Inhibition of nitric oxide synthesis causes preterm delivery in the mouse

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1 Human Reproduction vol.15 no.8 pp , 2000 Inhibition of nitric oxide synthesis causes preterm delivery in the mouse Gian Mario Tiboni 1 and Franca Giampietro NO has been recently postulated as having a role in the complex molecular interplay which regulates myometrial func- Sezione di Ostetricia e Ginecologia, Dipartimento di Medicina e Scienze dell Invecchiamento, Facoltà di Medicina e Chirurgia, tion during gestation (Norman, 1996; Sladek et al, 1997; Università G. d Annunzio, Chieti, Italy Yallampalli et al., 1998), and several animal and human studies 1 have been conducted on this subject during the last few years. To whom correspondence should be addressed at: Sezione di Ostetricia e Ginecologia, Dipartimento di Medicina e Scienze Evidence exists that generation of NO occurs in uterine dell Invecchiamento, Facoltà di Medicina e Chirurgia, Università tissues of several species, including the rat (Conrad et al., G. d Annunzio, Presidio Ospedaliero SS. Annunziata, Colle 1993; Izumi et al., 1993; Natuzzi et al., 1993; Yallampalli dell Ara, 66100, Chieti, Italy. et al., 1993, 1994), guinea-pig (Weiner et al., 1994), rabbit The aim of the present study was to investigate whether (Sladeck et al., 1993), sheep (Figueroa and Massmann, 1995) an inhibitor of nitric oxide (NO) synthesis provokes preterm and mouse (Huang et al., 1995; Moorhead et al., 1995). In delivery in a mouse model. ICR (CD-1) mice were injected the rabbit (Sladeck et al., 1993) and rat (Yallampalli et al., s.c. with N G -nitro-l-arginine methyl esther (L-NAME) at 1993), NO synthesis showed a phase-dependency, being up- 0, 40, 70 or 100 mg/kg on gestation day (GD) 15.5 and 16. regulated during gestation and down-regulated during labour. Delivery was considered preterm if it occurred before GD Notably, the contractility of pregnant rat uterine strips was 18. In a satellite study, the potential ability of the NO inhibited by NO and its precursor L-arginine (Yallampalli et al., donor sodium nitroprusside (SNP) to prevent L-NAMEto 1993; Izumi et al., 1993). The responsiveness of the rat uterus induced preterm delivery was tested. Five hours before the relaxant effect of NO was found to be decreased during the initiation of treatment regimen with L-NAME at labour (Yallampalli et al., 1993; Buhimschi et al., 1995b). 70 mg/kg, mice were implanted s.c. with micro-osmotic Studies on the human pregnant uterus have documented pumps infusing SNP at 0 or 10 µg/kg/min continuously myometrial NOS activity (Telfer et al., 1995; Ramsey et al., for 3 days. Administration of L-NAME evoked preterm 1996; Thomson et al., 1997; Bansal et al., 1997; Ekerhovd delivery. This response was noted in 64 and 60% of animals et al., 1999). The ability of exogenous NO to evoke myometrial treated with 70 and 100 mg/kg L-NAME respectively relaxation has also been determined (DeSimone et al., 1990; (P < 0.05 versus control value). Infusion with SNP provided Greenspoon and Kovacic, 1991; Buhimschi et al., 1995a; Lee complete and significant (P < 0.05 versus positive control and Chang, 1995). On the other hand, contrary to what has value) protection from L-NAME-initiated preterm delivery. been observed in animal models, myometrial tissue strips This is the first report to reveal that an inhibitor of NO obtained from pregnant women were not relaxed by L-arginine synthesis initiates preterm delivery in a mouse model. (Jones and Poston, 1997; Ekerhovd et al., 1999). A decline in Key words: L-NAME/mouse /nitric oxide/preterm delivery human myometrial NOS expression in association with labour and delivery has been reported (Bansal et al., 1997). Despite the large number of functional and molecular studies, the exact role of the NO system in the control of myometrial Introduction function during pregnancy has not yet been clearly defined. Prevention of preterm delivery is a major undertaking in We found intriguing the lack of substantial evidence that human health. Deliveries ending before term account for about inhibition of NO synthesis can precipitate parturition (Norman, 10% of all deliveries but for 75% of neonatal mortality and 1996; Sladek et al., 1997; Yallampalli et al., 1998). This study 50% of long-term neurological sequelae (Creasy, 1993). It is therefore aimed to address this investigative shortcoming by