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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden.
Address reprint requests to: Erling Ekerhovd, MD Department of Obstetrics and Gynecology Göteborg University Sahlgrenska University Hospital Göteborg S-413 45 Sweden
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Abstract |
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Methods: Myometrial tissue was obtained before the onset of labor and during labor at term. Production of NO was assessed by the use of nicotinamide dinucleotide phosphate diaphorase staining and by immunoblots for NO. Effects of NO were examined by adding L-arginine (the substrate for NO synthesis); NG-nitro-L-arginine methyl ester (an inhibitor of NO synthase); two NO donors, sodium nitroprusside and spermine NONOate; as well as 8-bromo cyclic guanosine monophosphate (8-bromo cGMP) (a second messenger analogue) to organ baths.
Results: Myometrial NO production was indicated by positive nicotinamide adenine dinucleotide phosphate diaphorase staining. Immunoblots detected endothelial NO synthase, whereas only a weak signal for inducible NO synthase was seen. The addition of L-arginine (10-4–10-3 mol/L) did not result in any change of contractility. NG-nitro-L-arginine methyl ester (10-3 mol/L) caused a minor increase of contractility in half of the specimens. Sodium nitroprusside, spermine NONOate, and 8-bromo cGMP resulted in a concentration-dependent inhibition of contractility (10-7–10-6 mol/L for sodium nitroprusside, 10-6–10-5 mol/L for spermine NONOate, and 10-5–10-3 mol/L for 8-bromo cGMP). However, at 10-5–10-4 mol/L, sodium nitroprusside exhibited a dose-dependent increase in the frequency of contractions. Women in prelabor did not differ from those in active labor.
Conclusion: The myometrium produces NO at term. Nitric oxide inhibits myometrial contractile activity. The responsiveness to NO is similar in nonlaboring and laboring women.
Nitric oxide (NO), a free radical gas, is an important modulator of contractile activity in smooth muscle in a variety of organs, exhibiting predominantly relaxing effects.1,2 It is generated from L-arginine by a group of enzymes called NO synthase.3 Three types of NO synthase isoforms have been identified and cloned. The constitutive isoforms, endothelial NO synthase and neuronal NO synthase, are both calcium-calmodulin dependent and both produce small amounts of NO (picomoles) for short periods. On the other hand, inducible NO synthase is calcium-calmodulin independent and produces large quantities of NO (nanomoles) for long periods when stimulated by cytokines or endotoxins. The action of NO is mediated by activation of soluble guanylate cyclase, thereby increasing cyclic guanosine monophosphate (cGMP). This substance in turn activates protein kinases, which ultimately leads to relaxation of smooth muscle (Figure 1
).
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Studies on the human pregnant uterus have demonstrated myometrial NO synthase activity.9–11 Of great clinical interest is the plausible role of NO in the maintenance of uterine quiescence during pregnancy and the efficacy of NO donors to inhibit premature contractions. Preterm delivery is the single most important contributor to perinatal morbidity and mortality in the developed world. At present, drugs to inhibit premature contractions are few and their efficacy is questionable.12 However, it is still not clear whether NO is involved in the regulation of uterine quiescence during pregnancy.13 A preliminary uncontrolled study during preterm labor suggested that NO may be an important inhibitor of premature contractions.14 On the other hand, NO inhibits spontaneous myometrial contractions in vitro, but the responsiveness to NO seems to be decreased during labor.15,16
The purpose of this in vitro study was to investigate the endogenous NO system in the human pregnant myometrium and to study the effects of exogenous NO on contractile activity of isolated myometrial tissue obtained from term pregnant women undergoing elective or emergency cesarean delivery before the onset of labor or during labor, respectively.
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Materials and Methods |
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During a 12-month period between October 1996 and September 1997, women undergoing cesarean delivery at term before labor (cervical dilatation less than 2 cm) or after the onset of labor (cervical dilatation greater than 4 cm) were recruited to the study. Only healthy women with no signs of pregnancy-related diseases and no medications were included. The indications for elective cesarean delivery (before the start of labor) were breech presentation with expected mechanical disproportion or maternal anxiety about vaginal delivery. The only indication for emergency cesarean (after the onset of labor) was acute fetal distress.
