Em, cytosolic calcium, and vascular tone in resistance PA and the DA. These observations support the concept that redox changes could signal the opposite effects of oxygen in the PA and DA.

O2 sensing in the human ductus arteriosus: regulation of voltage-gated K+ channels in smooth muscle cells by a mitochondrial redox sensor.

Functional closure of the human ductus arteriosus (DA) is initiated within minutes of birth by O2 constriction. It occurs by an incompletely understood mechanism that is intrinsic to the DA smooth muscle cell (DASMC). We hypothesized that O2 alters the function of an O2 sensor (the mitochondrial electron transport chain, ETC) thereby increasing production of a diffusible redox-mediator (H2O2), thus triggering an effector mechanism (inhibition of DASMC voltage-gated K+ channels, Kv). O2 constriction was evaluated in 26 human DAs (12 female, aged 9+/-2 days) studied in their normal hypoxic state or after normoxic tissue culture. In fresh, hypoxic DAs, 4-aminopyridine (4-AP), a Kv inhibitor, and O2 cause similar constriction and K+ current inhibition (I(K)). Tissue culture for 72 hours, particularly in normoxia, causes ionic remodeling, characterized by decreased O2 and 4-AP constriction in DA rings and reduced O2- and 4-AP-sensitive I(K) in DASMCs. Remodeled DAMSCs are depolarized and express less O2-sensitive channels (including Kv2.1, Kv1.5, Kv9.3, Kv4.3, and BK(Ca)). Kv2.1 adenoviral gene-transfer significantly reverses ionic remodeling, partially restoring both the electrophysiological and tone responses to 4-AP and O2. In fresh DASMCs, ETC inhibitors (rotenone and antimycin) mimic hypoxia, increasing I(K) and reversing constriction to O2, but not phenylephrine. O2 increases, whereas hypoxia and ETC inhibitors decrease H2O2 production by altering mitochondrial membrane potential (DeltaPsim). H2O2, like O2, inhibits I(K) and depolarizes DASMCs. We conclude that O2 controls human DA tone by modulating the function of the mitochondrial ETC thereby varying DeltaPsim and the production of H2O2, which regulates DASMC Kv channel activity and DA tone.

Sildenafil reverses O2 constriction of the rabbit ductus arteriosus by inhibiting type 5 phosphodiesterase and activating BK(Ca) channels.

Oxygen constriction causes functional closure of the ductus arteriosus (DA) at birth. Although DA closure is crucial for postnatal adaptation, patency of the DA is critical for survival of newborns with duct-dependent cardiac malformations. In these cases, DA patency is achieved by i.v. infusion of prostaglandin E1, which, though effective, is often associated with complications. We hypothesized that sildenafil, a specific phosphodiesterase type 5 inhibitor, is an effective DA vasodilator. In isolated DA rings from term (d 30) fetal rabbits, sildenafil (10(-6)-10(-4) M) and diethylamine NONOate (10(-7)-10(-5) M) induced dose-dependent relaxation of oxygen-constricted DA (-52 +/- 4% and -51 +/- 6%, respectively) that was inhibited by the soluble guanylyl-cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (5 x 10(-5) M). Sildenafil increased cyclic GMP levels. Iberiotoxin (200 nM), an inhibitor of calcium-sensitive potassium channels, decreased the vasodilatory effect of sildenafil and diethylamine NONOate (-30 +/- 2% and -27 +/- 4%, respectively). Oxygen inhibition of whole-cell K+ current and membrane depolarization were partially restored by sildenafil, and this was inhibited by iberiotoxin. Immunohistochemistry and immunoblotting confirmed the presence of phosphodiesterase type 5 and calcium-sensitive potassium channels in the DA smooth muscle cells. This is the first study to demonstrate that sildenafil dilates the DA by increasing soluble guanylyl-cyclase-derived cGMP levels and thereby activating calcium-sensitive potassium channels, causing membrane hyperpolarization. Sildenafil, already approved for human usage, might be an alternative or a useful adjunct to prostaglandin E1 as a bridge to cardiac surgery.

Factors that increase the contractile tone of the ductus arteriosus also regulate its anatomic remodeling.