generally agreed that the unavailability of pharmacological determining the potential capacity of a competitive inhibitor interventions effective in preventing preterm labour and result- of NOS to trigger delivery in a mouse model, which has not ant preterm delivery probably reflects the poor understanding to our knowledge been done before. of molecular mechanisms behind the initiation and maintenance of labour. The free radical and potent smooth muscle relaxant nitric Materials and methods oxide (NO) is synthesized by a family of enzymes known as Animals and breeding procedure NO synthases (NOS), which catalyse the conversion of Sexually mature ICR (CD-1) outbred mice (Harlan Italy, Udine, Italy) L-arginine to NO plus citrulline (Moncada et al., 1995). As is were used in the study. Animals were kept under controlled conditions well established, NOS activity can be competitively inhibited (room temperature of 22 1 C; 55 5% of relative humidity) on by a variety of L-arginine analogues (Moncada et al., 1995). a 12 h light/dark cycle, with rodent laboratory chow (Harlan Teklad ; 1838 European Society of Human Reproduction and Embryology

2 Nitric oxide and preterm delivery Harlan Italy) and municipal water provided ad libitum. After an acclimatization period of a week, females (three to four per cage) were co-habited overnight with males of the same stock and source, and examined for the presence of a copulatory plug at the end of the dark cycle (0800 h). The day on which the plug was observed was designated as gestation day (GD) 0. Study 1 The L-arginine analogue N G -nitro-l-arginine methyl esther (L-NAME), a competitive NOS inhibitor, was purchased from Research Biochemicals International (Natick, MA, USA). Dosing solutions were prepared by dissolving the L-NAME in sterile and apirogenic saline solution. On GD 15.5 (2000 h of gestation day 15) and 12 h later, on GD 16, animals were dosed with 0 (vehicle), 40, 70 or 100 mg L-NAME/kg body weight. The test article was injected s.c., in the interscapular region, using a 26 gauge needle. The volume administered was 10 ml/kg body weight. By observation of animals at intervals of 2 4 h, the timing of delivery was determined. Delivery was considered preterm if occurring before GD 18. In order to establish whether or not deliveries occurring before term were giving birth to all fetuses, maternal laparotomy was performed 12 h after the occurrence of parturition was noted. All term and preterm newborns were inspected for viability. Study 2 This study was undertaken to evaluate the potential ability of the NO donor sodium nitroprusside (SNP; Sigma Chemical Co., St. Louis, MO, USA) to prevent L-NAME-induced preterm delivery. Five hours before the initiation of the treatment regimen with L-NAME at 70 mg/kg, animals were implanted s.c. (in the lumbar region of the back) with a micro-osmotic pump (model 1035D; Alza, Palo Alto, CA, USA), delivering SNP at 10 µg/kg/min continuously for 3 days. Control animals were implanted with pumps filled with vehicle (saline solution). The implantation procedure was carried out under a light general anaesthesia induced by ether inhalation. Sterile stainless steel skin staplers were used to close implantation wounds. The same endpoints of study 1 were determined. Statistical analysis Fisher s exact test was used to evaluate differences between various experimental groups. The results were considered to be significant when the P value was Figure 1. Effect of L-NAME on gestation duration in ICR (CD-1) mice. Animals were injected s.c. with L-NAME on GD 15.5 and 16. Delivery was considered preterm if occurring before GD 18. The numbers in parentheses indicate the ratio of animals delivering preterm to total animals treated. *Significantly different compared with control group (P 0.05). irrespective of the timing of occurrence, always gave birth to the entire litter (data not shown). It was noted that the threshold dose (70 mg L-NAME/kg) for a significant elicitation of preterm delivery had no noticeable clinical effect on maternal wellbeing. On the other hand, a light and transient depression of spontaneous movement followed treatment with L-NAME at 100 mg/kg. The complete evaluation of neonatal viability was precluded by maternal cannibalism of newborns. Despite this investigative shortcoming, the overall impression was that the vitality of pups was related to the timing of delivery. In this regard, whereas