Antenatal betamethasone therapy augments isoproterenol and prostaglandin e2-mediated relaxation of preterm ovine pulmonary veins

ABSTRACT Antenatal glucocorticoid therapy improves pulmonary function in preterm newborns. We have determined the effect of antenatal glucocorticoid therapy on isoproterenol and

prostaglandin (PG) E2-mediated relaxation in preterm ovine pulmonary veins after birth. Ovine fetuses (121 and 126 d of gestation; term = 150 d) received an ultrasound guided intramuscular

injection of betamethasone, 0.5 mg/kg, or saline. Lambs were delivered 15 or 48 h later, ventilated for 3 h, and killed. Isolated fourth generation pulmonary veins were suspended in organ

chambers filled with modified Krebs-Ringer solution(95% O2, 5% CO2) at 37 °C, and their isometric tension was recorded. During contractions to U46619, isoproterenol and PGE2 induced greater

relaxations of pulmonary veins of betamethasone-treated lambs than those of control. Forskolin, an activator of adenylate cyclase, caused greater relaxation in veins of betamethasone-treated

lambs than in those of controls. A greater relaxation of veins treated with betamethasone than that of control veins also occurred in the presence of isobutylmethylxanthine, an inhibitor of

phosphodiesterases. All vessels relaxed similarly to 8-bromo-cAMP, a cell membrane-permeable analog of cAMP. When stimulated with isoproterenol, PGE2, and forskolin, adenylate cyclase

activity of crude membrane preparations of pulmonary veins treated with betamethasone was greater than that of controls. These results demonstrate that antenatal betamethasone therapy

potentiates isoproterenol and PGE2-mediated relaxation of pulmonary veins of preterm lambs; an enhanced adenylate cyclase activity explain in part the effect of antenatal glucocorticoid

therapy on pulmonary veins of preterm lambs. SIMILAR CONTENT BEING VIEWED BY OTHERS POSTNATAL BUDESONIDE IMPROVED LUNG FUNCTION IN PRETERM LAMBS EXPOSED TO ANTENATAL STEROIDS AND

CHORIOAMNIONITIS Article 17 February 2024 ANTENATAL CORTICOSTEROIDS: A REAPPRAISAL OF THE DRUG FORMULATION AND DOSE Article Open access 11 November 2020 VARIABLE EFFECT OF THE POST-PARTUM

MENSTRUAL CYCLE ON ALDOSTERONE AND RENIN IN WOMEN WITH RECENT PREECLAMPSIA Article 19 June 2024 MAIN Antenatal glucocorticoid treatment improves pulmonary function in the preterm infant

after birth(1–4). We have shown that a single dose of antenatal betamethasone augments nitric oxide-mediated relaxation of pulmonary veins of preterm lambs(5). Under a variety of conditions,

pulmonary veins exhibit marked vasoactivity and contribute to a significant part of pulmonary vascular resistance(6–11). A decrease in venous resistance may help to reduce pulmonary

vascular resistance and pulmonary edema after birth(6, 8–10). In the fetus and newborn, β-adrenergic agonists and PGE2 are important vasodilators of pulmonary vessels(12, 13). They activate

adenylate cyclase of vascular smooth muscle cells, which causes an increase in intracellular content of cAMP and consequently causes vasodilation(13, 14). In cultured smooth muscle cells of

rat mesenteric arteries, incubation with dexamethasone enhances adenylate cyclase activity(15). If this is also true under _in vivo_ conditions, antenatal glucocorticoid therapy may

potentiate action of β-adrenergic agonists and PGE2-mediated effects on pulmonary vessels of preterm lambs. The present study was designed to determine the effect of antenatal glucocorticoid

therapy on the response of isolated pulmonary veins of preterm lambs to the β-adrenergic agonist isoproterenol and PGE2. METHODS _ANIMALS_. Twenty-two pregnant ewes carrying singleton

fetuses(Nebeker Ranch, Palmdale, CA) were used for the study. At 121 or 126 d of gestation (term = 150 d), the fetus was injected intramuscularly in either the neck or shoulder (using a

