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Studies of the spontaneous motility and the effect of histamine on isolated myometrial strips of the nonpregnant human uterus: The influence of various uterine abnormalities
Studies of the spontaneous motility and the effect of histamine on isolated myometrial strips of the nonpregnant human uterus: The influence of various uterine abnormalities Inocencia Martinez-Mir, MD, PhD, Luis Estaii, MD, PhD, Francisco J. Morales-Olivas, MD, PhD, and Elena Rubio, MD, PhD Valencia, Spain We investigated the spontaneous uterine activity of isolated corpus uteri myometrial strips from 30 patients with non pathologic myometrium, 26 patients with uterine myoma, 23 patients with uterine adenomyosis, and three patients with uterine malignancy. We also investigated the influence of these conditions on the response of the uterus to histamine. The results show the same qualitative cyclic changes of the spontaneous motility of isolated myometrial strips throughout the menstrual cycle in all the abnormalities studied. These changes are characterized by a low amplitude and high frequency of spontaneous contractions in the proliferative phase and lower frequency with higher amplitude of contractions in the secretory phase. The isolated strips from patients with myomas present the highest spontaneous activity in reproductive age and preclimacteric women, but not in menopausal women. Histamine produced concentration-related contractions that are not significantly different in all the myometrial strips studied. (AM J OBSTET GVNECOL 1990;163:189-95.)
Key words: Isolated human uterus, histamine, uterine motility
It has been reported that the spontaneous motility of isolated muscular strips of the human uterus varies widely, with sexual phase, anatomic origin of the strip, pregnancy, and the experimental conditions used. I-3 Moreover, several authors have shown that there are wide variations in the frequency and force of contractions, as well as the response to drugs, of human myometrial strips from different uteri, although the cause of these large variations is still obscure. 3-5 Conversely, many studies of the isolated human uterus have been done with no consideration for the clinical diagnosis in each case; therefore the uterine abnormality of the women who had operations could be a source of the variation in the results described. In this investigation we studied the spontaneous uterine activity of isolated myometrial strips from patients with various uterine pathologic conditions and investigated the influence of those pathologic conditions on the response of the corpus uteri to histamine.
From the Departament de Farmacologia i Farmacotecnia, Facultat de Medicina, Universitat de Valencia. Received for publication June 21, 1989; revised February 2, 1990; accepted February 5, 1990. Reprint requests: Elena Rubio, MD, PhD, Departament de Farmacologia i Farmacotecnia, Facultat de Medicina, Avenida Blasco Ibanez, 17. 46010 Valencia, Espana. 611119896
Material and methods Myometrial tissue was obtained from 82 women undergoing hysterectomy because of various gynecologic pathologic conditions. A sample of each uterus obtained was sent for histologic examination to check the pathologic diagnosis and the phase of menstrual cycle. The specimens were divided on the basis of their final diagnosis as follows: group 1: 30 patients who underwent hysterectomy for gynecologic conditions that did not affect the uterus served as normal control subjects; group 2: 26 patients with uterine myoma; group 3: 23 patients with uterine adenomyosis; and group 4: three patients with uterine malignancy. Since it has been reported that menopause and the phase of the sexual cycle may influence uterine motility, subjects were then separated into subgroups according to the classification used by Sandberg et al.I as follows: proliferative group, 18 patients aged 29 to 51; secretory group, 20 patients aged 37 to 53; preclimateric group, 13 patients aged 41 to 57; and menopausal group, 31 patients aged 52 to 78. Isolated strips of uterus. Immediately after abdominal hysterectomy, muscle strips from an intermediate layer were cut longitudinally from the anterior part of the corpus of the uteri. The tissue was rapidly immersed in a Jalon solution of the following composition: sodium chloride 155.17 mmollL, potassium chloride
189
190 Martinez-Mir et al.
July 1990 Am J Obstet Gynecol
un
PROLI FERAl! VE GROUP
o SECRETORY
GROUP
f3 PRECLIMACTERIC GROUP •
MEMOPAU5AL GROUP
MY
AD
o M-P
MT
Fig. 1. Time in minutes for myometrial strips to start spontaneous motility. Strips were taken from uteri with nonpathologic conditions (N-P) (n = 46), myomas (MY) (n = 39), adenomyosis (AD) (n = 25), and malignanttumors (MT) (n = 5). Each value is the mean ± SEM.
5.68 mmol/L, calcium chloride 0.41 mmollL, sodium bicarbonate 5.95 mmollL, glucose 2.78 mmollL; samples were then transported to the laboratory. The tissue samples were stored at 4 0 C until the next day. Muscle strips measuring approximately 2 x 3 x 35 mm were dissected and then mounted in a 20 ml organ bath containing Jalon solution at 31 C and were continuously gassed with 95% oxygen and 5% carbon dioxide. Isometric tension was recorded by a U go Basile C40 7010 transducer (Milan, Italy) connected to a Ugo Basile mod Gemini 7070 recorder. Initial tension was set at 1 gm and the preparations were undisturbed for 1 hour before any drugs were added. At the end of this period the concentration-response curve to histamine was obtained by cumulatively adding the drug at increments of 1 log unit. Only one complete doseresponse curve to histamine was constructed for each myometrial strip because tachyphylaxis to histamine has been reported for the rat uterus. 5, 7 Immediately after completion of the pharmacomechanical studies, the tissue was removed from the bath, heated for 24 hours, and then weighed on a precision balance. Analysis of data. The spontaneous activity of the muscle strips developed in these experimental conditions was evaluated as described previously7 in terms 0
of (1) isometric tension, (2) frequency of contraction, (3) functional activity, and (4) period of time necessary for the tissues to develop spontaneous activity. The values for the isometric tension developed (expressed in milligrams of force per milligram of tissue dry weight) were obtained by calculating the mean amplitude of all the contractions recorded in a lO-minute interval. The frequency of contractions represents the number of contractions in the same period of time, and functional activity corresponds to the product of these two parameters expressed in arbitrary units. The period of time before the beginning of spontaneous uterine activity is expressed in minutes. The responses of the tissue resulting from the addition of histamine were directly determined as changes in isometric tension and transformed into tension (i.e., force per gram of tissue dry weight). The 50% effective concentration (EC so ) was calculated graphically from a plot of log concentration versus percentage of the maximum response (Emax) produced by each agonist in individual experiments. All data are shown as mean ± SEM. Statistical analysis of the data was done with Student's t test at the 5% significance level. Histamine was used as dihydrochloride (Sigma Chemical Co., St. Louis) and prepared in Jalon solution before being added to the bath. Drug concentrations refer to the free base and are expressed as a final bath concentration in moles per liter.
