Biomedical subjects

G R Saade

Publications and source records attributed to G R Saade.

At least 19 recordsLinked to original sources

PubMed2005

Nitric oxide donor-induced inhibition of pregnant rat uterine spontaneous contractile activity and release of nitric oxide from uterus measured by microdialysis.

Our aim was to study whether nitric oxide (NO) donor-induced inhibition of pregnant rat myometrium contractility correlates with the release of NO. Uterine rings from mid-pregnant and late pregnant Sprague-Dawley rats were used for isometric tension recording. Concentration-response relationships to sodium nitroprusside (SNP), nitroglycerine (NTG) and diethylamine (DEA)/NO were assessed. The time course of NO release after addition to the organ chambers of the 3 NO-donors was assessed by the detection of NO products NOx (NO3+NO2) using the microdialysis probe by a HPLC-NO detector system. DEA/ NO induced greater inhibition of the spontaneous contractile activity of uterine rings from mid-pregnant rats than SNP or NTG. In uterine rings from late pregnant rats, however, the maximal inhibition of the contractility by all 3 NO-donors were significantly less. The NOx levels measured in the uterine ring walls from either mid-pregnant or late pregnant rats significantly increased after DEA/ NO as compared to the basal levels or the levels after NTG or SNP. The decrease of NO-donor-induced inhibition of rat myometrium contractility, with unchanged formation of NOx, at term, suggests that the changes in NO signaling are responsible for gestational age-dependent attenuation of the inhibitory effect.

Animals↗

PubMed2004

Expression of inducible nitric oxide synthase messenger RNA, but not guanylate cyclase messenger RNA, depends on gestational age in rat myometrium.

We studied the expression of inducible nitric oxide (NO) synthase (iNOS) and soluble guanylate cyclase (sGC) mRNAs in pregnant rat myometrium. Expression of iNOS and sGC alpha1, beta1 and beta2 mRNA was analyzed in non-pregnant and pregnant (days 10, 14, 17 and 21) Wistar rats by reverse transcription-polymerase chain reaction. Expression of iNOS mRNA increased during pregnancy but decreased on day 21 of gestation. Expression of GC alpha1 mRNA was greater than GC beta1 mRNA at all time points. Expression of uterine GC alpha1 and GC beta1 mRNA did not change significantly during pregnancy and did not differ significantly from non-pregnant levels. The values of sGC beta2 mRNA were below the limit of detection. In conclusion, the expression of iNOS mRNA increased during pregnancy in the myometrium and decreased at term, while the expression of sGC mRNA was not affected by pregnancy. Thus, it is the changes in NO production, rather than changes in its target, that are responsible for uterine quiescence during pregnancy and initiation of labor.

Animals↗

PubMed2004

Effect of nitric oxide on contractions of uterine and cervical tissues from pregnant rats.

Our objective was to evaluate the role of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway in rat uterine and cervical contractility at mid- and late gestation. Rings of uterus and cervix from Sprague Dawley rats on day 14 of pregnancy (mid-) and day 21 of pregnancy (late) were equilibrated at 2 g passive tension in organ chambers filled with Krebs-Henseleit solution and bubbled with 5% CO2 in air (37 degrees C, pH approximately 7.4). Rings were treated with an inhibitor of outward potassium current, tetraethylammonium, to activate phasic contractions, and the concentration-response relationships to diethylamine/NO and 8-bromo-cGMP (8-br-cGMP) were assessed. Baseline spontaneous activity was significantly higher at term gestation in both uterine and cervical rings compared with mid-gestation. Spontaneous contractile activity was not apparent in cervical rings from rats in mid-gestation, but was persistent after treatment with tetraethylammonium. Oxyhemoglobin did not affect NO-induced inhibition of activation by tetraethylammonium contractile activity in either cervical or uterine tissues in mid- or late gestation. The 8-br-cGMP concentration-dependently inhibited tetraethylammonium-activated contractions that were more pronounced in uterine tissues compared with cervical tissues in both mid- and late gestation. We concluded that activation of the NO-cGMP pathway inhibits both uterine and cervical smooth muscle contractility. Both tissues demonstrated refractoriness to NO at term.

Animals↗

PubMed2004

Non-invasive transabdominal uterine electromyography correlates with the strength of intrauterine pressure and is predictive of labor and delivery.

