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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1732
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 5 2882-2887
Copyright © 2005 by The Endocrine Society

Self-Limitation of Intravenous Tocolysis with ß2-Adrenergic Agonists Is Mediated through Receptor G Protein Uncoupling

Torsten Frambach, Thomas Müller, Sebastian Freund, Stefan Engelhardt, Marc Sütterlin, Martin J. Lohse and Johannes Dietl

Departments of Obstetrics and Gynecology (T.F., T.M., M.S., J.D.) and Pharmacology and Toxicology (S.F., M.J.L.) and Rudolf-Virchow-Center, DFG Research Center for Experimental Biomedicine (S.E.), Bayerische Julius-Maximilians-Universität Würzburg, D-97080 Würzburg, Germany

Address all correspondence and requests for reprints to: Torsten Frambach, M.D., Department of Obstetrics and Gynecology, Josef-Schneider-Strasse 4, D-97080 Würzburg, Germany. E-mail: frambach_t{at}klinik.uni-wuerzburg.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Tocolysis with a ß-adrenergic receptor agonist is the most common approach to premature labor management after the 25th wk of pregnancy. However, prolonged treatment is associated with a marked loss of efficacy. The biochemical mechanisms involved remain unclear. This study was undertaken to investigate the effect of fenoterol on ß-adrenergic receptor signal transduction in human myometrium. Myometrial biopsy specimens were obtained from 40 women at cesarean section between the 25th and 34th wk of pregnancy. Nineteen patients had received no tocolysis (controls, group I) and 21 had been treated with fenoterol (<48 h in 10, group II; ≥48 h in 11, group III). As methods we used membrane preparation, adenylyl cyclase assay and cAMP RIA. Adenylyl cyclase activity was determined by the measurement of cAMP levels to evaluate signal transduction after stimulation of ß-adrenergic receptors with isoproterenol, G protein with GTP, and adenylyl cyclase with forskolin. The functional activity of GTP-binding regulatory proteins (Gs) and adenylyl cyclase was not altered by fenoterol treatment. In the control group, the increase in adenylyl cyclase activity in response to GTP plus isoproterenol was greater than in response to GTP alone. The increase was reduced by 50% in group II and was insignificant in group III. There was no correlation between gestational age and basal adenylyl cyclase activity. Intravenous tocolysis with the ß2-adrenergic receptor agonist fenoterol leads to complete desensitization of the ß-adrenergic receptor system. In addition to the known reduction in receptor number (down-regulation) as underlying mechanism, uncoupling of the receptor from the stimulatory G protein Gs was identified.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
THE ADMINISTRATION OF a tocolytic ß2-adrenergic receptor agonist is by far the most common approach to premature labor management after the 25th week of pregnancy. The agents used include ritodrine, salbutamol, terbutaline, and fenoterol. ß2-adrenergic receptors in the uterus are coupled to adenylyl cyclase via GTP-binding regulatory proteins (Gs). ß-Adrenergic receptor-mediated activation of adenylyl cyclase induces a rapid increase in intracellular cAMP and leads to relaxation of the myometrium via inhibition of the regulatory enzyme myosin light chain kinase and a reduction in free intracellular calcium (1). However, a pronounced fall-off in efficacy is seen with prolonged treatment and it is often impossible to prevent premature delivery. The problem of the loss of the tocolytic effect of ß-adrenergic receptor agonists has been described in various clinical (2) and experimental studies (3). In a review article, Higby et al. (4) showed that most clinical studies had found that the use of ß-adrenergic receptor agonists could delay delivery by only 24–48 h. Only three studies described prolongation of pregnancy by more than 48 h compared with a control group. Due to this rapid loss of efficacy by continuous stimulation with an agonist (also known as tachyphylaxis), the incidence of premature delivery (5) and the resultant perinatal morbidity and mortality (6) have remained unchanged for years. The mechanisms that lead to desensitization of the ß-adrenergic receptor system have been investigated in various tissues and cell lines (7). The most specific and rapid method of desensitization of G protein-linked receptors involves phosphorylation of the receptor by G protein-linked receptor kinases (GRKs) (8), followed by binding of the inhibitory protein arrestin, which leads to uncoupling of the receptor and its G protein (9). A much slower pathway is agonist-induced reduction in receptor numbers (down-regulation). Degradation of the receptor occurs by endocytosis, a process also known as sequestration or internalization (10). The decrease in receptor density may also be due to a decrease in the rate of receptor synthesis or mRNA concentration, which may result from a change in the rate of transcription (11), destabilization of the mRNA (12), or a change in translation efficiency (13).