Results The spontaneous motility of muscle strips isolated from 82 uteri was studied; 37.5% of all isolated strips showed spontaneous activity during the first hour in the organ bath. The mean ± SEM in minutes required for the uterine strips to start spontaneous motility is summarized in Fig. 1. There was a wide variability among the groups of women studied. Spontaneous motility of isolated uterine strips from patients with normal menstrual cycles. Spontaneous motility occurred in 35.9% of the muscle strips from uteri without pathologic conditions, 39.6% of the muscle strips from uteri with myomas, and 37.2% of the muscle strips from uteri with adenomyosis. Fig. 2 shows the frequency, force of contraction, and spontaneous uterine activity values obtained in the control group, as well as the myoma and adenomyosis groups. The spontaneous uterine activity in the myoma group was significantly higher than the value obtained in the control group. This latter value was not significantly different from that obtained in the adenomyosis g-roup. The highest spontaneous uterine activity observed in the myoma group was a result of a marked increase in force of contraction, which was not accompanied by any significant changes in frequency of contractions.
Influence of abnormality in isolated human uterus
Volume 163 Number 1, Part 1
Table I shows the frequency, force of contraction, and spontaneous uterine activity of the control, myoma, and adenomyosis groups in relation to the hormonal phase. It can be seen that the uterine activity developed by the isolated strip from uteri in the secretory phase was similar to the uterine activity developed in the proliferative phase, for each of the three groups. In addition, in the control group the statistical analysis revealed that the myometrial strips isolated from uteri in the secretory phase developed a spontaneous motility with a significantly lower force of contraction than that of the spontaneous motility of strips isolated from uteri in the proliferative phase. In contrast, the frequency of contraction of myometrium was higher in secretory phase uterus than in proliferative phase uterus. These results were similarly observed in both of two other groups (uteri with myomas and adenomyosis). Spontaneous motility of isolated uterine strips from preclimacteric patients. The percentages of isolated strips that developed spontaneous motility were 33.3%, 40%, and 50% in preparations from uteri with no abnormalities, myomas, and adenomyosis, respectively. Fig. 3 shows that the uterine activity of the isolated strips from a uterus with myomas was greater than that observed in preparations isolated from both uteri with adenomyosis and uteri with no pathologic conditions. These differences were a result of a significant increase in force of contraction, which was not accompanied by any significant changes in frequency of contractions. No significant differences in uterine activity (i.e., frequency and force of contractions) were found among uteri with non pathologic conditions, uteri with myomas, and uteri with adenomyosis in women with a normal menstrual cycle and uteri that were nonpathologic, had myomas, or adenomyosis in preclimacteric patients. Spontaneous motility of isolated uterine strips from menopausal patients. The percentages of isolated strips developing spontaneous motility in uteri with no abnormalities, myomas, adenomyosis, and malignant tumor groups were 30.1 %, 20%, 31.8%, and 31.3%, respectively. Fig. 4 shows that the values of uterine activity of the isolated strips from non pathologic, myoma, and adenomyosis groups were not significantly different, with no modifications in force and frequency of contractions. In contrast, the value of uterine activity was significantly higher in isolated strips of uteri with malignant tumors compared with each of the three groups in menopausal women. This increase in spontaneous uterine motility was mainly a result of an increase in force of contractions. Both uterine activity and force of contraction values were markedly reduced in isolated strips of uteri with
191
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SPONTANEOUS UTERINE MOTILITY Fig. 2. Frequency (contractions/ 10 min), force of contraction (gF/ gw), and spontaneous activity developed by isolated myo-
metrial strips of uteri from women with active sexual cycles and with non pathologic conditions ([ill) (n = 19), myomas (0) (n = 18), and adenomyosis (.) (n = 11). Each value is the mean ± SEM.
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UTERINE MOTILITY
Fig. 3. Frequency (contractions/ 10 min), force of contraction (gF/ gw), and spontaneous activity developed by isolated myo-
metrial strips of uteri from preclimacteric women with nonpathologic conditions ([ill) (n = 5), myomas (0) (n = 14), and adenomyosis (.) (n = 7). Each value is the mean ± SEM.
myomas compared with those of uteri with myomas of climacteric and women with normal cycles. In women with non pathologic uteri, there was a general tendency toward lower uterine activity and force of contractions with decreasing ovarian function. This
192 Martinez-Mir et al.
July 1990 Am J Obstet Gynecol
Table I. Spontaneous motility of myometrial strips isolated from uteri of women with non pathologic conditions, myoma, and adenomyosis in proliferative and secretory phases of women with active sexual cycles Nonpathologic conditions
PF (n
Uterine activity Frequency (contractionsllO min) Force (gFI gw) PF,
Prolif.~rative;
= 14)
I
SC (n
= 5)
Myomas
PF (n
= 8)
48.8 ± 13.6 4.5 ± 0.5
28.9 ± 11.8 1.9 ± 0.5*
114.6 ± 26.6 4.8 ± 0.9
13.2 ± 3.9
16.4 ± 5.5
31.1 ± 9.4
I
Adenomyosis
SC (n
=
10)
120.2 ± 28.4 2.0 ± 0.5* 63.9 ± 14.1*
PF (n
= 5)
I
SC (n
=
6)
75.8 ± 16.3 7.5 ± 2.2
51.6 ± 7.3 2.0 ± 0.4*
13.5 ± 3.4
33.5 ± 7.8*
SC, secretory. The number of isolated strips used is indicated in parentheses. Values are mean ± SEM.
*p < 0.05.