9-cm, 20-gauge spinal needle) with betamethasone 0.5 mg/kg body weight (Celestone Soluspan®, Schering Pharmaceuticals, Kenilworth, NJ; _n_ = 11) or 0.15 M saline (_n_ = 11). Fetal injection

procedures were performed with the ewe in a shearing position, held from behind by a seated assistant. A real time ultrasound system (Acusonic Opus I, Lane Cove, Australia) and a 5-mHZ

sector transducer were used to image the fetus and guide the intramuscular injection. The body weight of the fetus was estimated based on earlier studies; the injection volume was 2.5 mL,

and the betamethasone dose was based on previously demonstrated improvements in pulmonary function of premature ovine lambs(3). The injection procedure, including positioning of the ewe,

generally took <5 min. The procedure does not acutely alter the fetal catecholamine level(16). Animal handling and study protocols were reviewed and approved by the Harbor-UCLA Animal

Care and Use Review Committee. Fifteen hours later for 121-d gestation lambs and 48 h later for 126-d gestation lambs, the lambs were delivered by cesarean section, treated with surfactant

(Survanta, Ross Laboratories, Columbus, OH; 100 mg/kg) by direct intratracheal instillation, and then mechanically ventilated with 100% O2 for 3 h. It is necessary to mechanically ventilate

these lambs as spontaneously breathing preterm lambs at this gestation will not survive. We were interested in studying the function of the pulmonary vasculature after it had undergone the

postnatal transition. During this period, data were gathered to determine the effect of antenatal betamethasone therapy on a variety of physiologic responses(4). After 3 h of ventilation,

the lambs were killed with an overdose of pentobarbital (100 mg/kg, i.v.), and the lungs were removed. Fourth generation pulmonary veins were dissected from the lungs and cut into rings

(length, 3 mm; outside diameter, 1.5-2.0 mm). _ORGAN CHAMBER STUDY_. Rings of isolated fourth generation pulmonary veins were suspended in organ chambers filled with 10 mL of modified

Krebs-Ringer bicarbonate solution [composition (in mM): NaCl, 118.3; KCl, 4.7; CaCl2, 2.5; MgSO4, 1.2; KH2PO4, 1.2; NaHCO3, 25.0; glucose, 11.1] maintained at 37 ± 0.5 °C and aerated with

95% O2-5% CO2 (pH = 7.4). Each ring was suspended by two stirrups passed through the lumen. One stirrup was anchored to the bottom of the organ chamber; the other one connected to a

force-displacement transducer (model FT03C, Grass Instrument Co., Quincy, MA) for the measurement of isometric force(5, 17). At the beginning of each experiment, vessel rings were brought to

their optimal tension by stretching the tissues progressively until the contractile responses to 100 mM KCl were maximal. There was no significant difference in optimal resting tension

between pulmonary veins from control and betamethasone-treated lambs (0.31 ± 0.03 g _versus_ 0.29± 0.04 g; _n_ = 11 for each group, _p_ > 0.05). Relaxation of pulmonary veins to different

agents was determined during contraction to U46619 (3 × 10-8 M; a thromboxane A2 analog)(18). Relaxations induced by isoproterenol, PGE2, and 8-bromo-cAMP were tested in veins of 126-d

gestation; relaxation induced by forskolin was tested in both 121- and 126-d gestation lambs. The response induced by forskolin was not significantly different between veins of 121-d and

those of 126-d gestation lambs (see Figs. 3 and 4). To obtain concentration-response curves, these vasodilators were administrated in a cumulative fashion. For each vessel ring, only one

vasodilator was tested. To exclude the involvements of cyclooxygenase products and endothelium-derived nitric oxide(5, 11, 19, 20), all vessels were treated with indomethacin (10-5 M) plus