offspring delivered on GD 16 invariably appeared dead (often still surrounded by membranes and placenta), several pups delivered on GD 17 appeared alive when inspected immediately after delivery, but not later. On the other hand, when the gestation ended at term, offspring of mothers treated with L-NAME at various doses exhibited a viability that seemed comparable to that of controls (data not shown). Results Study 2 As illustrated in Figure 2, three of eight (37.5%) animals Study 1 implanted with vehicle-filled pumps delivered preterm. In all As shown in Figure 1, all control animals (n 13) delivered three instances, gestations ended on GD (Table II). at gestational term ( GD 18). On the other hand, treatment By contrast, mice infused with SNP at 10 µg/kg/min for 3 days with L-NAME caused mice to deliver before term (Figure 1). (n 12) showed a complete and statistically significant This response was noted in approximately 18, 64 and 60% of (P 0.05 versus positive control group) protection against pregnant mice injected with 40 (n 11), 70 (n 14) and the shortening effect of L-NAME at 70 mg/kg on gestation 100 (n 10) mg L-NAME/kg respectively. It must be noted, length (Figure 2). No clinical signs of maternotoxicity were however, that only incidences recorded in groups treated with observed in animals used in this study. 70 and 100 mg/kg were statistically significant (P 0.05) compared with the control value (Figure 1). Table I details the timing of delivery. As can be seen, the majority of preterm Discussion deliveries occurred between GD 16.5 and GD 17.5, and only Research conducted in the past decade has established the two animals (in the group exposed at the maximal level of ability of the human myometrium to generate NO (Telfer et al., L-NAME) delivered at an earlier time (on GD ). 1995; Ramsey et al., 1996; Bansal et al., 1997; Thomson Intriguingly, preterm delivery never occurred between GD 17.5 et al., 1997; Ekerhovd et al., 1999; Norman et al., 1999), and and GD18. Maternal laparotomies revealed that delivery, to relax in response to exogenous NO (DeSimone et al., 1839

3 G.M.Tiboni and F.Giampietro Table I. Effect of L-NAME a on the timing of delivery in ICR (CD-1) mice Dose (mg/kg) No. of treated No. (%) of animals delivering preterm b No. (%) of animals delivering at term animals GD GD GD GD GD GD GD (vehicle) 13 3 (23) 7 (54) 3 (23) (9) 1 (9) 4 (36) 3 (27) 2 (18) (43) 3 (21) 1 (7) 4 (29) (20) 3 (30) 1 (10) 1 (10) 2 (20) 1 (10) a L-arginine analogue N G -nitro-l-arginine methyl esther (L-NAME) was injected s.c. on GD 15.5 and 16. b Delivery was considered preterm if it occurred before GD 18. Table II. Effect of SNP a infusion on L-NAME b -induced preterm delivery in ICR (CD-1) mice Dose No. of treated No. (%) of animals delivering preterm c No. (%) of animals delivering at term animals GD GD GD GD GD GD GD L-NAME (70 mg/kg) vehicle 8 3 (38) 2 (25) 2 (25) 1 (13) L-NAME (70 mg/kg) SNP 12 4 (33) 5 (42) 3 (25) (10 µg/kg/min) a Sodium nitroprusside (SNP) was infused by micro-osmotic pumps delivering the drug at 10 µg/kg/min continuously for 3 days. Pumps were implanted s.c. 5 h before initiation of the treatment schedule with L-NAME at 70 mg/kg. Control animals were implanted with pumps delivering vehicle (saline solution). b L-NAME was injected s.c. on GD 15.5 and c Delivery was considered preterm if it occurred before GD 18. role of NO system in the control of myometrial contractility is lacking (Jones and Poston, 1997). In the search for additional information on mechanisms involved in uterine quiescence and contractility, we found in this study that treatment with L-NAME leads to preterm delivery in the mouse. This is to our knowledge the first time that a NOS inhibitor has been found per se to terminate gestation in a rodent model. The threshold dose for such a response was 70 mg L-NAME/kg given twice on GD 15.5 and GD 16, e.g. at a gestational stage when the murine conceptus is terminating organogenesis and is entering the fetal period of antenatal life. The effect of L-NAME on gestation duration did not fit a dose-response model, as shown by the fact that preterm delivery incidences following administration of 70 or 100 mg/kg were comparable. However, a possible dosedependency is suggested by the low rate of preterm delivery Figure 2. Effect of sodium nitroprusside (SNP) infusion on L- observed (although not significant) in the experimental group