Few studies have investigated the mechanisms involved in ß-adrenergic receptor desensitization in human myometrium. Berg et al. (14) investigated myometrial specimens from women who had been given terbutaline for premature labor. A significantly reduced number of receptors was observed in these patients. Similar findings were also noted by Michel et al. (15), who described a significant reduction in ß2-adrenergic receptor numbers in the myometrium of pregnant women who had been given hexoprenaline. Engelhardt et al. (16) reported isolated down-regulation of the ß2-adrenergic receptor in human myometrium after treatment with the ß-adrenergic agonist fenoterol, without any change in the corresponding mRNA. There was no difference in the density of {alpha}2-receptors or Gs and Gi protein {alpha}-subunits in comparison to a control group. The activity of ß-adrenergic receptor kinase was also the same in both treatment and control groups. In addition to the decrease in ß2-adrenergic receptors, which has been found in various investigations, other changes in the signal transduction cascade might also play an important role.

This study was undertaken to determine whether treatment with ß-adrenergic receptor agonists results in a functional change in ß-adrenergic receptors in human myometrium. Myometrial biopsy specimens were obtained between the 25th and 34th wk of pregnancy from women who had been treated with fenoterol and from control women. The coupling of myometrial ß-adrenergic receptors was evaluated by measuring the production of cAMP in response to the ß-agonist isoproterenol, in response to GTP, and in response to forskolin. We identified uncoupling of the G protein from the ß2-adrenergic receptor as an additional mechanism underlying the rapid loss of efficacy of tocolysis.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients and procurement of biopsies

The investigation was conducted in accordance with the guidelines of the Declaration of Helsinki and was approved by the ethics committee of the medical faculty of the University of Würzburg (study number 92/98). All patients gave written informed consent. Myometrial biopsies were obtained from 40 women at cesarean section performed at 25–34 wk gestation. A small specimen of myometrium was dissected from the upper margin of the incision in the lower uterine segment and immediately frozen in liquid nitrogen and stored at –80 C until analyzed. The patients were divided into three groups according to the treatment they had received: 1) no treatment (controls; n = 19), 2) fenoterol treatment for less than 48 h (n = 10), and 3) fenoterol treatment for 48 h or more (n = 11).

Chemicals and reagents

The 3H cAMP assay system used was purchased from Amersham Pharmacia Biotech (Buckinghamshire, UK). ATP, BSA (fraction V; fatty-acid free), creatine phosphate, creatine phosphokinase, GTP, isobutyl-1-methylxanthine, isoproterenol, and forskolin were purchased from Sigma-Aldrich (Taufkirchen, Germany).

Homogenate and membrane preparation has been described previously (17). Approximately 500 mg of frozen myometrial tissue was homogenized in 10 ml of ice-cold buffer (0.25 M sucrose, 0.01 M Tris-HCl, pH 7.4) with a Polytron homogenizer for three 10-sec periods separated by 20-sec cooling periods. Tissue homogenates were filtered through a double layer of gauze and centrifuged at 20,000 x g at 4 C for 10 min, after which the supernatant was carefully decanted. The pellet was resuspended in 3 ml of fresh homogenization buffer and centrifuged again at 20,000 x g at 4 C for 10 min. The second supernatant was mixed with the first and centrifuged at 50,000 x g at 4 C for 60 min. The resulting pellet was resuspended in 500 µl of 0.05 M Tris-HCl (pH 7.42), 0.01 M MgCl2, and the volume was adjusted to give the appropriate protein concentration. Protein was assayed by the method of Bradford (18). The membranes were used immediately for the adenylyl cyclase assay.