After delivery, myometrial tissue samples were obtained from the upper edge of the transverse incision of the lower uterine body and from a small longitudinal excision on the posterior wall of the fundal part of the uterine body. The samples were either snap frozen in liquid nitrogen and then stored at -70C for later analyses (nicotinamide adenine dinucleotide phosphate diaphorase staining, Western blotting) or transferred into ice-chilled buffer solution (contractility experiments) of the following composition (mmol/L): NaCl 122, KCl 4.7, CaCl2 2.5, MgCl2 · 6H2O2 1.19, KH2PO4 1.19, glucose 11.5, and N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid 5.0.
Frozen myometrial tissue specimens were mounted in OCT Tissuetec (Miles Inc., Elkhart, IN) for nicotinamide adenine dinucleotide phosphate diaphorase staining. Sections of 6 µm thickness were cut on a cryostat and fixed onto gelatine/chrome aluminum-coated slides. The slides were incubated with 1 mmol/L nicotinamide dinucleotide phosphate/0.2 mmol/L nitroblue tetrazolium/0.1 mol/L Tris-HCl (pH 7.2)/0.2% Triton X-100 for 60 minutes at 37C.17 As negative controls for the staining procedure, some sections were exposed to the staining solution but with omission of nicotinamide dinucleotide phosphate. All substances were purchased from Sigma Chemical Co. (St. Louis, MO).
Western blotting was carried out according to the present standard procedure of our laboratory. Tissues for endothelial and inducible NO synthase were prepared by homogenization in a PE-buffer (10 mmol/L potassium phosphate buffer, pH 6.8, and 1 mmol/L ethylenediaminetetra-acetic acid) containing 10 mmol/L 3-[(-3 cholamidopropyl)dimethylammonio] 1-propane sulfate, aprotinin (200 kallikrein inhibitory units/mL), leupeptin (1 mg/mL), pepstatin (1 mg/mL), and Pefablock (1 mg/mL; Boehringer, Mannheim, Mannheim, Germany). The homogenate was then sonicated twice (15 seconds each time) and centrifuged (10,000 x g; 10 minutes; 4C). The supernatants were stored at -70C until analysis. Protein concentrations were measured according to the Pierce BCA Protein Assay Reagent Kit (Pierce, Rockford, IL). Immediately before electrophoresis, NuPAGE reducing agent (0.5 mol/L 1,4-dithiothreitol; NOVEX, San Diego, CA) was added to the sample solutions to a final concentration of 10%. Samples were then heated at 70C for 10 minutes before loading on a NuPAGE (NOVEX) 4–12% Bis-Tris gel with the 3-(N-morpholino) propane sulfonic acid/ sodium dodecyl sulfate running buffers. Fifty micrograms of total protein was loaded into each lane, and prestained standards (Multimark; NOVEX) were used as markers. The proteins were then transferred to a polyvinyldifluoride membrane (Amersham, Buckinghamshire, UK) using the blotting system Mighty Small (Hoefer, San Francisco, CA). The membrane was incubated with specific antibodies against either endothelial NO synthase (mouse monoclonal; Transduction Laboratories, Lexington, KY) or inducible NO synthase (mouse monoclonal or mouse polyclonal; Transduction Laboratories). Immunoreactive protein was visualized by chemiluminescence using alkaline phosphatase–conjugated secondary goat antimouse antibodies (dilution 1:20,000) (Santa Cruz Biotechnology, San Diego, CA) and CDP Star (Tropix, Bedford, MA) as substrate. The membrane was exposed to ECL film (Amersham, Buckinghamshire, United Kingdom) at room temperature.
For semiquantitative measurement of the proteins on these Western blots, we used a software package in The Discovery Series Densitometric Systems (Pharmacia Biotech, Lund, Sweden) with Desk Top Plus Scanner. The optical density x mm2 from each band was measured. In each blot, one lane was loaded with protein from an appropriate positive control (human aorta endothelial cells for endothelial NO synthase, and interleukin-1ß + interferon-
stimulated human large intestine for inducible NO synthase).