NAME-initiated preterm delivery. L-NAME was injected s.c. at 70 treated with the lowest dose of L-NAME (40 mg/kg), and by mg/kg on GD 15.5 and 16. Delivery was considered preterm if it the fact that a trend toward an earlier timing of delivery with occurred before GD 18. Five hours before the initiation of the the increment of L-NAME concentration was seen. treatment regimen with L-NAME, animals were implanted s.c. with SNP is a drug that, without requiring enzymatic bioactivmicro-osmotic pumps delivering SNP at 10 µg/kg/min continuously ation, is readily converted to NO in biological systems (Sladek for 3 days. Control animals were implanted with micro-osmotic pumps filled with vehicle (saline solution). The numbers in et al., 1997). This NO donor has been found, albeit with some parentheses indicate the ratio of animals delivering preterm to total inconsistencies, to effect relaxation of pregnant myometrium animals treated. *Significantly different compared with control (Sladek et al., 1997). In the present study SNP was infused at group (P 0.05). a rate (10 µg/kg/min) that is within the human therapeutic zone (although at the higher extreme) (Gerber and Nies, 1990) 1990; Greenspoon and Kovacic, 1991; Lee and Chang, 1995; and it was found to provide complete protection from preterm Buhimschi et al., 1995a). These findings have provided impetus for new research, with the primary aim of developing effective tocolytic approaches. Unfortunately consensus regarding the 1840 delivery. This result suggests that L-NAME evoked preterm delivery via inhibition of NO synthesis and not by alternative pharmacological or toxicological mechanisms. Biological

4 Nitric oxide and preterm delivery plausibility for this hypothesis is also provided by the observa- parameter for initiation of preterm delivery than the area under tion that the mouse uterus is a NO-producing organ (Huang the concentration-time curve, a parameter indicative of total et al., 1995; Moorhead et al., 1995), and that uterine horns of exposure. This idea seems worthy of further investigation. pregnant mice exhibited isometric tension increments after Collectively, data obtained in this investigation are consistent application of a NOS inhibitor (Boquet et al., 1998). with the idea that the NO system may play a role in the Over the last decade, a number of investigations (Yallampalli regulation of myometrial contractility, and that inappropriate and Garfield, 1993; Diket et al., 1994; Molnar et al., 1994; synthesis of this mediator may trigger preterm delivery. In Buhimschi et al., 1995b; Salas et al., 1995; Helmbrecht et al., addition this study, by providing the first evidence that a NOS 1996; Yallampalli et al., 1996) have been made into the inhibitor is capable of initiating delivery in a rodent model, gestational response to inhibitors of NO synthesis in rats. In establishes a novel investigative platform from which further these investigations, L-NAME and other L-arginine analogues exploration of the functional role of the NO system in the were found to induce fetal growth restriction with (Yallampalli pregnant myometrium may be launched. and Garfield, 1993; Molnar et al., 1994; Buhimschi et al. 1995b; Helmbrecht et al., 1996; Yallampalli et al., 1996) or without (Diket et al., 1994) other signs evocative of a pre- References eclampsia-like syndrome, but not preterm delivery. At present, Bansal, R.K., Goldsmith, P.C., He, Y. et al. (1997) A decline of myometrial nitric oxide synthase expression is associated with labor and delivery. J. to our knowledge, the only existing evidence for a cause-effect Clin. Invest., 99, relationship between inhibition of NO synthesis and preterm Boquet, M, Cebral, E., Motta, A. et al. (1998) Relationship between mouse delivery is represented by an investigation carried out on the uterine contractility, nitric oxide and prostaglandin production in early pregnancy. Prostaglandins Leukot. Essent. Fatty Acids, 59, guinea-pig (Chwalisz et al., 1996). It is interesting to note in Buhimschi, I., Yallampalli, C., Dong, Y.L. et al. (1995a) Involvement of a that study that administration of L-NAME, possibly due to an nitric oxide-cyclic guanosine monophosphate pathway in control of human impairment of cervical ripening, besides shortening gestation uterine contractility during pregnancy. Am. J. Obstet. Gynecol., 172, length also caused a prolongation of the delivery process