Permanent closure of the full-term newborn ductus arteriosus (DA) occurs only if profound hypoxia develops within the vessel wall during luminal obliteration. We used fetal and newborn baboons and lambs to determine why the immature DA fails to remodel after birth. When preterm newborns were kept in a normoxic range (Pa(O(2)): 50-90 mmHg), 86% still had a small patent DA on the sixth day after birth; in addition, the preterm DA wall was only mildly hypoxic and had only minimal remodeling. The postnatal increase in Pa(O(2)) normally induces isometric contractile responses in rings of DA; however, the excessive inhibitory effects of endogenous prostaglandins and nitric oxide, coupled with a weaker intrinsic DA tone, make the preterm DA appear to have a smaller increment in tension in response to oxygen than the DA near term. We found that oxygen concentrations, beyond the normoxic range, produce an additional increase in tension in the preterm DA that is similar to the contractile response normally seen at term. We predicted that preterm newborns, kept at a higher Pa(O(2)), would have increased DA tone and would be more likely to obliterate their lumen. We found that preterm newborns, maintained at a Pa(O(2)) >200 mmHg, had only a 14% incidence of patent DA. Even though DA constriction was due to elevated Pa(O(2)), obliteration of the lumen produced profound hypoxia of the DA wall and the same features of remodeling that were observed at term. DA wall hypoxia appears to be both necessary and sufficient to produce anatomic remodeling in preterm newborns.

Redox control of oxygen sensing in the rabbit ductus arteriosus.

How the ductus arteriosus (DA) closes at birth remains unclear. Inhibition of O2-sensitive K+ channels may initiate the closure but the sensor mechanism is unknown. We hypothesized that changes in endogenous H2O2 could act as this sensor. Using chemiluminescence measurements with luminol (50 [mu]M) or lucigenin (5 [mu]M) we showed significantly higher levels of reactive O2 species in normoxic, compared to hypoxic DA. This increase in chemiluminescence was completely reversed by catalase (1200 U ml-1). Prolonged normoxia caused a significant decrease in K+ current density and depolarization of membrane potential in single fetal DA smooth muscle cells. Removal of endogenous H2O2 with intracellular catalase (200 U ml-1) increased normoxic whole-cell K+ currents (IK) and hyperpolarized membrane potential while intracellular H2O2 (100 nM) and extracellular t-butyl H2O2 (100 [mu]M) decreased IK and depolarized membrane potential. More rapid metabolism of O2- with superoxide dismutase (100 U ml-1) had no significant effect on normoxic K+ currents. N-Mercaptopropionylglycine (NMPG), duroquinone and dithiothreitol all dilated normoxic-constricted DA rings, while the oxidizing agent 5,5'-dithiobis-(2-nitrobenzoic acid) constricted hypoxia-dilated rings. NMPG also increased IK. We conclude that increased H2O2 levels, associated with a cytosolic redox shift at birth, signal K+ channel inhibition and DA constriction.

Endothelin-receptor blockade does not alter closure of the ductus arteriosus.

Endothelin-1 (ET-1) is synthesized within the wall of the ductus arteriosus (DA) and is a potent constrictor of the DA in vitro. However, the role of endogenous ET-1 in closure of the DA at birth remains unclear. Therefore, we studied the effects of a selective ETA-receptor antagonist (PD-156707), or its vehicle, on DA closure in 13 late-gestation fetal lambs during the first 5 h after birth. We also studied the effects of ETA-receptor blockade on DA constriction induced by oxygen, indomethacin (a cyclooxygenase inhibitor), and LY-83583 (a soluble guanylate cyclase inhibitor) in vitro (n = 9 ductus arteriosus rings). In vehicle-treated lambs in vivo, the DA constricted during the 5-h study period after birth: DA resistance increased (from 0.007 +/- 0.01 to 3.406 +/- 4.15 mmHg. ml-1. min. kg-1; P < 0.05); the pressure gradient across the DA increased (from 1.4 +/- 2.1 to 25.2 +/- 9.4 mmHg; P < 0.05); and DA blood flow decreased (from 193.5 +/- 48.0 to 19.3 +/- 14.3 ml. kg-1. min-1; P < 0.05). In vitro, the DA was constricted by exposure to 30% oxygen (23 +/- 14% net active tension; P < 0.05), indomethacin (5 x 10(-6) M, 22 +/- 5% net active tension; P < 0.05), LY-83583 (10(-5) M, 24 +/- 10% net active tension; P < 0.05), and ET-1 (10(-7) M, 19 +/- 4% net active tension; P < 0.05). Although PD-156707 blocked both the in vivo and in vitro effects of exogenous ET-1, it had no effect on postnatal ductus constriction nor on in vitro ductus contractile responses to oxygen, indomethacin, or LY-83583. This study suggests that endogenous ET-1 does not play an important role in closure of the DA at birth.