Myometrial tissue for contractility experiments was taken immediately to the laboratory. Myometrial strips were cut with microscissors under a stereomicroscope. Within 1 hour after delivery, strips measuring approximately 6 x 1 x 1 mm were mounted vertically in organ-bath chambers and incubated in buffer of the same composition as previously mentioned. The buffer was bubbled continuously with oxygen. The strips were suspended under a resting tension of 5 mN and were allowed to equilibrate for approximately 2 hours until regular contractile activity was established. Drugs to be tested were then added at increasing concentrations with an interval of 40 minutes and without washout between each concentration examined. Each strip was exposed to only one drug. The tension generated was recorded by a Grass FT 03D transducer (Grass Instruments, Quincy, MA) connected to an RPS 7D Grass polygraph recorder.
L-arginine (the substrate for endogenous NO synthesis), NG-nitro-L-arginine methyl ester (a competitive inhibitor of NO synthesis), sodium nitroprusside (an NO donor), and 8-bromo cGMP (an analogue of the second messenger) were all purchased from Sigma Chemical Co. Spermine NONOate ((Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]-amino}-diazen-1-ium-1,2-diolate]) (an NO donor) and spermine (the parent compound of spermine NONOate without NO) were purchased from Alexis Co. (Läufelfingen, Switzerland). All drugs were dissolved in buffer solution before administration to the organ baths.
At least eight myometrial strips from the upper and the lower uterine body obtained from eight women were included in each experiment. On several occasions, more than one strip from each woman was exposed to the same concentrations of the drug tested to assess reproducibility. Contractile activity was evaluated by estimating the area under the tension curve (mean ± standard error of the mean [SEM]) using computerized planimetry (FlexiTrace 1. 02; Tree Star, Inc., Santa Barbara, CA) so that changes in the frequency of contractions, amplitude of contractions, and changes in basal muscle tone could be taken into consideration. Furthermore, in some experiments, changes in the frequency of contractions were estimated separately (mean ± SEM). After the establishment of regular contractile activity, a period of 40 minutes immediately before the administration of each of the drugs tested was chosen as a control. Equally long test periods starting after the administration of a drug were compared with the control periods. Statistical comparisons were performed by means of one-way analysis of variance as well as unpaired and paired Student t tests where appropriate. A value of P < .05 was considered significant.
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Positive nicotinamide adenine dinucleotide phosphate diaphorase staining, histochemically visualized as a dark blue deposit, was seen in the entire myometrium as well as in the walls of blood vessels of all three women in each group (Figure 2). No difference in staining could be observed between tissue specimens obtained from nonlaboring and laboring women. The staining intensity also did not differ between samples obtained from the upper and the lower uterine segments. Staining was absent in control specimens exposed to the staining solution with the omission of nicotinamide adenine dinucleotide phosphate.
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Spontaneous contractile activity in myometrial strips obtained from women before the onset of labor appeared in 80 of 96 strips from the upper uterine body and 88 of 96 strips from the lower uterine body. In contrast, only 32 of 48 strips from the upper uterine body and 35 of 48 strips from the lower uterine body obtained from laboring women developed regular contractile activity. In preliminary experiments, it was evident that the period between the surgical procedure and the in vitro experiment was critical for the establishment of spontaneous contractions in specimens from laboring women. Maximal activity in terms of integrated contractile force appeared approximately 120 minutes after the application of a passive tension of 5 mN. Contractile activity could be registered for up to 6 hours after exposure to a drug. The frequency of contractions (mean ± SEM) was 1.4 ± 0.13 contractions per 10 minutes in strips obtained from the upper uterine body, which was significantly (P < .05) lower than 2.1 ± 0.25 contractions per 10 minutes in strips from the lower uterine body. These values corresponded to contraction intervals of 7.1 minutes and 4.8 minutes, respectively. There were no significant differences in the frequency of contractions, amplitude of contractions, or duration of contractions of strips obtained from nonlaboring and laboring women. The contractile patterns of strips from women given regional spinal anesthesia did not differ from those obtained from women under general anesthesia.
All myometrial strips exhibiting spontaneous contractile activity were used for pharmacologic experiments. However, to reduce the time from specimen collection to the start of the experiment to less than 1 hour, we examined a limited number of strips from each woman.