OBJECTIVE: The study was conducted to investigate whether the strength of uterine contractions monitored invasively by intrauterine pressure catheter could be determined from transabdominal electromyography (EMG) and to estimate whether EMG is a better predictor of true labor compared to tocodynamometry (TOCO). STUDY DESIGN: Uterine EMG was recorded from the abdominal surface in laboring patients simultaneously monitored with an intrauterine pressure catheter (n = 13) or TOCO (n = 24). Three to five contractions per patient and corresponding electrical bursts were randomly selected and analyzed (integral of intrauterine pressure; integral, frequency, amplitude of contraction curve on TOCO; burst energy for EMG). The Mann-Whitney test, Spearman correlation and receiver operator characteristics (ROC) analysis were used as appropriate (significance was assumed at a value of p < 0.05). RESULTS: EMG correlated strongly with intrauterine pressure (r = 0.764; p = 0.002). EMG burst energy levels were significantly higher in patients who delivered within 48 h compared to those who delivered later (median [25%/75%]: 96,640 [26,520-322,240] vs. 2960 [1560-10,240]; p < 0.001), whereas none of the TOCO parameters were different. In addition, burst energy levels were highly predictive of delivery within 48 h (AUC = 0.9531; p < 0.0001). CONCLUSION: EMG measurements correlated strongly with the strength of contractions and therefore may be a valuable alternative to invasive measurement of intrauterine pressure. Unlike TOCO, transabdominal uterine EMG can be used reliably to predict labor and delivery.

Abdomen↗

PubMed2003

Amniotic fluid index measured with the aid of color flow Doppler.

OBJECTIVE: To determine whether using color flow Doppler to identify the umbilical cord affects amniotic fluid index (AFI) measurements. METHODS: A total of 2236 AFI measurements between 24 and 42 weeks in singleton gestations with no known or suspected fetal anomalies and < 14 days' discrepancy between menstrual and ultrasonographic dating were included. Color flow Doppler was used to identify loops of umbilical cord; these were excluded from the measurement. Polynomial regression was used to generate means and centiles. Data were grouped according to completed weeks of gestation and descriptive statistics were calculated. At each week of gestation, the number and percentage of pregnancies diagnosed as < or = 2.5th, < or = 5th, > or = 95th, and > or = 97.5th centile according to a 'standard' nomogram derived without using color flow Doppler were calculated. RESULTS: The AFI decreased significantly over gestational age, starting at 31 weeks (p < 0.05 by ANOVA). The relationship between AFI and gestational age was best modeled by a second-degree polynomial (p < 0.001). The median and range of the proportion of AFIs that fell outside the ranges of the standard nomogram at each completed gestational age was: 6.0 (2.3-35.4)% for the < or = 2.5th centile, 9.9 (3.1-37.5)% for the < or = 5th centile, 3.8 (0-30)% for the > or = 95th centile, and 1.8 (0-20)% for the > or = 97.5th centile. The 2.5th and 5th centiles using the current data were lower than those of the 'standard', and the difference increased with advancing gestation. Upper centiles were also different. CONCLUSION: The AFI measured using color flow Doppler overestimates oligohydramnios and may underestimate polyhydramnios when a standard AFI table obtained without color flow Doppler is used. Normal values specific for measurement method should be used for reference.

Amniotic Fluid↗

PubMed2003

Effects of L-type Ca(2+)-channel blockade, K(+)(ATP)-channel opening and nitric oxide on human uterine contractility in relation to gestational age and labour.

Relative uterine inactivity during pregnancy changes to vigorous rhythmic contractility during labour. We hypothesized that mechanisms involved in the regulation of uterine quiescence and contractility differ between term and preterm myometrium and in labour and non-labour states. Myometrial strips, prepared from biopsies taken at Caesarean section from labouring and non-labouring women preterm and at term, were mounted in organ chambers for isometric tension recording. Oxytocin (10(-9) mol/l) was added to maintain stable contractions, and effects of various inhibitors of uterine contractility were studied. The inhibitory effects of L-type Ca(2+)-channel blocker nifedipine and ATP-sensitive K(+)-channel opener pinacidil were greater in myometrium from the non-labour versus the labour group, both preterm and at term. In addition, pinacidil's effect was greater at term compared with preterm in the non-labour group. Mg(2+) and the nitric oxide donor sodium nitroprusside significantly inhibited contractility in all groups without significant differences with regard to labour or gestational age. Decreased inhibition of human uterine contractility by L-type Ca(2+)-channel blockers and K(+)(ATP)-channel openers in preterm and term labour may reflect changes in expression and activity of these channels. Effects of nitric oxide and Mg(2+) are not affected by gestational age or labour.

Adult↗

PubMed2003

Nitric oxide and its role during pregnancy: from ovulation to delivery.