Adenylyl cyclase assay

Adenylyl cyclase activity was measured in a medium containing 50 mM Tris-HCl (pH 7.4), 5 mM MgSO4, 5 mM creatine phosphate, 12 U of creatine phosphokinase, 0.5 mM ATP, 0.1% BSA and the agent to be tested. The incubations were conducted in the presence of 1 mM isobutyl-1-methylxanthine to inhibit cAMP degradation by phosphodiesterase. Adenylyl cyclase activity was evaluated in response to 0.1 mM GTP and 0.1 mM forskolin in the presence of 0.1 mM GTP. ß-Adrenergic stimulation was evaluated by the addition of 0.1 mM isoproterenol in the presence of 0.1 mM GTP. The reaction was started by the addition of 100 µg membrane fraction and incubation of the mixture at 30 C for 10 min with constant shaking. The enzymatic reaction was stopped by transfer of the tubes to a boiling water bath for 3 min. After centrifugation at 12,000 x g at 4 C for 30 min the supernatant was used to determine cAMP production by RIA. All assays were conducted in duplicate. The results were expressed as picomoles of cAMP per milligram of protein per 10 min. The assay has been described previously (19).

Statistical analysis

The data were expressed as mean ± SEM. Statistical analysis was carried out using paired t test or ANOVA where appropriate. P values less than 0.05 were considered significant.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
The mean age of the 40 patients was 29.5 yr (range from 21–38 yr). The mean gestational age was similar in all three groups: 31.2 ± 0.6 wk in group I, 31.2 ± 1.1 wk in group II, and 30.2 ± 1.1 wk in group III (Table 1Go). All patients but three received MgSO4 and all but two received corticosteroids to accelerate fetal lung maturation. All patients in the fenoterol group received fenoterol at the dosage indicated (1, 2, or 3 µg/min). Treatment was given over 4.45 ± 1 d (2–12 d) in group III and 27.5 ± 1.6 h (14–38 h) in group II. None of the patients in the control group (group I) received catecholamines. None of the patients in the study received ß-adrenergic receptor antagonists.


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  		TABLE 1. Clinical characteristics of patients undergoing cesarean section

 
Basal adenylyl cyclase activity was similar in the control and treatment groups: 206 ± 13 pmol cAMP per milligram of protein per 10 min in group I (controls), 202 ± 19 pmol cAMP per milligram of protein per 10 min in group II (fenoterol < 48 h), and 204 ± 18 pmol cAMP per milligram of protein per 10 min in group III (fenoterol > 48 h) (Table 2Go). There was no correlation between gestational age and basal adenylyl cyclase activity (Fig. 1Go).


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  		TABLE 2. Adenylyl cyclase activity of the myometrium under different conditions

 


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  		FIG. 1. Relationship between basal adenylyl cyclase activity of the myometrium under different conditions. No correlation was detectable. Ordinate, Basal adenylyl cyclase activity in picomoles of cAMP per milligram of protein per 10 min; abscissa, gestational age of patients in weeks.

 
Adenylyl cyclase activity in response to forskolin, which acts predominantly at the catalytic unit of adenylyl cyclase but at least partly involves Gs (20), was almost the same in all groups (1663 ± 127 pmol cAMP per milligram of protein per 10 min in group I, 1617 ± 114 pmol cAMP per milligram of protein per 10 min in group II, and 1686 ± 182 pmol cAMP per milligram of protein per 10 min in group III; Table 2Go and Fig. 2Go). Adenylyl cyclase activity in response to GTP, which activates G proteins, was 326 ± 20 pmol cAMP per milligram of protein per 10 min in group I, 321 ± 29 pmol cAMP per milligram of protein per 10 min in group II, and 323 ± 25 pmol cAMP per milligram of protein per 10 min in group III (Table 2Go and Fig. 2Go). These results show that the induction of adenylyl cyclase activity by forskolin and GTP was not affected by fenoterol treatment, indicating that the functional activity of Gs and the catalytic unit of adenylyl cyclase was not altered.



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  		FIG. 2. Effect of isoproterenol (100 µm) on adenylyl cyclase activity in membrane preparations of pregnant myometria in patients without tocolysis as control (n = 19), with fenoterol less than 48 h (n = 10), and with fenoterol greater than or equal to 48 h (n = 11) in the presence of 100 µm GTP (right) compared to GTP alone (left).