Table II. Effective concentration 50% value and maximal contractile effect for histamine on the myometrial strips isolated from uteri with non pathologic conditions, myomas, adenomyosis, and malignant tumors of preclimacteric and menopausal women and women with active sexual cycles Active sexual cycle Nonpathologic Myoma Adenomyosis Preclimateric N on pathologic Myoma Adenomyosis Menopausal Nonpathologic Myoma Adenomyosis Malignant tumor
n
EC 50 (moll L)
Emax (gFI gw)
16 13 8
6.37 ± 2.1 x 10- 5 2.93 ± 1.1 x 10- 5 9.23 ± 4.4 x 10- 5
47.6 ± 6.9 58.0 ± 7.1 53.4 ± 18.0
4 12 4
9.43 ± 6.2 x 10- 6 2.32 ± 0.7 x 10- 5 1.30 ± 0.7 x 10- 5
83.0 ± 14.7 34.6 ± 6.5 46.1 ± 7.6
17 10 6 6
2.10 4.60 3.31 6.42
± ± ± ±
0.6 1.4 3.1 2.4
x x x x
10- 5 10- 5 10- 5 10- 5
31.8 24.8 40.6 57.5
± ± ± ±
6.9 9.6 6.7 13.3
EC50 , 50% Effective concentration value; E_, maximal contractile effect; n, number of experiments.
tendency was revealed to be significant in the menopausal group. Effect of histamine. Histamine (10- 8 to 10- 3 mol/L) induced concentration-related contractions of the human uterine strips. The force of contraction increased and reached a maximum with 10- 4 mollL histamine. The EC 50 value determined from concentrationresponse curves was 5.2 ± 1.0 x 10- 5 mollL. The uterine response to histamine varied according to the amount of spontaneous activity shown by the preparation. When the uterine strip exhibited weaker spontaneous activity, this activity declined progressively during a concentration-response curve to histamine. Conversely, when the spontaneous activity developed by the uterine strip was higher, histamine, at the lowest concentrations, produced a superimposed contraction; at higher concentrations, the relaxations between contractions was incomplete, so the force of contractions was increased in a manner similar to that observed when a weaker spontaneous activity is present.
Table II shows that for women with normal menstrual cycles, histamine produced the same maximum degree of contraction and had similar EC 50 values in each group irrespective of the uterine pathologic condition. In contrast, muscle taken during the secretory phase of the menstrual cycle developed a higher maximal response to histamine than muscle taken during the proliferative phase. However, this difference in responsiveness was not statistically significant (Fig. 5). The histamine response of myometrial strips from both preclimacteric and menopausal groups was similar to that of the group with normal menstrual cycles. Similarly, the EC 50 and maximal effect of histamine were unaffected by the pathoiogic condition of the uterus (Table II).
Comment The foregoing results confirm previous findings documenting that there was a wide variation in the spon-
Influence of abnormality in isolated human uterus
Volume 163 Number I, Part I
taneous contractility of myometrial strips from different uteri. 1·3 Our results do not support the observation of Lossius and Nesheim 4 who reported that 99% of the muscle strips from nonpregnant uteri showed spontaneous activity. Their study was made with 18 uteri, and the temperature used was 37 0 C. The greater number and lower temperature used in our study could explain the differences between results. Conversely, our results agree with those of Garrioch,2 showing that the isolated human myometrium usually begins spontaneous activity within 30 minutes. It has been reported that uterine spontaneous motility varies according to the phase of the sexual cycle; however, previous reports on differences in spontaneous uterine activity in vitro during the menstrual cycle have been conflicting. I. 2, 4, 8 Lossius and Nesheim 4 found no modification in the frequency of contraction in relation to hormonal phase. Sandberg et al. I found three different types of spontaneous motility in strips from the uterine corpus, although they could not demonstrate any difference between proliferative and secretory phases. However, Garrioch 2 has shown a low amplitude associated with high frequency in the early phase, and that the latter stages are characterized by lower frequency and higher amplitude contractions. Similar observations were found in our study. Moreover, our results are also in agreement with previous in vivo findings. 8 Our findings in spontaneous activity of the uterus from normal preclimacteric and menopausal women are in accordance with those of Sandberg et al.,1 who reported a scanty and an intermediate motility in menopausal and preclimacteric groups, respectively. However, the absence of a quantitative study does not permit a more detailed discussion. In addition, similar results have been shown in uterine activity in vivo. 8 Adam et al. 9 have shown marked atrophy in circular and longitudinal uterine layers in preparations taken from ovariectomized guinea pigs. Similar myometrial atrophy during menopause could explain the lower spontaneous uterine activity observed in our study group. This study explores the possibility that uterine pathologic conditions may mediate changes in spontaneous activity. Our results revealed significant differences between pathologic specimens and normal tissues. In the strips of myomatous uteri, the results show a marked increase in spontaneous uterine activity in both reproductive-aged and preclimacteric women. In contrast, no differences were found when the women were of postmenopausal age. Although in our series no study was done to explain these differences, the occurrence
193
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o SPONTANEOUS UTERINE MOTILITY Fig. 4. Frequency (contractions/lO min), force of contraction (gF/ gw), and spontaneous activity developed by isolated myo-
metrial strips of uteri from menopausal women with nonpathologic conditions ([I!]) (n = 22), myomas (0) (n = 7), adenomyosis (_) (n = 7), and malignant tumors (El) (n = 5). Each value is the mean ± SEM.
of increased quantities of steroid receptors in myomas could be related to our results. Soules and McCartylO observed normal qualitative cyclic changes in steroid receptors during the menstrual cycle in leiomyomas. Their study agrees with our results, which show two normal cyclic patterns of spontaneous uterine activity in strips taken from uteri with myomas. Dai et al. II suggested that histamine has negligible effects in the human uterus. In contrast, our results show that histamine produces a dose-related contraction of isolated strips of the human uterus and confirm the results described by Farmer and Lehrer. 12 A similar contractile effect of histamine in guinea pig uterus has been reported. Our results also show that the contractile effect of histamine is quantitatively the same, whether the specimen is obtained during either of the two stages of the menstrual cycle or after the menopause. A decrease during aging in sensitivity to histamine has been reported in guinea pig trachea, but as in our results, this change in the contractile effect of histamine is absent in bronchial and parenchymal preparations. 13 In contrast, Eltze 14 failed to find changes in the inhibitory response to histamine on the isolated rat uterus during the menstrual cycle. Similarly, in our study no significant differences in the uterine contractile effect of histamine are shown in the proliferative or secretory phases. It is well documented that in some airway diseases
194 Martinez-Mir et al.
July 1990 Am J Obstet Gynecol
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HISTAMINE (-Ioe.) Fig. 5. Dose-response curves to histamine on isolated myometrial strips taken from uteri of women with non pathologic conditions (A), myomas (B), and adenomyosis (C) of women with active sexual cycles, in proliferative (e) and secretory (.) phases. Each point shows the mean from at least four experiments, and the SEM is shown.
there is hyperreactivity to histamine, and it has been suggested that the existence of hypertrophy and hyperplasia of airway smooth muscle may account for the heightened reactivity to contractile agonists. In this sense, the myometrial strips used in this study were obtained from uteri with pathologic conditions that produce quantitative and qualitative modifications of the smooth muscle mass. Hence, it seems likely that the contractile response to histamine could be modified according to the pathologic conditions. Our results failed to demonstrate a significant modification of Ee 50 and Em= of histamine when the dose-response curves of histamine were performed on isolated myometrial strips obtained from different pathologic groups of uteri. The fact that the strips used in our study were taken from macroscopically normal areas of the uterus could explain the lack of modifications in the doseresponse curves of histamine found. Pathogenic mechanisms other than those proposed in airway abnormality must occur in uterine pathology and also could explain the different results obtained with histamine in these two tissues. In summary, the results of this study provide evidence that the spontaneous motility of the isolated strips of human corpus uteri varies according to the uterine pathologic condition and also varies in relationship with menopause. They also confirm the existence of two different sexual phase-related patterns in spontaneous motility of the isolated myometrial strip of human uteri. In addition, it was not possible to demonstrate a significant change in the uterine response to histamine with the uterine abnormality studied.