To investigate the effect of endogenous NO production on contractile activity before the onset of labor, we exposed myometrial strips to either L-arginine (10-4–10-3 mol/L), the substrate for endogenous NO synthesis, or NG-nitro-L-arginine methyl ester (10-3 mol/L), a competitive inhibitor of NO synthase activity (Figure 4). The administration of L-arginine to the organ baths did not result in any measurable change in contractile activity. NG-nitro-L-arginine methyl ester caused a slight but nonsignificant increase in contractile activity in four of eight strips from the upper segment and five of eight strips from the lower segment from eight women. This change was due to a minor increase in the frequency of contractions, but a subtle increase in basal tone was also registered.
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and 6). A concentration-dependent inhibition of contractile activity in terms of frequency and amplitude was observed when sodium nitroprusside was administered at 10-7 and 10-6 mol/L. At 10-5 mol/L and greater, a dose-dependent increase in the frequency of contractions was registered. At 10-4 mol/L, a minor increase in the amplitude of contractions could be observed compared with contractions at 10-5 mol/L. The response was similar in all strips tested, and no difference was observed between the upper and the lower uterine body.
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). Not only was a decrease noted in the amplitude and frequency of contractions, but at 10-5 mol/L, a slight decrease in baseline tone also was observed. In six strips (four from the upper segment and two from the lower segment) of 34 strips tested (at least eight strips from the upper as well as the lower uterine body of eight nonlaboring and eight laboring women), spontaneous contractions were completely abolished during the test period (Figure 8). Three of the strips exhibiting no contractions at 10-5 mol/L (one from the upper segment and two from the lower segment from three individuals) were obtained from spontaneously laboring women. These strips all regained gradual spontaneous contractile activity within 1–2 hours, without any washout. No significant difference in responsiveness to spermine NONOate could be registered between strips obtained from nonlaboring and laboring women.
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The addition of 8-bromo cGMP resulted in a concentration-dependent inhibition of spontaneous contractions in strips from both the upper and the lower uterine body (Figure 9). This change was mainly manifested by a decrease in the amplitude of contractions. No change in the frequency of contractions was noted at 10-5 and 10-4 mol/L. At 10-3 mol/L, six of 32 strips exhibited a decrease in the frequency of contractions. No significant difference was observed between strips obtained from the upper and the lower uterine segment or from laboring versus nonlaboring women.
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Discussion |
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It is well known that myometrial tissue from the lower and the upper uterine segments exhibits different spontaneous contractile activity in vitro.18 Therefore, to evaluate any difference in response to NO-mediated effects, tissue specimens were obtained from the upper edge of the transverse incision of the lower uterine segment as well as from a small longitudinal excision on the fundal part of the posterior wall of the uterine body.
Nicotinamide adenine dinucleotide phosphate diaphorase staining does not differentiate between the activities of the different isoforms of NO synthase. Although the NO synthase isoforms all are nicotinamide adenine dinucleotide phosphate diaphorases, the reaction with nicotinamide dinucleotide phosphate diaphorase is specific to NO synthase only if there are no other active nicotinamide dinucleotide phosphate–requiring enzymes present. On the other hand, a major change in NO synthase activity between the experimental groups is likely to be reflected in the intensity of the staining. Such a change was not evident between specimens from women before and after the start of labor, indicating that endogenous myometrial NO synthase activity is not circumstantially influenced by the onset of parturition.
Another indication of unchanged NO production at parturition is the results of the Western blot analysis, which clearly demonstrated that human myometrial tissue expresses endothelial NO synthase, but with no significant difference in such expression before and after the onset of labor. The level of inducible NO synthase seems to be very low because it was not detectable using the monoclonal antibody and was barely detectable using the polyclonal antibody. This finding is in line with a recent study using a rabbit polyclonal antibody to human inducible NO synthase, which concluded that the expression of inducible NO synthase is highest in the myometrium of preterm women who are not in labor and that the expression of inducible NO synthase is low at term.19 This indicates that inducible NO synthase activity may be involved in the regulation of uterine quiescence during pregnancy and that a gradual decrease in myometrial inducible NO synthase activity may occur during the last weeks of pregnancy before the onset of labor.