nitro-L-arginine (10-4 M) before they were contracted with U46619. Indomethacin plus nitro-L-arginine raised the basal tension of pulmonary veins of control and betamethasone by 0.45 ± 0.07

g (_n_ = 22) and 0.39 ± 0.10 g (_n_= 22), respectively. These values were not significantly different(_p_ > 0.05). _ADENYLATE CYCLASE ASSAY_. Pulmonary veins were homogenized in 10

volumes of ice-cold Tris/HCl buffer (50 mM, pH 7.6) containing DTT (1 mM), EDTA (0.5 mM), IBMX (1 mM), and phenymethylsulfonyl fluoride (1 mM). The homogenate was then filtered through two

layers of gauze, and adenylate cyclase activity was determined on the resultant crude membrane preparation by a modification of the method of Shaul _et al._(22). Further purification of the

membrane was not performed because isoproterenol-sensitive adenylate cyclase activity decreases with subsequent steps of smooth muscle membrane preparation(21, 22). The protein

concentrations of the homogenate were determined by Bradford(23) method using BSA as the standard. Pulmonary vessel membranes (20 μg of protein) were incubated at 30°C for 10 min in 150 μL

of HEPES buffer [composition: HEPES (50 mM), Tris-HCl (10 mM), DTT (0.1 mM), ATP (1 mM), MgCl2 (10 mM), creatine phosphate (12 mM), creatine phosphokinase (185 U/mL), ascorbic acid (0.5 mM),

and IBMX (1 mM)] under control conditions or in the presence of isoproterenol(10-6 M), PGE2 (3 × 10-7 M), or forskolin (3× 10-6 M). Preliminary experiments confirmed the linearity of

adenylate cyclase activity at the protein concentrations up to 40 μg and incubation times up to 20 min. The reaction was terminated by placing the assay tubes in a boiling water bath for 5

min. The samples were then centrifuged at 10 000 × _g_ for 15 min. The supernatant was extracted with 4 volumes of water-saturated diethyl ether and lyophilized. The lyophilized samples were

resuspended in 0.5 mL of sodium acetate buffer (0.05 M, pH 6.2), and the content of cAMP was measured using a cAMP RIA kit(Biomedical Technologies Inc., Stoughton, MA). The amount of cAMP

produced during the incubation was calculated by subtracting the cAMP content of blanks in which the adenylate cyclase activity was inhibited before the onset of incubation, yielding

adenylate cyclase activity expressed as picomoles of cAMP/mg of protein/min. _DRUGS_. The following drugs were used (unless otherwise specified, all were obtained from Sigma Chemical Co.,

St. Louis, MO): 8-bromo-adenosine 3′5′-cyclic monophosphate (8-bromo-cAMP), forskolin, indomethacin, IBMX, isoproterenol bitartrate,_N_G-nitro-L-arginine (Research Biochemicals

International, Natick, MA), phentolamine mesylate (Research Biochemicals International), PGE2, and U46619(9,11-dideoxy-11α,9α-epoxymethanoprostaglandin PGF2α). IBMX was dissolved in ethanol

(final concentration in an organ chamber, 0.1%). Preliminary experiments indicated that ethanol at this concentration did not significantly affect contraction of the tissues to U46619 nor

the relaxation to isoproterenol and PGE2 (data not shown). Indomethacin(10-5 M) was prepared in equimolar Na2CO3. This concentration of Na2CO3 did not significantly affect the pH of the

solution in the organ chamber. The other drugs were prepared using distilled water. _DATA ANALYSES_. Contractions are expressed as gram tension developed. Relaxations are expressed as

percent of contraction of tissues to U46619. Data are shown as means ± SEM. When data from two groups of vessels were compared, a _t_ test for unpaired observations was used. When data from

the same group of vessels, before and after stimulation, were compared, a _t_ test for paired observations was used. Comparison of mean values of more than two groups was made with a one-way