Buhimschi, I., Yallampalli, C., Chwalisz, K. et al. (1995b) Preclampsia-like (Chwalisz et al., 1996). This result appears consistent with the conditions produced by nitric oxide inhibition: effects of L-arginine, view that NO is relevant to the process of natural cervical D-arginine and steroid hormones. Hum. Reprod., 10, ripening (Buhimshi et al., 1996; Thomson et al., 1996; Buhimschi, I., Ali, M., Jain, V. et al. (1996) Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labour. Hum. Chwalisz et al., 1997; Tschugguel et al., 1999) and has Reprod., 11, contributed to the recent proposal that for successful gestation Chwalisz, K. and Garfield, R.E. (1988) Role of nitric oxide in the uterus and and parturition a spatial regulation in NOS activity/expression cervix: implications for the management of labour. J. Perinat. Med., 26, must occur in uterine tissues. While during gestation NO Chwalisz, K. and Garfield, R.E.. (1998) New molecular challenges in the generation would be up-regulated in myometrium and down- induction of cervical ripening: nitric oxide as the final metabolic indicator regulated in the cervix, assuring uterine relaxation and cervical of cervical ripening. Hum. Reprod., 13, competence, the opposite effects would occur during labour, Chwalisz, K., Buhimschi I. and Garfield, R.E. (1996) Role of nitric oxide in leading to myometrial contraction and cervical ripening (for obstetrics Prenat. Neonat. Med., 1, Chwalisz, K., Shao-Quing, S., Garfield, R.E. et al. (1997) Cervical ripening review see Chwalisz and Garfield, 1988, 1998). In this regard, in guinea-pigs after local application of nitric oxide. Hum. Reprod. 12, it is possible that the relative contribution of the NO system in this dual role may significantly differ depending on the Conrad, K.P., Joffe, G.M., Kruszyna, H. et al. (1993) Identification of increased nitric oxide biosynthesis during pregnancy in rats. FASEB J., 7, species, and that interspecies variations may partly account Creasy, R.K. (1993) Preterm delivery prevention: where we are? Am. J. for the discrepant responses to NO inhibitors noted between Obstet. Gynecol., 168, the rat, guinea pig and mouse. DeSimone, C.A., Norris, M.C. and Leighton, B.L. (1990) Intravenous Besides the putative role played by a species-specific nitroglycerin aids manual extraction of a retained placenta. Anesthesiology, 73, 787. intrinsic sensitivity, it is also conceivable that the ability of L- Diket, A.L., Pierce, M.R., Munshi, U.K. et al. (1994) Nitric oxide inhibition NAME to terminate the mouse pregnancy is dependent on the causes intrauterine growth retardation and hind-limb disruption in rats. Am. experimental conditions selected. This is also apparent from J. Obstet. Gynecol., 171, results of a pilot study carried out in our laboratory (unpublished Ekerhovd, E., Weidegard, B. and Brannstrom, M. et al. (1999) Nitric oxide- mediated effects of myometrial contractility at term during prelabor and observations) where ICR (CD-1) mice received L-NAME in labor. Obstet. Gynecol., 93, drinking water at an estimated daily dose of 0 (n 8), 140 Figueroa, J.P. and Massmann, G.A. (1995) Estrogen increases nitric oxide (n 9) or 280 (n 9) mg/kg/day. Exposure was continued synthase activity in the uterus of nonpregnant sheep. Am. J. Obstet. Gynecol., 173, from GD (term gestation) when pregnancies were Gerber, J.G. and Nies, A.S. (1990) Antihypertensive agents and the drug terminated and several fetal end-points evaluated. Under these therapy of hypertension. In Goodman Gilman, Rall, T.W., Nies, A.S. and circumstances, L-NAME was found to retard the fetal growth Taylor. P. (eds) The pharmacological basis of therapeutics. Pergamon Press, process, but not to elicit preterm delivery. Therefore it may New York, pp Greenspoon, J.S. and Kovacic, A. (1991) Breech extraction facilitated by be that initiation of preterm delivery by L-NAME requires a glyceryl trinitrate sublingual spray. Lancet, 338, particular pattern of NO system down-regulation, and that this Helmbrecht, G.D., Farhat, M.Y., Lochbaum, L. et al. (1996) L-Arginine condition is achieved with bolus injection but not with chronic reverse the adverse pregnancy changes induced by nitric oxide synthase administration. In other words, from a pharmacokinetic point inhibition in the rat. Am. J. Obstet. Gynecol., 175, of view, it would seem that the maximal concentration reached by L-NAME in the systemic circulation is a more critical Huang, J., Roby, K.F., Pace, J.L. et al. (1995) Cellular localization and hormonal regulation of inducible nitric oxide synthase in cycling mouse uterus. J. Leukoc. Biol. 57,