Adrenomedullin Blocks Closure of the Ductus Arteriosus in Newborn Lambs.† 144

Adrenomedullin (ADM) is a potent vasodilator peptide. To evaluate the effects of ADM on the ductus arteriosus (DA), we studied 16 near-term fetal sheep. We examined isolated rings of DA from 6 fetuses and measured isometric force generation to obtain concentration-response curves. ADM dilated the precontracted DA in a dose-dependent manner (ED50=3.5×10-8 M). This effect was not inhibited by Nw-nitro-L-arginine methyl ester. In 10 fetuses, we examined whether exogenous ADM inhibits closure of the DA after birth in vivo. Catheters were inserted into the main pulmonary artery and the ascending aorta to measure pressures, and into the superior vena cava (SVC) to administer drugs. An ultrasonic flow transducer was placed around the DA and the left pulmonary artery to measure flow continuously. Fetuses were delivered by cesarean section, two days after surgery, and were mechanically ventilated for 4 hours. In 5 fetuses, ADM was infused continuously into the SVC (0.18μg/kg*min) starting 45 min prior to delivery; 5 non-infused fetuses acted as controls. Hemodynamic variables were statistically compared between the two groups before and every 30 min after delivery. The mean pressure gradient from the ascending aorta to the pulmonary artery (mmHg), blood flow (ml/min*kg), and resistance (mmHg*min*kg/ml) across the DA in the ADM and control groups are shown in the table (*: p<0.05). At necropsy, in opposition to the controls, each DA was widely open in ADM group. These in-vitro and in-vivo data suggest that ADM has potent vasodilatory effects on the DA in fetal sheep and that this peptide can inhibit natural closure of the DA after birth.

The effect of passive stretch on the response of the fetal rabbit ductus arteriosus to indomethacin, noradrenaline and prostaglandin E2.

The aim of this study was to determine the effect of varying stretch of the ductus arteriosus on its contractile response to indomethacin and noradrenaline, and its relaxant response to prostaglandin (PG) E2. Isolated rings of ductus arteriosus obtained from fetal New Zealand White rabbits at 28 days gestation were mounted in vitro for measurement of isometric tension by a transducer connected to a vernier control. The responses of the ductus to drugs at varying degrees of passive stretch were corrected to a standard contraction in response to 65 mM potassium at a standard level of stretch. Increasing stretch across the range 1.0-5.9 mN increased the contractile response to indomethacin and noradrenaline (the latter in the presence of 1 microM indomethacin and 1 or 10 nM PGE2) in a virtually identical manner. The sensitivity of the vessel to noradrenaline in the presence and absence of indomethacin and its sensitivity to the relaxant effect of PGE2 in the presence of indomethacin were unaffected by increasing stretch. The extent of contractile tone present which was not inhibited by endogenous PGE2 increased with increasing stretch. It was concluded that: (1) the contractile response to indomethacin can be profoundly altered by the degree of spontaneous tone in the vessel; (2) the magnitude of the contraction induced by indomethacin is not a good index of the degree of inhibition exerted by locally produced PGs in the vessel; and (3) locally produced PGs are likely to have a physiological role in maintaining patency of the ductus arteriosus in utero.

Contractile effects of prostanoids on fetal rabbit ductus arteriosus.

We wished to determine whether any evidence indicates that the ductus arteriosus has prostanoid receptors coupled to contractile pathways and whether the sensitivity of the ductus to the dilator effect of prostaglandin E2 (PGE2) was inhibited by other prostanoids. Rings of ductus arteriosus were isolated from fetal New Zealand White rabbits (28 days of gestation) and mounted in vitro. In the presence of 1 microM indomethacin, the vessel was relaxed with either 300 nM forskolin or 10 nM PGE2, and cumulative concentration-contraction response curves to several synthetic prostanoids were obtained with or without a receptor antagonist when available. The vessel was also precontracted with 1 microM indomethacin and 25 mM K+ in 13-14.5 kPa O2, and cumulative concentration-relaxation response curves to PGE2 were obtained with and without addition of prostanoids. In 300 nM forskolin, both U46619 and sulprostone caused concentration-dependent contractions of the ductus in the nanomolar range (EC50 values, i.e., the interpolated molar concentration of the drug causing 50% of its own eventual maximum response of 33 and 42 nM, respectively). Responses to GR63799X and PGF2 alpha were complicated by the fact that these agonists caused relaxation at high concentrations (> or = 30 nM). The response to U46619 was shifted to the right by the thromboxane receptor antagonist EP 092. In 10 nM PGE2, U46619, sulprostone, and GR63799X elicited similar contractile responses, whereas PGF2 alpha had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactions between indomethacin, noradrenaline and vasodilators in the fetal rabbit ductus arteriosus