 
Adenylyl cyclase activity in response to isoproterenol, which directly activates the ß2-adrenergic receptor, is shown in Table 2Go. In the control group, there was a greater increase in adenylyl cyclase activity than after GTP stimulation alone (397 ± 22 vs. 326 ± 20 pmol cAMP per milligram of protein per 10 min, respectively; P < 0.01). This increase was reduced by almost 50% after treatment with fenoterol less than 48 h (361 ± 28 vs. 321 ± 29 pmol cAMP per milligram of protein per 10 min; P < 0.01) and was hardly detectable after treatment greater than or equal to 48 h (328 ± 29 vs. 323 ± 25 pmol cAMP per milligram of protein per 10 min (P = 0.2; Figs. 2Go and 3Go).



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  		FIG. 3. Progressive decrease of isoproterenol stimulated adenylyl cyclase activity with increasing duration of tocolytic treatment. Adenylyl cyclase activity was determined in myometrial membranes from patients after tocolytic treatment for less than 48 h and greater than or equal to 48 h respectively and from control patients. Data are given as GTP + isoproterenol increase of adenylyl cyclase activity minus adenylyl cyclase activity stimulated with GTP alone. Data are given as mean ± SEM. *, P < 0.01 vs. control; **, P < 0.001 vs. control; #, P < 0.01 vs. less than 48 h.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
A reduction in efficacy occurs in the course of prolonged treatment with ß-adrenergic receptor agonists for premature labor and it is often impossible to avoid premature delivery. The mechanisms underlying this desensitization of the ß-adrenergic receptor system at the molecular level have been investigated in various tissues and species (7). The two most important mechanisms contributing to the reduced efficacy observed with prolonged treatment appear to be first, a reduction in receptor density and second, uncoupling of the receptor from postreceptor systems. Few studies have investigated the molecular events involved in this phenomenon in human myometrium (14, 16, 21). In this study, we investigated the effect of treatment with the ß-adrenergic receptor agonist fenoterol on signal transduction at the ß2-adrenergic receptor. Adenylyl cyclase activity was evaluated in membrane extracts prepared from myometrial biopsies. Signal transduction was assessed by the measurement of cAMP by RIA after stimulation of the receptor with isoproterenol, G protein with GTP, and adenylyl cyclase with forskolin.

No significant differences in basal cAMP values were found between the control group and the two different treatment groups (Table 2Go), and the basal values in the control group were consistent with earlier findings published by members of this research group (16) and other authors (22). By contrast, Berg et al. (14) described a reduction in basal cAMP values after treatment with the ß-adrenergic receptor agonist terbutaline. We found no correlation between gestational age (25–34 wk) and basal cAMP values in this study. Both stimulation of G protein by GTP and stimulation of the catalytic subunit of adenylyl cyclase by forskolin led to activation of adenylyl cyclase. GTP was found to increase activity by approximately 50% of the corresponding basal rates and forskolin by approximately 800%, with no significant differences between the individual groups investigated (Table 2Go). These findings indicate that the stimulation of adenylyl cyclase activity by forskolin and GTP is not influenced by treatment with fenoterol, so that the function of Gs and the catalytic subunit of adenylyl cyclase is not impaired.

The addition of isoproterenol, which acts directly on the receptor, provoked an increase in adenylyl cyclase activity in all three groups, but only after the addition of exogenous GTP. Therefore, it is necessary to compare this increase with that resulting from GTP alone. The increase in activity varied among the three groups. Isoproterenol and GTP together produced a much greater increase in adenylyl cyclase activity than GTP alone. This increase in activity was reduced by 50% in patients treated with fenoterol for less than 48 h. In patients who had received fenoterol for 48 h or more, the addition of isoproterenol + GTP resulted in an increase of only 3% more than GTP alone. The efficacy of tocolytic therapy thus decreases after a treatment duration of 48 h or more, where it is barely detectable at the cellular level. There is uncoupling of the receptor from the G protein, an effect that is known to be involved in desensitization, but has not previously been described in human myometrium. Lecrivain et al. (23) reported receptor desensitization in rat myometrium after the administration of isoproterenol. Activators such as GTP and forskolin produced no change in adenylyl cyclase activity, but treatment with isoproterenol rapidly led to uncoupling of the receptor and treatment was found to be without effect after just 3 h. Caritis et al. (24) observed a decrease in ß2-adrenergic receptor numbers and adenylyl cyclase activity in sheep myometrium after ritrodrine infusion. They described a 70% reduction in adenylyl cyclase activity after 24 h, but a more detailed investigation of the changes in the signal cascade was not undertaken.