We thank the staff of the Obstetric and Gynaecologic Service of the Hospital Clinico U niversitario for their cooperation in providing specimens of uterus, P. S. Derrick for correcting the English text, and D. Marti for preparing the illustrations.
REFERENCES I. Sandberg F, Ingelman-Sundberg A, Lindgren L, Ryden
2.
3. 4. 5.
6. 7. 8.
G. In vitro studies of the motility of the human uterus. Part I. The spontaneous motility in different parts of the nonpregnant uterus during sexual cycle and in the menopause and its correlation with the actomyosin content. ] Obstet Gynaecol Br Emp 1957;64:334-41. Garrioch DB. The effect of indomethacin on spontaneous activity in the isolated human myometrium and on the response to oxytocin and prostaglandin. Br ] Obstet GynaecoI1978;85:47-52. Garrett WJ. The effect of adrenaline, noradrenaline and dihydroergotamine on excised human myometrium. Br ] Pharmacol 1955;10:39-44. Lossius K, Nesheim Bl. Response to isoprenaline in the human pregnant and non-pregnant myometrium. Acta Pharmacol Toxicol 1976;39: 198-208. Sandberg F, Ingelman-Sundberg A, Lindgren L, Ryden G. In vitro studies of the motility of the human uterus. Part III. The effect of adrenaline, noradrenaline and acetylcholine on the spontaneous motility in different parts of the pregnant and nonpregnant uterus. ] Obstet Gynaecol Br Emp 1957;64:965-72. Tozzi S. The mechanism of action of histamine on the isolated rat uterus. ] Pharmacol Exp Ther 1973;187: 5ll-7. Cortijo], Esplugues J, Morales-Olivas F], Rubio E. The inhibitory effect of histamine on the motility of rat uterus in vivo. Eur] Pharmacol 1984;97:7-12. Hein PR, Eskes T, Stolte L, Braaksma]],]anssens], Hoer ]M. The influence of steroids on the motility in the nonpregnant human uterus. In: ]osimovich ]B, ed. Uterine contraction-side effect of steroidal contraceptives. New York: John Wiley, 1973:107-28.
Volume 163 Number 1, Part I
9. Adam SP, Hartley ML, Pennefather 1N, Story M, Handberg C. Uterine contractility and actions of catecholamines in longitudinal and circular uterine layers from ovariectomised guinea-pig: the effect of ovarian steroids. 1 Auton PharmacoI1985;5:317-24. 10. Soules MR, McCarty KS. Leiomyomas: steroid receptor content. AM1 OBSTET CYNECOL 1982;143:6-11. II. Dai S, Ogle CW, Leung PMK. The lack of effect of histamine on spontaneous activity in the isolated human myometrium. Agents Actions 1982; 12:608-11. 12. Farmer 1B, Lehrer DN. The effect of isoprenaline on the
Influence of abnormality in isolated human uterus
contraction of smooth muscle produced by histamine, acetylcholine or other agents. 1 Pharm Pharmacol 1966; 18:649-56. 13. Brink C, Duncan PC, Midzenski M, Douglas 1S. Response and sensitivity of female guinea-pig respiratory tissues to agonists during ontogenesis. 1 Pharmacol Exp Ther 1980;215:426-33. 14. Eltze M. Proestrus and metaestrus rat uterus, a rapid and simple in vitro method for detecting histamine H 2receptor antagonism. Drug Res 1979;29:1107-12.
A new tocolytic agent: Development of an oxytocin antagonist for inhibiting uterine contractions Laird Wilson, Jr., PhD: Michael T. Parsons, MD: Luella Ouano, MD: and George Flouret, PhDb
Chicago, Illinois A potent oxytocin antagonist has been developed and tested on both the rat and human uterus. In the rat the oxytocin antagonist: (1) inhibited in vitro and in vivo uterine contractions in the nonpregnant animal in response to exogenous oxytocin, (2) inhibited milk letdown, and (3) disrupted the progress of labor. In addition, the oxytocin antagonist inhibited the in vitro contractile response to exogenous oxytocin of human myometrial tissue obtained by cesarean section at term. The results of these studies suggest that the oxytocin antagonist can be used to study the role of oxytocin in labor and has the potential of inhibiting preterm labor in humans. (AM J OBSTET GVNECOL 1990;163:195-202.)
Key words: Oxytocin antagonist, uterine contractions, tocolytic, pre term labor
The contribution of maternal and fetal oxytocin to the initiation and progress of labor is poorly understood. The studies in the literature are conflicting and enigmatic. There are reports that oxytocin levels in the peripheral plasma in humans increase with gestational age or remain unchanged, 1,2 increase at different stages of labor, or show no alterations. 3 , 4 Similar ambiguities also exist with studies in other species. There are indications the fetus might be an important contributor of oxytocin to labor,s, 5 but other studies refute these data. 6 Also, there are reports that imply that maternal oxytocin does not playa role in parturition in rats 7 • 8 or humans. 9 From the Department of Obstetrics and Gynecology, University of Illinois at Chicago, College of Medicine," and the Department of Physiology, Northwestern University Medical Schooz.! Supported in whole or in part by National Institutes of Health grant no. HD 22567 and by the Earl M. Bane Charitable Trust. Received for publication October 3, 1989; revised February 12, 1990; accepted March 1, 1990. Reprint requests: Laird Wilson, Jr., PhD, Department of Obstetrics and Gynecology, University of Illinois at Chicago, College of Medicine, 840 South Wood St., Chicago, IL 60612.