1. Interactions between indomethacin, noradrenaline and vasodilators were studied in rings of ductus arteriosus isolated from fetal rabbits. The effect of incubation with prostaglandin E2 (PGE2) on the noradrenaline concentration-contraction response curve was studied in the presence and absence of indomethacin. Also, the ductus was pre-contracted with 10 microM noradrenaline and concentration-relaxation response curves (CRRC) to PGE2, cicaprost, cromakalim and forskolin were obtained in the presence and absence of indomethacin. 2. In the absence of indomethacin, PGE2 (from 1 nM to 100 nM) decreased the pEC50 to noradrenaline to a maximum of 0.4 to 0.5 log units (i.e. an approximately three fold increase in EC50 [M]). In the presence of 1 microM indomethacin, PGE2 (0.1 nM to 100 nM) decreased the pEC50 to noradrenaline by 2.39 log units (i.e. a 245 fold increase in EC50). By comparing the control pEC50 to noradrenaline with the relationship between the pEC50 to noradrenaline and [PGE2] in 1 microM indomethacin, the effect of endogenous PGE2 synthesized in the vessel wall was estimated as being equivalent to a bath concentration of approximately 1 nM exogenous PGE2. 3. When the vessel was pre-contracted with 10 microM noradrenaline, indomethacin had no effect on the CRRC to PGE2 but did alter the CRRC to other vasodilators. The sensitivity of the vessel to cicaprost, cromakalim and forskolin was decreased in 1 microM indomethacin compared with control. Forskolin caused complete relaxation in the presence and absence of indomethacin. Indomethacin decreased the maximum response to cromakalim but increased the maximum response to cicaprost. PGE2, 0.3 nm, partially reversed the effect of indomethacin on the sensitivity of the vessel to forskolin.4. We conclude that under varying experimental conditions, indomethacin increased the sensitivity of the ductus to the effects of PGE2 but decreased its sensitivity to other vasodilators. Both effects can be explained by elimination of endogenous PGE2. However, indomethacin increased the maximum response to cicaprost, which cannot be explained by elimination of endogenous PGE2 but may be due to elimination of endogenous prostacyclin.

DECREASED CONTRACTILITY OF THE DUCTUS ARTERIOSUS IN EXPERIMENTAL PULMONIC STENOSIS

Delayed closure of the ductus arteriosus (DA) after birth has been observed in newborn infants with critical pulmonic stenosis (PS) and in lambs with experimental PS. This delayed closure may be the result of decreased ability to contract when exposed to oxygen or to increased production of or sensitivity to the endogenous DA vasodilator, prostaglandin(PG)E2. To determine if the abnormal hemodynamic pattern during fetal life associated with PS alters the responsiveness of the DA, we operated on 10 fetal lambs of gestational ages 70-77 days(term is 145 days) and placed a band around the pulmonary artery. Catheterization at 137-142 days showed severe pulmonic stenosis with RV pressure significantly higher in the experimental lambs (110 ± 8, ± SEM, n=10) than RV pressure in control lambs (61 ± 7, n=4, p<.001). We then studied isolated rings of DA from these lambs. The oxygen-induced increase in tension in rings of DA from lambs with PS was significantly decreased (2.55 ± 0.38, n=10) compared to rings from control lambs (4.03 ± 0.51, n=6, p<.03). There was no difference between the 2 groups in either the amount of PGE2 released or in the sensitivity (ED50) of the rings to PGE2. There was also no difference in the increase in tension when endogenous PGE2 was inhibited by indomethacin. We conclude that delayed closure of the DA in experimental PS is not caused by increased sensitivity to and production of PGE2 in the DA (as it is in premature lambs) but rather is the result of a diminished ability of the DA to contract when exposed to oxygen.

