Contrasting effects of diethylenetriamine–nitric oxide, a spontaneously releasing nitric oxide donor, on pregnant rat uterine contractility in vitro versus in vivo


      Objective: The aim of the study was to investigate the in vitro (on tension) and in vivo (on intrauterine pressure) effects of a spontaneously releasing nitric oxide adduct, diethylenetriamine–nitric oxide, on rat uterine contractility. Study design: Contractile responses to the nitric oxide donor diethylenetriamine–nitric oxide on isometric tension of rat uterine strips (in vitro) and on intrauterine pressure (in vivo) in anesthetized and conscious animals were quantified at late gestation and during preterm and term labor. Preterm labor was induced with the administration of a single injection of the antiprogestin onapristone (10 mg). All control animals were injected with diethylenetriamine, the parent compound, without nitric oxide. Results: The nitric oxide donor diethylenetriamine–nitric oxide relaxes rat uterine tissues when given in vitro during gestation (median effective dose 0.30 ± 0.09 mmol/L) but fails to have an effect on uterine tissues from laboring term and preterm animals in the muscle bath. Intraperitoneal injection of the nitric oxide adduct in doses of 5 mg and 50 mg produced a significant and sustained decrease in intrauterine pressure in both delivering and nondelivering animals compared with intrauterine pressure values before administration. Analysis of intrauterine pressure levels at different time frames (before injection, immediately after injection, and after 30, 60, and 90 minutes) in anesthetized rats between days 19 and 21 of gestation shows that the dose of 5 mg diethylenetriamine–nitric oxide significantly (p < 0.05) decreased contractility starling at 30 minutes after administration. Similarly, during labor diethylenetriamine–nitric oxide (5 mg intraperitoneally) decreased contractility (p < 0.05) but only starting at 60 minutes after injection. However, with the dose of 50 mg diethylenetriamine–nitric oxide contractility was reduced 30 minutes (p < 0.05) after treatment during pregnancy (days 19 to 21). The same dose of diethylenetriamine–nitric oxide produced a greater relaxation immediately after intraperitoneal injection (p < 0.05) in the laboring group. Diethylenetriamine–nitric oxide (50 mg) also induced an earlier onset and greater relaxation in animals delivering preterm compared with nondelivering animals at the same stage of gestation. The intrauterine pressure maintained constant contractility levels throughout the 100-minute recording period in the control groups of anesthetized and conscious animals that were injected with diethylenetriamine at the equivalent doses. In the preterm laboring group the effects were similar in both anesthetized and conscious animals. Conclusion: Although in vitro studies of uterine muscle show decreased inhibitory responses to nitric oxide donors during spontaneous term labor and preterm labor compared with tissues collected during late pregnancy (day 19), studies in vivo demonstrate that nitric oxide donors can decrease uterine contractility even more effectively during delivery. The results suggest that nitric oxide donors may act indirectly or that the fetal-placental unit increases the availability of nitric oxide in vivo. Therefore, despite what in vitro studies alone suggest, nitric oxide donor drugs may be very effective in suppressing either term or preterm labor.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to American Journal of Obstetrics & Gynecology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Holmes LC
        • DiCarlo FJ.
        Nitroglycerin: the explosive drug.
        J Chem Educ. 1971; 48: 573-576
        • Moncada S
        • Palmer RMG
        • Higgs EA.
        Nitric oxide: physiology, pathophysiology and pharmacology.
        Pharmacol Rev. 1991; 43: 109-142
        • Yallampalli C
        • Izumi H
        • Byam-Smith M
        • Garfield RE
        An l-arginine–nitric oxide–cyclic guanosine monophosphate system exists in the uterus and inhibits contractility during pregnancy.
        Am J Obstet Gynecol. 1994; 170: 175-185
        • Izumi H
        • Yallampalli C
        • Garfield RE
        Gestational changes in l-arginine–induced relaxation of pregnant rat and human myometrial smooth muscle.
        Am J Obstet Gynecol. 1993; 169: 1327-1337
        • Chwalisz K
        • Ciesla I
        • Garfield RE.