ANOVA test with Student-Newman-Keuls test for _post hoc_ testing of multiple comparison. All analyses were performed using a commercially available statistics package (SigmaStat, Jandel

Scientific, San Rafael, CA). Statistical significance was accepted when the _p_ value (two-tailed) was less than 0.05. In all experiments, _n_ represents the number of veins from different

lambs. RESULTS _ORGAN CHAMBER STUDIES_. Relaxation of isolated pulmonary veins was determined after their tensions were raised with U46619 (3 × 10-8 M). There was no significant difference

in the increases in tension elicited with U46619 between veins from control and those from betamethasone-treated lambs (1.83 ± 0.22 g _versus_ 1.76± 0.25 g; _n_ = 11 for each group, _p_ >

0.05). During contraction, isoproterenol and PGE2 caused concentration-dependent relaxations of pulmonary veins with threshold concentrations at 10-9 M and 3 × 10-9 M, respectively.

Relaxations induced by these agents were significantly greater in veins of betamethasone-treated lambs than in those of controls (Figs. 1 and 2). Forskolin, an activator of adenylate

cyclase(24), also caused greater relaxation of pulmonary veins of betamethasone-treated lambs than those of controls (Fig. 3). In the presence of IBMX (10-5 M), an inhibitor of

phosphodiesterases(25), forskolin-induced relaxation of all vessels was augmented; however, relaxation of veins treated with betamethasone was significantly greater than of control veins

(Fig. 4). When stimulated with 8-bromo-cAMP, a cell membrane permeable analog of cAMP(26), pulmonary veins of control lambs relaxed to a similar extent as those from betamethasone-treated

lambs (Fig. 5). _ADENYLATE CYCLASE ACTIVITY ASSAY_. The basal activity of adenylate cyclase of pulmonary veins of control and betamethasone-treated lambs was 4.99 ± 0.69 pmol of cAMP/mg of

protein/min (_n_ = 7) and 7.921 ± 0.80 pmol of cAMP/mg of protein/min (_n_ = 7), respectively. These values were significantly different (_p_ < 0.05). When stimulated with isoproterenol

(10-6 M), PGE2 (3× 10-7 M), and forskolin (3 × 10-6 M), the activities of adenylate cyclase of pulmonary venous preparations treated with betamethasone were significantly greater than those

of control (Fig. 6). DISCUSSION The present study demonstrated that a single dose of antenatal betamethasone significantly augmented relaxation of pulmonary veins toβ-adrenergic agonist

isoproterenol and PGE2. The augmented responses to these vasodilators were observed at concentrations as low as 10-9 M to 3 × 10-9 M. Thus, the effect of betamethasone seems to occur within

the physiologic range of concentration ofβ-adrenergic agonist and PGE2(27–30). Isoproterenol and PGE2 cause vasodilation by activating adenylate cyclase and subsequently increasing the

intracellular content of cAMP in the smooth muscle cell(13, 14, 31). In the present study, forskolin, an activator of adenylate cyclase(24), also caused greater relaxation of pulmonary veins

of betamethasone-treated lambs than of control. Moreover, under basal conditions and after isoproterenol, PGE2, and forskolin, adenylate cyclase activity of the crude membrane preparation

of pulmonary veins treated with betamethasone was greater than that of control. Thus, an enhanced adenylate cyclase activity was at least partially responsible for the augmented relaxation

of pulmonary veins of preterm lambs after betamethasone treatment. These results are consistent with the report that, in cultured smooth muscle cells of rat mesenteric arteries, 24- and 48-h

incubation with dexamethasone enhances adenylate cyclase activity(15). We found that isoproterenol and PGE2, at concentrations inducing comparable relaxations of veins as that of forskolin,

caused a smaller increase in adenylate cyclase activity than did forskolin. Such a phenomenon has been observed in both pulmonary and nonpulmonary smooth muscles by other investigators. The