5 G.M.Tiboni and F.Giampietro Izumi, H., Yallampalli, C. and Garfield, R.E. (1993) Gestational changes in L-arginine-induced relaxation of pregnant rat and human myometrial smooth muscle. Am. J. Obstet. Gynecol., 169, Jones, G.D. and Poston, L. (1997) The role of endogenous nitric oxide synthesis in contractility of term and preterm human myometrium. Br. J. Obstet. Gynecol., 104, Lee, J.K. and Chang, K.C., (1995) Different sensitivity to nitric oxide of human pregnant and nonpregnant myometrial contractility. Pharm. Comm., 5, Molnar, M., Suto, T., Toth, T. et al. (1994) Prolonged blockade of nitric oxide synthesis in gravid rats produced sustained hypertension, proteinuria, thrombocytopenia and intrauterine growth retardation. Am. J. Obstet. Gynecol., 170, Moncada, S.R., Palmer, M.G. and Higgs, E.A. (1995) Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol. Rev., 43, Moorhead, C.S., Lawhun, M. and Nieder, G.L. (1995) Localization of NADPH diaphorase in the mouse uterus during the first half of pregnancy and during an artificially induced decidual reaction. J. Histochem. Cytochem., 43, Natuzzi, E.S., Ursell, P.C., Harrison, M. et al. (1993) Nitric oxide synthase activity in the pregnant uterus decreases at parturition. Biochem. Biophys. Res. Commun., 194, 1 8. Norman, J.E. (1996) Nitric oxide and the myometrium. Pharmacol. Ther., 70, Norman, J.E., Thomson, A.J., Telfer, J.F. et al. (1999) Myometrial consistutive nitric oxide synthase expression is increased during human pregnancy. Mol. Hum. Reprod., 5, Ramsay, B., Sooranna, S.R. and Johnson, M.R. (1996) Nitric oxide synthase activities in human myometrium and villous trophoblast throughout pregnancy. Obstet. Gynecol., 87, Salas, S.P., Altermatt, F., Campos, M. et al. (1995) Effects of long-term nitric oxide synthesis inhibition on plasma volume expansion and fetal growth in the pregnant rat. Hypertension, 26, Sladek, S.M., Regenstein, A.C., Lykins, D. et al. (1993) Nitric oxide synthase activity in pregnant rabbit uterus decreases on the last day of pregnancy. Am. J. Obstet. Gynecol., 169, Sladek, S.M., Magness, R.R. and Conrad, K.P. (1997) Nitric oxide and pregnancy. Am. J. Physiol., 272, Telfer, J.F., Lyall, F., Norman, J.E. et al. (1995) Identification of nitric oxide synthase in human uterus. Hum. Reprod., 10, Thomson, A.J., Lunan, C.B., Howat, C.L. et al. (1996) Randomised trial of nitric oxide versus prostaglandin for cervical ripening before first-trimester termination of pregnancy. Lancet., 352, Thomson, A.J., Telfer, J.F., Kohnen, G. et al. (1997) Nitric oxide synthase activity and localization do not change in uterus and placenta during human parturition. Hum. Reprod., 12, Tschugguel, W., Schneeberger, C., Unfried, G. et al. (1998) Induction of inducible nitric oxide synthase expression in human secretory endometrium. Hum. Reprod., 13, Tschugguel, W., Schneeberger, C., Lass, H. et al. (1999) Human cervical ripening is associated with an increase in cervical inducible nitric oxide synthase expression. Biol. Reprod., 60, Weiner, C.P., Lizasoain, I., Baylis, S.A. et al. (1994) Induction of calciumdependent nitric oxide synthesis by sex hormones. Proc. Natl Acad. Sci. USA, 91, Yalampalli, C. and Garfield, R.E. (1993). Inhibition of nitric oxide synthesis in rats during pregnancy produced signs similar to those of preeclampsia. Am. J. Obstet. Gynecol., 169, Yallampalli, C., Garfield, R.E. and Byam-Smith, M. (1993) Nitric oxide inhibits uterine contractility during pregnancy but not during delivery. Endocrinology, 133, Yallampalli, C., Izumi, H., Byam-Smith, M. et al. (1994) An L-arginine-nitric oxide-cyclic guanosine monophosphate system exists in the uterus and inhibits contractility during pregnancy. Am. J. Obstet. Gynecol., 170, Yallampalli, C., Buhimschi, I., Chwalisz, K. et al. (1996) Preterm birth in rats produced by the synergistic action of a nitric oxide inhibitor (N G -nitro-larginine methyl ester) and an antiprogestin (onapristone). Am. J. Obstet. Gynecol., 175, Yallampalli, C., Dong, Y.L., Gangula, P.R. et al. (1998) Role and regulation of nitric oxide in the uterus during pregnancy and parturition. J. Soc. Gynecol. Invest., 5, Received on March 13, 2000; accepted on May 22,

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