        Inhibition of nitric oxide (NO) synthesis induces preterm parturition and preeclampsia-like conditions in guinea pigs.
        in: Proceedings of the Forty-first Annual Meeting of the Society for Gynecologic Investigation; 1994 Mar 23-26; Chicago, Illinois The Society, Chicago1994
        • Yallampalli C
        • Buhimschi I
        • Chwalisz K
        • Garfield RE
        • Dong Y-L.
        Preterm birth in rats produced by the synergistic action of a nitric oxide inhibitor (NG-nitro-l-arginine methyl ester) and an antiprogestin (onapristone).
        Am J Obstet Gynecol. 1996; 175: 207-212
        • Buhimschi I
        • Yallampalli C
        • Dong Y-L
        • Garfield RE
        Involvement of a nitric oxide–cyclic guanosine monophosphate pathway in control of human uterine contractility during pregnancy.
        Am J Obstet Gynecol. 1995; 172: 1577-1584
        • Peng AT
        • Gorman RS
        • Shulman SM
        • DeMarchis E.
        Intravenous nitroglycerin for uterine relaxation in the postpartum patient with retained placenta.
        Anesthesiology. 1989; 7: 173-183
        • DeSimone CA
        • Norris MC
        • Leighton BL.
        Intravenous nitroglycerin aids manual extraction of a retained placenta.
        Anesthesiology. 1990; 73: 787
        • Altabef KM
        • Spencer JT
        • Zinberg S.
        Intravenous nitroglycerin for uterine relaxation of an inverted uterus.
        Am J Obstet Gynecol. 1992; 166: 1237-1238
        • Rolbin SH
        • Hew EM
        • Bernstein A.
        Uterine relaxation can be life saving [letter].
        Can J Anaesth. 1991; 38: 939-940
        • Greenspoon JS
        • Kovacic A.
        A breech extraction facilitated by glyceryl trinitrate spray.
        Lancet. 1991; 338: 124-125
        • Lees C
        • Campbell S
        • Jauniaux E
        • Brown R
        • Ramsay B
        • Gibb D
        • et al.
        Arrest of preterm labour and prolongation of gestation with glyceryl trinitrate, a nitric oxide donor.
        Lancet. 1994; 343: 1325-1326
        • Yallampalli C
        • Garfield RE.
        Uterine contractile responses to endothelin-1 and endothelin receptors are elevated during labor.
        Biol Reprod. 1994; 51: 640-645
        • Buhimschi I
        • Ali M
        • Jain V
        • Chwalisz K
        • Garfield RE.
        Differential regulation of nitric oxide in the rat uterus and cervix during pregnancy and labor.
        Hum Reprod. 1996; 8: 101-112
        • Natuzzi ES
        • Ursel PC
        • Harrison MB
        • Buscher C
        • Reimer RK.
        Nitric oxide synthase activity in the pregnant uterus decreases at parturition.
        Biochem Biophys Res Commun. 1993; 194: 1-8
        • Yallampalli C
        • Garfield RE
        • Byam-Smith M.
        Nitric oxide inhibits uterine contractility during pregnancy but not during delivery.
        Endocrinology. 1993; 133: 1899-1902
        • Ramsay B
        • Sooranna SR
        • Johnson MR.
        Nitric oxide synthase activities in human myometrium and villous trophoblast throughout pregnancy.
        Obstet Gynecol. 1996; 86: 249-253
        • Jones GD
        • Poston L.
        The role of endogenous nitric oxide synthesis in contractility of term or preterm human myometrium.
        Br J Obstet Gynaecol. 1997; 104: 241-245
        • Jennings RW
        • MacGillivray TE
        • Harrison MR.
        Nitric oxide inhibits preterm labor in the rhesus monkey.
        J Matern Fetal Med. 1993; 2: 170-175
        • Sekiba K
        • Yoshioka T.
        Changes in lipid peroxidation and superoxide dismutase activity in human placenta.
        Am J Obstet Gynecol. 1979; 135: 368-371
        • Stamler JS
        • Simon DI
        • Osborne JA
        • Mullins ME
        • Jaraki O
        • Michel T
        • et al.
        S-Nitrosylation of proteins with nitric oxide: synthesis and characterization of biologically active compounds.