Nitric oxide (NO) is a major paracrine mediator and important regulatory agent in various female reproductive processes, such as ovulation, implantation, pregnancy maintenance, labor and delivery. Ovulation: Circulating NO-products are increased during follicle development and decreased right after ovulation. INOS-inhibition results in a 50% reduction of ovulation, an effect completely reversed by an NO. Endometrium/Implantation: NO also regulates endometrial functions such as endometrial receptivity, implantation and menstruation. NO-donors may be useful for promoting fertility, while NO-inhibitors might be used for contraception. Uterine contractility: Throughout gestation myometrial NO-production is upregulated thus contributing to achieve uterine quiescence. Close to term, NO-production decreases promoting effective contractions resulting in labor. Clinical trials have demonstrated that NO-donors are effective tocolytics. Cervical ripening: In contrast to the myometrium, NO-production in the cervix is low during gestation and becomes upregulated once pregnancy advances to term. NO-donors are effective and safe cervical ripening agents. This finding from animal studies has been confirmed by several clinical trials. Vasoreactivity: In blood vessels, NO is a potent vasodilator and platelet-aggregation-inhibitor. Lack of NO during gestation was related to the development of pregnancy-induced hypertension and preeclampsia. In conclusion, NO-donors and NOS-inhibitors may provide novel, effective, safe, and inexpensive drugs to regulate and steer various functions in female reproductive life. The benefits reach from contraception to preventing possibly lethal pregnancy complications such as preeclampsia. Introducing NO-donors as tocolytics and cervical ripening agents may contribute to a reduction of fetal and maternal perinatal morbidity and mortality.

Animals↗

PubMed2002

Calcitonin gene-related peptide dilates the pregnant rat uterine vascular bed via guanylate cyclase, ATP- and Ca-sensitive potassium channels and gap junctions.

We studied the mechanism of calcitonin gene-related peptide (CGRP)-induced vasorelaxation in isolated uterine vascular beds of pregnant rats. The vascular beds were perfused in situ with Krebs buffer containing dextran and indomethacin, an inhibitor of cyclooxygenase. Baseline perfusion pressure was maintained with norepinephrine. When applied as a bolus, CGRP caused a decreased perfusion pressure in uterine vascular beds that was dose-dependent and equal in both mid-pregnant and late-pregnant rats. The non-selective inhibitor of nitric oxide synthase (NOS), Nomega-nitro-L-arginine methyl ester (L-NAME), did not significantly affect CGRP-induced vasodilatation in vascular beds of either group. CGRP-induced vasodilatation was not influenced by preincubation with the inhibitors of adenylate cyclase (SQ 22536 or MDL 12330A), but was significantly attenuated by the selective inhibitor of soluble guanylate cyclase (ODQ). The vasorelaxant effect of CGRP was not significantly influenced by the inhibitor of voltage-gated potassium (KV) channels (4-aminopyridin), but was significantly attenuated by an inhibitor of calcium-regulated potassium (KCa) channels (tetraethylammonium) and by an inhibitor of adenosine triphosphate-sensitive potassium (KATP) channels (glibenclamide). The gap junction uncoupling agent (carbenoxolone) also significantly attenuated the CGRP-induced decrease in perfusion pressure. We conclude that vasorelaxation induced by CGRP in the pregnant rat uterine vascular bed is not dependent on endothelial nitric oxide. In the uterine circulation of late-pregnant rats, the CGRP effect involves activation of soluble guanylate cyclase, but not adenylate cyclase, and does involve KCa and KATP channels and gap junctions.

Adenosine Triphosphate↗

PubMed2002

Gender differences in contractile and relaxing responses of aortic rings from lipopolysaccharide-treated rats.

Aortic rings from male and female Sprague-Dawley rats were placed in organ chambers filled with Krebs solution, and the isometric tension was recorded. There were no gender differences in responses to potassium chloride or phenylephrine in either intact or endothelium-denuded rings from control animals. Treatment with 10 mg/kg of lipopolysaccharide (LPS) attenuated the contractile response to potassium chloride in intact, but not in endothelium-denuded rings, and suppressed the phenylephrine contractions in rings both with and without endothelium from male and female rats. Endothelium-dependent and--independent relaxation by acetylcholine and the nitric oxide donor diethylamine/NO, respectively, did not depend on gender and were equally suppressed by LPS treatment. Treatment with LPS accentuated the effects of oxyhemoglobin in rings with and without endothelium and this was significantly larger in rings from females compared to males. Thus, gender differences were present in the effect of LPS on vascular responses. LPS induced a greater inhibition of depolarization by potassium chloride, but not receptor-activated contractions, in aortic rings from female verus male rats.

Acetylcholine↗

PubMed2001

The effect of 17beta-estradiol on isolated omental arteries from preeclamptic women.