Additional studies have shown that oxytocin receptor levels increase dramatically in uterine tissue just before and at the time of labor in several species, including rats and humans. to, II This is interpreted to mean that enhanced secretion of oxytocin is not required and that constant levels of oxytocin in the face of augmented uterine sensitivity to oxytocin would result in incremental changes in uterine activity that culminate in labor. Recent reports have focused on the development of an oxytocin antagonist for inhibiting uterine contractions. 12- 15 The purpose of the present study was to develop a potent oxytocin antagonist to be used to study the role of oxytocin in pregnancy and labor and for the potential clinical use of inhibiting preterm labor in humans. The results of this study show that a potent oxytocin antagonist has been developed; oxytocin appears to be important in the labor process in rats, and the oxytocin antagonist inhibits the response of human myometrial tissue to exogenous oxytocin in vitro. These data suggest that the oxytocin antagonist has the potential of inhibiting preterm labor in humans.
195
Key words: Isolated human uterus, histamine, uterine motility
It has been reported that the spontaneous motility of isolated muscular strips of the human uterus varies widely, with sexual phase, anatomic origin of the strip, pregnancy, and the experimental conditions used. I-3 Moreover, several authors have shown that there are wide variations in the frequency and force of contractions, as well as the response to drugs, of human myometrial strips from different uteri, although the cause of these large variations is still obscure. 3-5 Conversely, many studies of the isolated human uterus have been done with no consideration for the clinical diagnosis in each case; therefore the uterine abnormality of the women who had operations could be a source of the variation in the results described. In this investigation we studied the spontaneous uterine activity of isolated myometrial strips from patients with various uterine pathologic conditions and investigated the influence of those pathologic conditions on the response of the corpus uteri to histamine.
From the Departament de Farmacologia i Farmacotecnia, Facultat de Medicina, Universitat de Valencia. Received for publication June 21, 1989; revised February 2, 1990; accepted February 5, 1990. Reprint requests: Elena Rubio, MD, PhD, Departament de Farmacologia i Farmacotecnia, Facultat de Medicina, Avenida Blasco Ibanez, 17. 46010 Valencia, Espana. 611119896
Material and methods Myometrial tissue was obtained from 82 women undergoing hysterectomy because of various gynecologic pathologic conditions. A sample of each uterus obtained was sent for histologic examination to check the pathologic diagnosis and the phase of menstrual cycle. The specimens were divided on the basis of their final diagnosis as follows: group 1: 30 patients who underwent hysterectomy for gynecologic conditions that did not affect the uterus served as normal control subjects; group 2: 26 patients with uterine myoma; group 3: 23 patients with uterine adenomyosis; and group 4: three patients with uterine malignancy. Since it has been reported that menopause and the phase of the sexual cycle may influence uterine motility, subjects were then separated into subgroups according to the classification used by Sandberg et al.I as follows: proliferative group, 18 patients aged 29 to 51; secretory group, 20 patients aged 37 to 53; preclimateric group, 13 patients aged 41 to 57; and menopausal group, 31 patients aged 52 to 78. Isolated strips of uterus. Immediately after abdominal hysterectomy, muscle strips from an intermediate layer were cut longitudinally from the anterior part of the corpus of the uteri. The tissue was rapidly immersed in a Jalon solution of the following composition: sodium chloride 155.17 mmollL, potassium chloride
189
190 Martinez-Mir et al.
July 1990 Am J Obstet Gynecol
un
PROLI FERAl! VE GROUP
o SECRETORY
GROUP
f3 PRECLIMACTERIC GROUP •
MEMOPAU5AL GROUP
MY
AD
o M-P
MT
Fig. 1. Time in minutes for myometrial strips to start spontaneous motility. Strips were taken from uteri with nonpathologic conditions (N-P) (n = 46), myomas (MY) (n = 39), adenomyosis (AD) (n = 25), and malignanttumors (MT) (n = 5). Each value is the mean ± SEM.
5.68 mmol/L, calcium chloride 0.41 mmollL, sodium bicarbonate 5.95 mmollL, glucose 2.78 mmollL; samples were then transported to the laboratory. The tissue samples were stored at 4 0 C until the next day. Muscle strips measuring approximately 2 x 3 x 35 mm were dissected and then mounted in a 20 ml organ bath containing Jalon solution at 31 C and were continuously gassed with 95% oxygen and 5% carbon dioxide. Isometric tension was recorded by a U go Basile C40 7010 transducer (Milan, Italy) connected to a Ugo Basile mod Gemini 7070 recorder. Initial tension was set at 1 gm and the preparations were undisturbed for 1 hour before any drugs were added. At the end of this period the concentration-response curve to histamine was obtained by cumulatively adding the drug at increments of 1 log unit. Only one complete doseresponse curve to histamine was constructed for each myometrial strip because tachyphylaxis to histamine has been reported for the rat uterus. 5, 7 Immediately after completion of the pharmacomechanical studies, the tissue was removed from the bath, heated for 24 hours, and then weighed on a precision balance. Analysis of data. The spontaneous activity of the muscle strips developed in these experimental conditions was evaluated as described previously7 in terms 0
of (1) isometric tension, (2) frequency of contraction, (3) functional activity, and (4) period of time necessary for the tissues to develop spontaneous activity. The values for the isometric tension developed (expressed in milligrams of force per milligram of tissue dry weight) were obtained by calculating the mean amplitude of all the contractions recorded in a lO-minute interval. The frequency of contractions represents the number of contractions in the same period of time, and functional activity corresponds to the product of these two parameters expressed in arbitrary units. The period of time before the beginning of spontaneous uterine activity is expressed in minutes. The responses of the tissue resulting from the addition of histamine were directly determined as changes in isometric tension and transformed into tension (i.e., force per gram of tissue dry weight). The 50% effective concentration (EC so ) was calculated graphically from a plot of log concentration versus percentage of the maximum response (Emax) produced by each agonist in individual experiments. All data are shown as mean ± SEM. Statistical analysis of the data was done with Student's t test at the 5% significance level. Histamine was used as dihydrochloride (Sigma Chemical Co., St. Louis) and prepared in Jalon solution before being added to the bath. Drug concentrations refer to the free base and are expressed as a final bath concentration in moles per liter.
Results The spontaneous motility of muscle strips isolated from 82 uteri was studied; 37.5% of all isolated strips showed spontaneous activity during the first hour in the organ bath. The mean ± SEM in minutes required for the uterine strips to start spontaneous motility is summarized in Fig. 1. There was a wide variability among the groups of women studied. Spontaneous motility of isolated uterine strips from patients with normal menstrual cycles. Spontaneous motility occurred in 35.9% of the muscle strips from uteri without pathologic conditions, 39.6% of the muscle strips from uteri with myomas, and 37.2% of the muscle strips from uteri with adenomyosis. Fig. 2 shows the frequency, force of contraction, and spontaneous uterine activity values obtained in the control group, as well as the myoma and adenomyosis groups. The spontaneous uterine activity in the myoma group was significantly higher than the value obtained in the control group. This latter value was not significantly different from that obtained in the adenomyosis g-roup. The highest spontaneous uterine activity observed in the myoma group was a result of a marked increase in force of contraction, which was not accompanied by any significant changes in frequency of contractions.