        Proc Natl Acad Sci U S A. 1991; 89: 444-448
        • Minaniyama Y
        • Takemura S
        • Inoue M.
        Albumin is an important vascular tonus regulator as a reservoir of nitric oxide.
        Blochem Biophys Res Commun. 1996; 225: 112-115
        • Scharfstein JS
        • Keaney JF
        • Silvka A
        • Welch GN
        • Vita JA
        • Stamler JS
        • et al.
        In vivo transfer of nitric oxide between a plasma protein-bound reservoir and low molecular weight thiols.
        J Clin Invest. 1994; 94: 1432-1439
        • Salvemini D
        • Misko TP
        • Masferrer JL
        • Seibert K
        • Currie MG
        • Needleman P.
        Nitric oxide activates cyclooxygenase enzymes.
        Proc Natl Acad Sci U S A. 1993; 90: 7240-7244
        • Franchi AM
        • Chaud M
        • Rettori V
        • Subuto A
        • McCann SM
        • Gimeno M.
        Role of nitric oxide in eicosanoid synthesis and uterine motility in estrogen-treated rat uteri.
        Proc Natl Acad Sci U S A. 1994; 91: 539-543
        • Villar MJ
        • Ceccatelli S
        • Ronnqvist M
        • Hokfelt T.
        Nitric oxide synthase increases in hypothalamic magno-cellular neurons after salt loading in the rat: an immunohistochemical and in situ hybridization study.
        Brain Res. 1994; 644: 273-281
        • Grozdanovic Z
        • Mayer B
        • Baumgarten HG
        • Bruning G.
        Nitric oxide synthase-containing nerve fibers and neurons in the genital tract of the female mouse.
        Cell Tissue Res. 1994; 275: 355-360
        • Stamler JS
        • Singel DJ
        • Loscalzo J.
        Biochemistry of nitric oxide and its redox-activated forms [review].
        Science. 1992; 258: 1898-1902
        • Feelisch M
        • Kelm M.
        Biotransformation of organic nitrates to nitric oxide by vascular smooth muscle and endothelial cells.
        Blochem Biophys Res Commun. 1991; 180: 286-293
        • Feelish M
        • Noack EA.
        Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase.
        Eur J Pharmacol. 1987; 139: 19-30
        • Schror K
        • Woditsch I
        • Forster S.
        Generation of nitric oxide from organic nitrovasodilators during passage through the coronary vascular bed and its role in coronary vasodilation and nitrate tolerance.
        Blood Vessels. 1991; 28: 62-66
        • Ignarro LJ
        • Lippton H
        • Edwards JC
        • Baricos WH
        • Hyman AL
        • Kadowitz PJ
        • et al.
        Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates.
        J Pharmacol Exp Ther. 1981; 218: 739-749
        • Fung HL
        • Chong S
        • Kowaluk E.
        Mechanisms of nitrate action and vascular tolerance.
        Eur Heart J. 1989; 10: 2-6
        • Hrabie DA
        • Klose JR
        • Wink DA
        • Keefer LK.
        New nitric oxide-releasing zwitterions derived from polyamines.
        J Org Chem. 1993; 58: 1472-1476
        • Mooradian DL
        • Hutsell TC
        • Keefer LK.
        Nitric oxide (NO) donor molecules: Effect of NO release rate of vascular smooth muscle cell proliferation in-vitro.
        J Cardiovasc Pharmacol. 1995; 25: 674-678
        • Higby K
        • Xenakis MJ
        • Pauerstein CJ.
        Do tocolytic agents stop preterm labor? A critical and comprehensive review of efficacy and safety.
        Am J Obstet Gynecol. 1993; 168: 1247-1259
        • Eronen M
        • Personen E
        • Kurki T
        • Ylikorkala O
        • Hallman M
        The effects of indomethacin and a β-sympathomimetic agent on the fetal ductus arteriosus during treatment of premature labor: a randomized double-blind study.
        Am J Obstet Gynecol. 1991; 164: 141-146
        • Besinger RE
        • Niebyl JR
        • Keyes WG
        • Johnson TR.
        Randomized comparative trial of indomethacin and ritodrine for the long-term treatment of preterm labor.
        Am J Obstet Gynecol. 1991; 164: 981-986