underlying mechanism is not clear(21, 22). cAMP is degraded by phosphodiesterases(25). Therefore, it is no surprise that IBMX, an inhibitor of phosphodiesterases(25), augmented relaxation

of all vessels to forskolin. In the presence of IBMX, forskolin still caused greater relaxation of pulmonary veins from betamethasone-treated lambs than those from control lambs. Because the

inhibition of phosphodiesterases with IBMX did not reduce the difference in forskolin-induced relaxation between control and betamethasone-treated veins, phosphodiesterases seem unlikely to

contribute significantly to the effect of betamethasone treatment on pulmonary veins of preterm lambs. The basal activity of adenylate cyclase activity was greater in betamethasone-treated

veins than in the control. This would result in a greater basal content of cAMP in betamethasone-treated veins and thus we expected that the treated veins could show a greater relaxation to

8-bromo-cAMP (a cell membrane-permeable analog of cAMP)(26) than control veins. However, all vessels relaxed similarly to those treated with 8-bromo-cAMP. Because 8-bromo-cAMP does not

stimulate adenylate cyclase activity, the difference in basal activity of adenylate cyclase between control and treated veins may not be large enough to make betamethasone-treated veins

relax significantly more to the cAMP analog than do control veins. However, when adenylate cyclase is stimulated by isoproterenol, PGE2, and forskolin, the difference in the activity of

adenylate cyclase between control and betamethasone groups resulted in a greater relaxation of treated veins to these agents. Pulmonary vascular resistance is regulated not only by

vasoactivity of pulmonary arteries but also the vasoactivity of pulmonary veins(6). There is a body of literature showing that pulmonary veins exhibit significant vasoactivity in response to

a variety of vasoactive mediators(6–11). In the present study, we demonstrated that antenatal glucocorticoid therapy augments relaxation of pulmonary veins of preterm lambs to a

β-adrenergic agonist and PGE2. In premature human infants, antenatal glucocorticoid therapy improves pulmonary function and reduces the incidences of respiratory distress syndrome(1, 2). If

our present results are applicable to humans _in vivo,_ an augmentation of adenylate cyclase-cAMP-mediated response of pulmonary veins after glucocorticoids may help to reduce pulmonary

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ACKNOWLEDGEMENTS The authors gratefully acknowledge the contribution of Drs. M. Gore Ervin, Machiko Ikegami, Alan H. Jobe, James F. Padbury, and Daniel H. Polk to the study. We thank Jean

Morris and James Humme for technical assistance and Nancy Feldman of secretarial help. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pediatrics, Harbor-UCLA Medical Center,

University of California, Los Angeles, School of Medicine, Torrance, 90509, California Yuansheng Gao, Haiyan Zhou, Jean-Francois Tolsa, Hai Shen & J Usha Raj Authors * Yuansheng Gao View

author publications You can also search for this author inPubMed Google Scholar * Haiyan Zhou View author publications You can also search for this author inPubMed Google Scholar *

Jean-Francois Tolsa View author publications You can also search for this author inPubMed Google Scholar * Hai Shen View author publications You can also search for this author inPubMed 

Google Scholar * J Usha Raj View author publications You can also search for this author inPubMed Google Scholar ADDITIONAL INFORMATION Supported by the National Institute of Child Health

and Human Development, Grant HD-29713, and le Fonds de Perfectionnement du CHUV, la Societe Academique Vaudoise, Lausanne, Switzerland. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT

THIS ARTICLE CITE THIS ARTICLE Gao, Y., Zhou, H., Tolsa, JF. _et al._ Antenatal Betamethasone Therapy Augments Isoproterenol and Prostaglandin E2-Mediated Relaxation of Preterm Ovine

Pulmonary Veins. _Pediatr Res_ 42, 545–549 (1997). https://doi.org/10.1203/00006450-199710000-00021 Download citation * Received: 12 August 1996 * Accepted: 16 June 1997 * Issue Date: 01

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