Influence of abnormality in isolated human uterus
Volume 163 Number 1, Part 1
Table I shows the frequency, force of contraction, and spontaneous uterine activity of the control, myoma, and adenomyosis groups in relation to the hormonal phase. It can be seen that the uterine activity developed by the isolated strip from uteri in the secretory phase was similar to the uterine activity developed in the proliferative phase, for each of the three groups. In addition, in the control group the statistical analysis revealed that the myometrial strips isolated from uteri in the secretory phase developed a spontaneous motility with a significantly lower force of contraction than that of the spontaneous motility of strips isolated from uteri in the proliferative phase. In contrast, the frequency of contraction of myometrium was higher in secretory phase uterus than in proliferative phase uterus. These results were similarly observed in both of two other groups (uteri with myomas and adenomyosis). Spontaneous motility of isolated uterine strips from preclimacteric patients. The percentages of isolated strips that developed spontaneous motility were 33.3%, 40%, and 50% in preparations from uteri with no abnormalities, myomas, and adenomyosis, respectively. Fig. 3 shows that the uterine activity of the isolated strips from a uterus with myomas was greater than that observed in preparations isolated from both uteri with adenomyosis and uteri with no pathologic conditions. These differences were a result of a significant increase in force of contraction, which was not accompanied by any significant changes in frequency of contractions. No significant differences in uterine activity (i.e., frequency and force of contractions) were found among uteri with non pathologic conditions, uteri with myomas, and uteri with adenomyosis in women with a normal menstrual cycle and uteri that were nonpathologic, had myomas, or adenomyosis in preclimacteric patients. Spontaneous motility of isolated uterine strips from menopausal patients. The percentages of isolated strips developing spontaneous motility in uteri with no abnormalities, myomas, adenomyosis, and malignant tumor groups were 30.1 %, 20%, 31.8%, and 31.3%, respectively. Fig. 4 shows that the values of uterine activity of the isolated strips from non pathologic, myoma, and adenomyosis groups were not significantly different, with no modifications in force and frequency of contractions. In contrast, the value of uterine activity was significantly higher in isolated strips of uteri with malignant tumors compared with each of the three groups in menopausal women. This increase in spontaneous uterine motility was mainly a result of an increase in force of contractions. Both uterine activity and force of contraction values were markedly reduced in isolated strips of uteri with
191
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SPONTANEOUS UTERINE MOTILITY Fig. 2. Frequency (contractions/ 10 min), force of contraction (gF/ gw), and spontaneous activity developed by isolated myo-
metrial strips of uteri from women with active sexual cycles and with non pathologic conditions ([ill) (n = 19), myomas (0) (n = 18), and adenomyosis (.) (n = 11). Each value is the mean ± SEM.
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SPONTANEOUS
UTERINE MOTILITY
Fig. 3. Frequency (contractions/ 10 min), force of contraction (gF/ gw), and spontaneous activity developed by isolated myo-
metrial strips of uteri from preclimacteric women with nonpathologic conditions ([ill) (n = 5), myomas (0) (n = 14), and adenomyosis (.) (n = 7). Each value is the mean ± SEM.
myomas compared with those of uteri with myomas of climacteric and women with normal cycles. In women with non pathologic uteri, there was a general tendency toward lower uterine activity and force of contractions with decreasing ovarian function. This
192 Martinez-Mir et al.
July 1990 Am J Obstet Gynecol
Table I. Spontaneous motility of myometrial strips isolated from uteri of women with non pathologic conditions, myoma, and adenomyosis in proliferative and secretory phases of women with active sexual cycles Nonpathologic conditions
PF (n
Uterine activity Frequency (contractionsllO min) Force (gFI gw) PF,
Prolif.~rative;
= 14)
I
SC (n
= 5)
Myomas
PF (n
= 8)
48.8 ± 13.6 4.5 ± 0.5
28.9 ± 11.8 1.9 ± 0.5*
114.6 ± 26.6 4.8 ± 0.9
13.2 ± 3.9
16.4 ± 5.5
31.1 ± 9.4
I
Adenomyosis
SC (n
=
10)
120.2 ± 28.4 2.0 ± 0.5* 63.9 ± 14.1*
PF (n
= 5)
I
SC (n
=
6)
75.8 ± 16.3 7.5 ± 2.2
51.6 ± 7.3 2.0 ± 0.4*
13.5 ± 3.4
33.5 ± 7.8*
SC, secretory. The number of isolated strips used is indicated in parentheses. Values are mean ± SEM.
*p < 0.05.
Table II. Effective concentration 50% value and maximal contractile effect for histamine on the myometrial strips isolated from uteri with non pathologic conditions, myomas, adenomyosis, and malignant tumors of preclimacteric and menopausal women and women with active sexual cycles Active sexual cycle Nonpathologic Myoma Adenomyosis Preclimateric N on pathologic Myoma Adenomyosis Menopausal Nonpathologic Myoma Adenomyosis Malignant tumor
n
EC 50 (moll L)
Emax (gFI gw)
16 13 8
6.37 ± 2.1 x 10- 5 2.93 ± 1.1 x 10- 5 9.23 ± 4.4 x 10- 5
47.6 ± 6.9 58.0 ± 7.1 53.4 ± 18.0
4 12 4
9.43 ± 6.2 x 10- 6 2.32 ± 0.7 x 10- 5 1.30 ± 0.7 x 10- 5
83.0 ± 14.7 34.6 ± 6.5 46.1 ± 7.6
17 10 6 6
2.10 4.60 3.31 6.42
± ± ± ±
0.6 1.4 3.1 2.4
x x x x
10- 5 10- 5 10- 5 10- 5
31.8 24.8 40.6 57.5
± ± ± ±
6.9 9.6 6.7 13.3
EC50 , 50% Effective concentration value; E_, maximal contractile effect; n, number of experiments.
tendency was revealed to be significant in the menopausal group. Effect of histamine. Histamine (10- 8 to 10- 3 mol/L) induced concentration-related contractions of the human uterine strips. The force of contraction increased and reached a maximum with 10- 4 mollL histamine. The EC 50 value determined from concentrationresponse curves was 5.2 ± 1.0 x 10- 5 mollL. The uterine response to histamine varied according to the amount of spontaneous activity shown by the preparation. When the uterine strip exhibited weaker spontaneous activity, this activity declined progressively during a concentration-response curve to histamine. Conversely, when the spontaneous activity developed by the uterine strip was higher, histamine, at the lowest concentrations, produced a superimposed contraction; at higher concentrations, the relaxations between contractions was incomplete, so the force of contractions was increased in a manner similar to that observed when a weaker spontaneous activity is present.