On the other hand, the Western blots for both endothelial NO synthase and inducible NO synthase did demonstrate a substantial banding, corresponding to proteins of lower molecular weight. These components may represent cross-reactive proteins or degradation products of the very NO synthase enzymes.
The administration of L-arginine to organ baths was not followed by any measurable change in spontaneous myometrial contractility. These results may be explained either by a prevailing endogenous saturation of the substrate for NO synthesis or by a truly low enzyme activity at term pregnancy. Normally, L-citrulline, a byproduct of NO synthesis, is recycled back to L-arginine.20 The regeneration of L-arginine provides a sufficient level of substrate for NO synthesis under most conditions. The observed lack of response to L-arginine is in agreement with studies of NO synthase activity in vascular smooth muscle, in which external L-arginine dependence is rarely registered.21 However, the present finding in the human myometrium is contrary to what has been observed in the rat uterus, where administration of L-arginine to organ baths caused a concentration-dependent inhibition of contractile activity.6
On the other hand, NG-nitro-L-arginine methyl ester, a competitive inhibitor of NO synthesis, caused only a modest but nonsignificant change in contractile activity. If an endogenous NO system were involved in uterine relaxation during pregnancy, one should expect a substantial increase in contractile activity when the strips were exposed to NG-nitro-L-arginine methyl ester. The lack of significant response to NG-nitro-L-arginine methyl ester gives further support for the idea that myometrial NO synthase activity is low at term before the onset of labor.
Sodium nitroprusside has been widely used clinically to treat cardiovascular disease. The production of NO by sodium nitroprusside is believed to be based on biotransformation or spontaneous degradation mechanisms.22,23 The present study clearly demonstrates that sodium nitroprusside inhibits spontaneous myometrial contractions in a concentration-dependent manner at 10-7 and 10-6 mol/L before the start of labor. It also shows that at 10-5 and 10-4 mol/L, an increase occurs in the frequency of contractions and the amplitude of contractions. This paradoxic effect of sodium nitroprusside cannot be ascribed to NO itself, but rather to other effects of sodium nitroprusside. Hypothetically, it may be proposed that the stimulating effect on the frequency of contractions could be mediated by prostaglandins because NO has been shown to activate cyclo-oxygenase and to stimulate uterine contractility in the rat.24,25
Spermine NONOate is a nucleophile/NO complex that releases NO spontaneously at a predictable rate without enzymatic involvement.26 At a temperature of 37C and pH of 7.4, the half-life of spermine NONOate is 39 minutes. Decomposition of one molecule of the complex produces two molecules of NO but also one molecule of free spermine, a polyamine with several bioeffector roles of its own, including hypotensive activity. This NO donor exerted a clear inhibition of contractions both before and after the start of labor. To exclude any relaxing effect of the parent compound, we added pure spermine to the organ baths (10-6–10-5 mol/L). The administration of spermine did not cause any change in contractile activity, demonstrating that free spermine was devoid of measurable activity and that the response observed for spermine NONOate was due to NO release.
Administration of 8-bromo cGMP resulted in a dose-dependent inhibition of contractions. However, a clear decrease in the frequency of contractions, similar to that observed for spermine NONOate, was not registered even at 10-3 mol/L. This observation may indicate that NO could exert some of its relaxing effect through other mechanisms than cGMP, ie, by altering the transmembrane fluxes of potassium ions.27
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Footnotes |
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Received August 24, 1998. Received in revised form December 7, 1998. Accepted December 17, 1998.
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References |
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21. Rees DD, Palmer RMJ, Schulz R, Hodson HF, Moncada S. Characterization of three inhibitors of endothelial nitric oxide synthase in vitro and in vivo. Br J Pharmacol 1990;101:746–52.[Medline]
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26. Maragos CM, Morley D, Wink DA, Dunams TM, Saavedra JE, Hoffman A, et al. Complexes of NO with nucleophiles as agents for controlled biological release of nitric oxide. Vasorelaxant effects. J Med Chem 1991;34:3242–7.[Medline]
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