270 EXOGENOUS ARACHIDONIC ACID IS NOT CONVERTED TO PROSTAGLANDIN E2 BY THE LAMB DUCTUS ARTERIOSUS

Prostaglandin (PG) E2 regulates the patency of the ductus arteriosus (DA) in the fetus and preterm neonate. Numerous investigators have used exogenous arachidonic acid (aa), a precursor of PG synthesis, to study the biological effects of endogenous PG production. We have shown that 0.2 μg/m1 aa relaxes isometrically-constricted rings of lamb DA in vitro. Since inhibitors of PGE2 production block this relaxation, we postulated that the conversion of exogenous aa to PGE2 causes the relaxation of the DA. To test this hypothesis, we incubated rings of DA from 8 fetal lambs in buffer containing 0.2 μg/ml aa: 47±25 pg immunoreactive PGE2/mg wet weight/90 min incubation (±SEM, n=8) was measured. This is consistent with the above hypothesis. To see if the measured PGE2 is formed from the exogenous aa added to the incubation media or from the endogenous aa pools within the tissue, we incubated another group of rings in buffer containing 14C-labeled aa. We measured the conversion of 14C-aa to PGE2 and tissue phospholipids by radiochromatographic analysis. Only 0.048±0.019 pg radiolabeled PGE2/mg wet weight/90 min incubation (±SEM, n=9) was measured. Thus, only 0.1% of the PGE2 produced when aa is added to rings of DA is formed from the added aa. Although PGE2 mediates the relaxation caused by exogenous aa, the exogenous aa is not converted to PGE2. Rather, exogenous aa appears to be a potent stimulator of phospholipid breakdown in the DA; the subsequent endogenous aa released is the actual source of the PGE2 produced.

Developmental response to indomethacin: A comparison of isometric tension with PGE 2 formation in the lamb ductus arteriosus

We studied the effects of oxygen and indomethacin on the isometric contractile response and the production of PGE 2 in isolated rings of lamb ductus arteriosus from animals of different gestational ages (100 to 144 days; term is 150 days). Rings of ductus arteriosus from animals less than 110 days released significantly less PGE 2 than did rings from animals greater than 120 days. The indomethacin-induced increase in muscle tension in relation to the decrease in endogenous PGE 2 production in preparations from animals less than 110 days gestation was greater than in animals older than 120 days. These findings do not support the hypothesis that immature animals have a larger indomethacin-induced contraction due to an increased production of PGE 2 earlier in gestation. They are, however, consistent with a decreased sensitivity to PGE 2 in the more mature animals; they also support the hypothesis that the decreased effectiveness of indomethacin on the ductus arteriosus from later gestation animals reflects primarily a decrease in the sensitivity of the vessel to PGE 2 during development.

Formation of prostacyclin (PGI 2) by the ductus arteriosus of fetal lambs at different stages of gestation

Prostaglandins appear to play a role in maintaining patency of the ductus arteriosus during gestation. Prostacyclin (PGI 2) is the major product of prostaglandin biosynthesis in the lamb ductus arteriosus. This factor is both a vasodilator and a potent inhibitor of human platelet aggregation. We used inhibition of platelet aggregation as a sensitive bioassay to measure PGI 2 generation in rings of ductus arteriosus from fetal lambs. Mechanical manipulation accelerated the rate of PGI 2 released from the tissue 10 to 50 times. Tranylcypromine, an antagonist of prostacyclin synthetase, suppressed production of PGI 2 by rings of ductus arteriosus. Rings from immature animals (98–103 days gestation, term is 150 days) released significantly more PGI 2 (190 ± 28 ng/g wet weight/ 20 min, n=9) than did those from near term animals (136–146 days; 106 ± 23 ng/g wet weight/20 min, n=10). The capacity of the ductus arteriosus to generate more PGI 2 earlier in gestation is consistent with the observation that vessels from animals less than 110 days gestation have a significantly larger indomethacin induced contraction than do vessels near term.

Patent ductus arteriosus: a new light on an old problem.

Summary: It has been suggested previously that delayed closure of the ductus arteriosus in premature infants is related to an ineffective constriction in response to an increase in arterial PO2. The contractile effects of increased PO2 and excess K+ were studied in rings of ductus arteriosus from early (70 ± 4 days, n> = 9) and late (137 ± 3 days, n> = 11) gestation fetal lambs. Studies were performed in a laboratory using overhead fluorescent lighting or in a dark, enclosed box. Room light relaxed the oxygen-induced contraction in immature vessels but had no significant effect on the K+-induced contraction. Room light did not alter either the oxygen or K+-induced contractile responses in mature vessels. When comparing oxygen induced contractions in room light in immature vessels (0.27 ± 0.13 g, n> =9) vs. mature vessels (0.82 ± 0.06 g, n> = 11) there appeared to be an increased response to oxygen with advancing gestational age. However, when the oxygen-induced responses of immature (0.59 ± 0.15 g, n> = 9) and mature (0.82 ± 0.06 g, n> = 11) vessels were performed in an environment excluding room light, no significant gestational difference was observed. The role of oxygen in delayed closure of the ductus arteriosus of premature infants will need further evaluation. Speculation: The difference in sensitivity to photorelaxation between rings of ductus arteriosus from immature and mature lambs may be associated with biochemical differences in vessels between early and late gestation.