Table II shows that for women with normal menstrual cycles, histamine produced the same maximum degree of contraction and had similar EC 50 values in each group irrespective of the uterine pathologic condition. In contrast, muscle taken during the secretory phase of the menstrual cycle developed a higher maximal response to histamine than muscle taken during the proliferative phase. However, this difference in responsiveness was not statistically significant (Fig. 5). The histamine response of myometrial strips from both preclimacteric and menopausal groups was similar to that of the group with normal menstrual cycles. Similarly, the EC 50 and maximal effect of histamine were unaffected by the pathoiogic condition of the uterus (Table II).
Comment The foregoing results confirm previous findings documenting that there was a wide variation in the spon-
Influence of abnormality in isolated human uterus
Volume 163 Number I, Part I
taneous contractility of myometrial strips from different uteri. 1·3 Our results do not support the observation of Lossius and Nesheim 4 who reported that 99% of the muscle strips from nonpregnant uteri showed spontaneous activity. Their study was made with 18 uteri, and the temperature used was 37 0 C. The greater number and lower temperature used in our study could explain the differences between results. Conversely, our results agree with those of Garrioch,2 showing that the isolated human myometrium usually begins spontaneous activity within 30 minutes. It has been reported that uterine spontaneous motility varies according to the phase of the sexual cycle; however, previous reports on differences in spontaneous uterine activity in vitro during the menstrual cycle have been conflicting. I. 2, 4, 8 Lossius and Nesheim 4 found no modification in the frequency of contraction in relation to hormonal phase. Sandberg et al. I found three different types of spontaneous motility in strips from the uterine corpus, although they could not demonstrate any difference between proliferative and secretory phases. However, Garrioch 2 has shown a low amplitude associated with high frequency in the early phase, and that the latter stages are characterized by lower frequency and higher amplitude contractions. Similar observations were found in our study. Moreover, our results are also in agreement with previous in vivo findings. 8 Our findings in spontaneous activity of the uterus from normal preclimacteric and menopausal women are in accordance with those of Sandberg et al.,1 who reported a scanty and an intermediate motility in menopausal and preclimacteric groups, respectively. However, the absence of a quantitative study does not permit a more detailed discussion. In addition, similar results have been shown in uterine activity in vivo. 8 Adam et al. 9 have shown marked atrophy in circular and longitudinal uterine layers in preparations taken from ovariectomized guinea pigs. Similar myometrial atrophy during menopause could explain the lower spontaneous uterine activity observed in our study group. This study explores the possibility that uterine pathologic conditions may mediate changes in spontaneous activity. Our results revealed significant differences between pathologic specimens and normal tissues. In the strips of myomatous uteri, the results show a marked increase in spontaneous uterine activity in both reproductive-aged and preclimacteric women. In contrast, no differences were found when the women were of postmenopausal age. Although in our series no study was done to explain these differences, the occurrence
193
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o SPONTANEOUS UTERINE MOTILITY Fig. 4. Frequency (contractions/lO min), force of contraction (gF/ gw), and spontaneous activity developed by isolated myo-
metrial strips of uteri from menopausal women with nonpathologic conditions ([I!]) (n = 22), myomas (0) (n = 7), adenomyosis (_) (n = 7), and malignant tumors (El) (n = 5). Each value is the mean ± SEM.
of increased quantities of steroid receptors in myomas could be related to our results. Soules and McCartylO observed normal qualitative cyclic changes in steroid receptors during the menstrual cycle in leiomyomas. Their study agrees with our results, which show two normal cyclic patterns of spontaneous uterine activity in strips taken from uteri with myomas. Dai et al. II suggested that histamine has negligible effects in the human uterus. In contrast, our results show that histamine produces a dose-related contraction of isolated strips of the human uterus and confirm the results described by Farmer and Lehrer. 12 A similar contractile effect of histamine in guinea pig uterus has been reported. Our results also show that the contractile effect of histamine is quantitatively the same, whether the specimen is obtained during either of the two stages of the menstrual cycle or after the menopause. A decrease during aging in sensitivity to histamine has been reported in guinea pig trachea, but as in our results, this change in the contractile effect of histamine is absent in bronchial and parenchymal preparations. 13 In contrast, Eltze 14 failed to find changes in the inhibitory response to histamine on the isolated rat uterus during the menstrual cycle. Similarly, in our study no significant differences in the uterine contractile effect of histamine are shown in the proliferative or secretory phases. It is well documented that in some airway diseases
194 Martinez-Mir et al.
July 1990 Am J Obstet Gynecol
8
7
8
1!5
4
38
7
1!5
8
4
38
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3
HISTAMINE (-Ioe.) Fig. 5. Dose-response curves to histamine on isolated myometrial strips taken from uteri of women with non pathologic conditions (A), myomas (B), and adenomyosis (C) of women with active sexual cycles, in proliferative (e) and secretory (.) phases. Each point shows the mean from at least four experiments, and the SEM is shown.
there is hyperreactivity to histamine, and it has been suggested that the existence of hypertrophy and hyperplasia of airway smooth muscle may account for the heightened reactivity to contractile agonists. In this sense, the myometrial strips used in this study were obtained from uteri with pathologic conditions that produce quantitative and qualitative modifications of the smooth muscle mass. Hence, it seems likely that the contractile response to histamine could be modified according to the pathologic conditions. Our results failed to demonstrate a significant modification of Ee 50 and Em= of histamine when the dose-response curves of histamine were performed on isolated myometrial strips obtained from different pathologic groups of uteri. The fact that the strips used in our study were taken from macroscopically normal areas of the uterus could explain the lack of modifications in the doseresponse curves of histamine found. Pathogenic mechanisms other than those proposed in airway abnormality must occur in uterine pathology and also could explain the different results obtained with histamine in these two tissues. In summary, the results of this study provide evidence that the spontaneous motility of the isolated strips of human corpus uteri varies according to the uterine pathologic condition and also varies in relationship with menopause. They also confirm the existence of two different sexual phase-related patterns in spontaneous motility of the isolated myometrial strip of human uteri. In addition, it was not possible to demonstrate a significant change in the uterine response to histamine with the uterine abnormality studied.