At present, it remains unclear, whether this uncoupling of the ß-adrenergic receptor simply contributes to the observed loss of ß-adrenergically mediated adenylyl cyclase stimulation or whether this involves the regulation of additional signaling pathways. In this respect, switching of the ß2-adrenergic receptor from Gs to Gi protein coupling by protein kinase A has been reported (25). It is tempting to speculate, that such a switch of ß2-adrenergic receptor coupling occurs also in the human myometrium after chronic exposure to tocolytic agents.

In the few in vivo investigations in which uncoupling of the ß-adrenergic receptor has been studied, this process was found to be associated with increased ß-adrenergic receptor kinase activity (26). This phenomenon has been most extensively investigated in the heart and may play an important role in uncoupling in human myometrium. Brenninkmeijer et al. (27) identified four of the six known GRK subtypes in pregnant myometrium (GRK-2, 4, 5, and 6). As Engelhardt et al. (16) reported, the total GRK activity does not appear to be influenced by treatment with tocolytic agents.

In addition to treatment with ß2-adrenergic receptor agonists, patients with premature labor before the 34th wk of pregnancy are often given magnesium (MgSO4) to augment the relaxant effect and cortisone to stimulate fetal lung maturation. However, the administration of corticosteroids may affect the comparability of patient groups studied as it is known that they may induce a renewed increase in receptor density after down-regulation (28). Caritis et al. (24) showed that the down-regulation and desensitization of receptors associated with prolonged administration of the ß2-adrenergic receptor agonist ritodrine could be partly reversed with dexamethasone. Although it is possible that the administration of cortisone had some effect on desensitization, the results of our study show even after corticosteroid administration that there is uncoupling of G protein. It should be pointed out that the various patient groups in our study were of similar gestational age. This is of particular relevance because it is most probable that there is a change in receptor function as pregnancy progresses, as Litime et al. (19) demonstrated in untreated women at the end of pregnancy.

In addition to the results demonstrated in this study, the administration of ß-adrenergic agonists also leads to a decrease in ß-adrenergic receptor density in human myometrium. This was noted by Berg et al. (14) in the case of terbutaline. Engelhardt et al. (16) also found a reduction in ß2-adrenergic receptors after fenoterol administration: receptor density decreased from 6.3 ± 0.6 fmol/mg protein in untreated patients to 2.8 ± 0.4 fmol/mg protein in women who had received fenoterol. This was not associated with a decrease in the relevant mRNA, which has been described in various studies as an essential part of the mechanism of ß-adrenergic receptor down-regulation (29). It can therefore be assumed that there is direct degradation of the receptor in human myometrium (16).

In summary, it can be said that there appear to be two important mechanisms involved in the tachyphylaxis that develops in human myometrium during treatment with ß-adrenergic receptor agonists. First, there is a reduction in receptor numbers (down-regulation) and second, as we have shown in this investigation, there is a change in receptor function due to uncoupling from G protein. The isoproterenol stimulated adenylyl cyclase activity is impaired by 98%, whereas the reduction of receptor numbers only account for a decrease of about 56%. The loss of receptor function through uncoupling represents a major mechanism contributing to the loss of efficacy of tocolytic treatment with ß-adrenergic agonists. Interfering with ß-receptor uncoupling could represent a novel therapeutic strategy to improve current medical therapy for preterm labor.


   Acknowledgments
 
The advice of Joelle Cohen-Tannoudji (University P.M. Curie, Paris, France) regarding the determination of adenylyl cyclase activity is gratefully acknowledged. We thank Barbara Ruck for her help in the preparation of this manuscript.


   Footnotes
 
This work was supported in part by grants from the Free State Bavaria and Universitätsbund Würzburg.

First Published Online February 22, 2005

Abbreviation: GRK, G protein-linked receptor kinase.

Received August 31, 2004.

Accepted February 16, 2005.


   References
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 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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