We thank the staff of the Obstetric and Gynaecologic Service of the Hospital Clinico U niversitario for their cooperation in providing specimens of uterus, P. S. Derrick for correcting the English text, and D. Marti for preparing the illustrations.
REFERENCES I. Sandberg F, Ingelman-Sundberg A, Lindgren L, Ryden
2.
3. 4. 5.
6. 7. 8.
G. In vitro studies of the motility of the human uterus. Part I. The spontaneous motility in different parts of the nonpregnant uterus during sexual cycle and in the menopause and its correlation with the actomyosin content. ] Obstet Gynaecol Br Emp 1957;64:334-41. Garrioch DB. The effect of indomethacin on spontaneous activity in the isolated human myometrium and on the response to oxytocin and prostaglandin. Br ] Obstet GynaecoI1978;85:47-52. Garrett WJ. The effect of adrenaline, noradrenaline and dihydroergotamine on excised human myometrium. Br ] Pharmacol 1955;10:39-44. Lossius K, Nesheim Bl. Response to isoprenaline in the human pregnant and non-pregnant myometrium. Acta Pharmacol Toxicol 1976;39: 198-208. Sandberg F, Ingelman-Sundberg A, Lindgren L, Ryden G. In vitro studies of the motility of the human uterus. Part III. The effect of adrenaline, noradrenaline and acetylcholine on the spontaneous motility in different parts of the pregnant and nonpregnant uterus. ] Obstet Gynaecol Br Emp 1957;64:965-72. Tozzi S. The mechanism of action of histamine on the isolated rat uterus. ] Pharmacol Exp Ther 1973;187: 5ll-7. Cortijo], Esplugues J, Morales-Olivas F], Rubio E. The inhibitory effect of histamine on the motility of rat uterus in vivo. Eur] Pharmacol 1984;97:7-12. Hein PR, Eskes T, Stolte L, Braaksma]],]anssens], Hoer ]M. The influence of steroids on the motility in the nonpregnant human uterus. In: ]osimovich ]B, ed. Uterine contraction-side effect of steroidal contraceptives. New York: John Wiley, 1973:107-28.
Volume 163 Number 1, Part I
9. Adam SP, Hartley ML, Pennefather 1N, Story M, Handberg C. Uterine contractility and actions of catecholamines in longitudinal and circular uterine layers from ovariectomised guinea-pig: the effect of ovarian steroids. 1 Auton PharmacoI1985;5:317-24. 10. Soules MR, McCarty KS. Leiomyomas: steroid receptor content. AM1 OBSTET CYNECOL 1982;143:6-11. II. Dai S, Ogle CW, Leung PMK. The lack of effect of histamine on spontaneous activity in the isolated human myometrium. Agents Actions 1982; 12:608-11. 12. Farmer 1B, Lehrer DN. The effect of isoprenaline on the
Influence of abnormality in isolated human uterus
contraction of smooth muscle produced by histamine, acetylcholine or other agents. 1 Pharm Pharmacol 1966; 18:649-56. 13. Brink C, Duncan PC, Midzenski M, Douglas 1S. Response and sensitivity of female guinea-pig respiratory tissues to agonists during ontogenesis. 1 Pharmacol Exp Ther 1980;215:426-33. 14. Eltze M. Proestrus and metaestrus rat uterus, a rapid and simple in vitro method for detecting histamine H 2receptor antagonism. Drug Res 1979;29:1107-12.
A new tocolytic agent: Development of an oxytocin antagonist for inhibiting uterine contractions Laird Wilson, Jr., PhD: Michael T. Parsons, MD: Luella Ouano, MD: and George Flouret, PhDb
Chicago, Illinois A potent oxytocin antagonist has been developed and tested on both the rat and human uterus. In the rat the oxytocin antagonist: (1) inhibited in vitro and in vivo uterine contractions in the nonpregnant animal in response to exogenous oxytocin, (2) inhibited milk letdown, and (3) disrupted the progress of labor. In addition, the oxytocin antagonist inhibited the in vitro contractile response to exogenous oxytocin of human myometrial tissue obtained by cesarean section at term. The results of these studies suggest that the oxytocin antagonist can be used to study the role of oxytocin in labor and has the potential of inhibiting preterm labor in humans. (AM J OBSTET GVNECOL 1990;163:195-202.)
Key words: Oxytocin antagonist, uterine contractions, tocolytic, pre term labor
The contribution of maternal and fetal oxytocin to the initiation and progress of labor is poorly understood. The studies in the literature are conflicting and enigmatic. There are reports that oxytocin levels in the peripheral plasma in humans increase with gestational age or remain unchanged, 1,2 increase at different stages of labor, or show no alterations. 3 , 4 Similar ambiguities also exist with studies in other species. There are indications the fetus might be an important contributor of oxytocin to labor,s, 5 but other studies refute these data. 6 Also, there are reports that imply that maternal oxytocin does not playa role in parturition in rats 7 • 8 or humans. 9 From the Department of Obstetrics and Gynecology, University of Illinois at Chicago, College of Medicine," and the Department of Physiology, Northwestern University Medical Schooz.! Supported in whole or in part by National Institutes of Health grant no. HD 22567 and by the Earl M. Bane Charitable Trust. Received for publication October 3, 1989; revised February 12, 1990; accepted March 1, 1990. Reprint requests: Laird Wilson, Jr., PhD, Department of Obstetrics and Gynecology, University of Illinois at Chicago, College of Medicine, 840 South Wood St., Chicago, IL 60612.
Additional studies have shown that oxytocin receptor levels increase dramatically in uterine tissue just before and at the time of labor in several species, including rats and humans. to, II This is interpreted to mean that enhanced secretion of oxytocin is not required and that constant levels of oxytocin in the face of augmented uterine sensitivity to oxytocin would result in incremental changes in uterine activity that culminate in labor. Recent reports have focused on the development of an oxytocin antagonist for inhibiting uterine contractions. 12- 15 The purpose of the present study was to develop a potent oxytocin antagonist to be used to study the role of oxytocin in pregnancy and labor and for the potential clinical use of inhibiting preterm labor in humans. The results of this study show that a potent oxytocin antagonist has been developed; oxytocin appears to be important in the labor process in rats, and the oxytocin antagonist inhibits the response of human myometrial tissue to exogenous oxytocin in vitro. These data suggest that the oxytocin antagonist has the potential of inhibiting preterm labor in humans.
195