OBJECTIVE: To study the effect of 17beta-estradiol on isolated omental arteries from preeclamptic women. STUDY DESIGN: Rings of omental artery with intact endothelium were mounted in organ chambers for isometric tension recording. We studied the effect of pharmacological concentrations of 17beta-estradiol on potassium chloride-induced tension and the concentration-contraction relationships for norepinephrine and calcium. RESULTS: Cumulative application of 17beta-estradiol, in a concentration-dependent manner, relaxed potassium chloride contracted rings. Sixty minutes of incubation with 17beta-estradiol (10(-5)mol/l) attenuated the tension developed in response to potassium chloride, norepinephrine and calcium. Tamoxifen (10(-6)mol/l) did not antagonize the inhibitory actions of 17beta-estradiol. CONCLUSIONS: Pharmacological concentrations of 17beta-estradiol retain the capability for relaxing omental artery rings from preeclamptic women. The loss of refractoriness to norepinephrine, increased responsiveness to calcium ions and decreased ability of 17beta-estradiol to inhibit calcium-induced tension may be responsible for increased vascular reactivity in preeclampsia.

Adult↗

PubMed2001

New developments in the management of preterm labor.

Current management of preterm labor has not changed the incidence of preterm delivery; therefore, significant research effort has been concentrated on the search for new methods of management. New tocolytics like inhibitors of cyclooxygenase 2 and nitric oxide donors have been tested in animal models and in preliminary clinical trials with promising results. Inhibition of cervical ripening may be one alternative to tocolysis. This new approach has a potential to be a valuable method of management of preterm labor if human studies confirm the promising results reported in animals. Growing evidence suggests that premature delivery may be associated with infection or fetal growth abnormalities, with dire consequences to the fetus. If these associations are to be included in risk and benefit assessment, then inhibition of preterm labor may prove to be detrimental to the fetus.

Cerebral Palsy↗

PubMed2001

Amniotic fluid concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 during pregnancy and labor.

OBJECTIVE: This study was undertaken to determine whether obstetric factors affect the concentrations of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in the amniotic fluid. STUDY DESIGN: We prospectively collected amniotic fluid samples from 109 women at various stages of pregnancy and labor and determined matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 concentrations by means of enzyme-linked immunosorbent sandwich assay systems. With multiple regression analysis we evaluated relationships between amniotic fluid matrix metalloproteinase 9 concentration and tissue inhibitor of metalloproteinase 1 concentration and the following factors: gestational age, presence of labor, cervical dilatation, membrane status, presence of clinical chorioamnionitis, and microbial colonization of the amniotic fluid. RESULTS: The detectable presence of amniotic fluid matrix metalloproteinase 9 was independently associated with intra-amniotic infection, labor, cervical dilatation, and spontaneous rupture of membranes. Chorioamnionitis and amniotic fluid matrix metalloproteinase 9 concentrations were correlated with tissue inhibitor of metalloproteinase 1 levels. CONCLUSIONS: Intra-amniotic infection, advanced labor, and rupture of membranes before the onset of labor were independently associated with the presence of matrix metalloproteinase 9 in the amniotic fluid. Both pathologic and physiologic processes appear to produce shifts in the balance between degradation and synthesis of the extracellular matrix.

Amniotic Fluid↗

PubMed2001

Marked variation in responses to long-term nitric oxide inhibition during pregnancy in outbred rats from two different colonies.

OBJECTIVE: Some but not all studies have shown that long-term nitric oxide synthase inhibition during pregnancy induces symptoms similar to those of preeclampsia that include hypertension, proteinuria, and intrauterine growth restriction. This study was undertaken to compare the effects of long-term nitric oxide synthase inhibition during pregnancy on blood pressure and fetal weight between Sprague-Dawley rats from outbred colonies of two different suppliers. STUDY DESIGN: Osmotic minipumps were inserted on day 10 or day 17 of pregnancy in Sprague-Dawley rats obtained from Charles River Laboratories, Inc, Wilmington, Mass, or Harlan Sprague Dawley, Inc, Indianapolis, Ind. The pumps were set to deliver vehicle only (control group) or N omega-nitro-L -arginine methyl ester (a nitric oxide synthase inhibitor) at a rate of 50 mg/d until postpartum day 7. Systolic blood pressures were measured daily with the tail-cuff method. Neonatal weights and survival were recorded. RESULTS: N omega-nitro-L -arginine methyl ester infusion initiated on gestational day 10 increased blood pressure relative to control levels in all rats studied. Harlan rats were much more sensitive to the hypertensive effect of N omega-nitro-L -arginine methyl ester. When N omega-nitro-L -arginine methyl ester infusion was initiated on gestational day 17, blood pressure increased only in Harlan rats. Pups born to Harlan rats treated with N omega-nitro-L -arginine methyl ester had lower birth weights and a higher stillbirth rate than did pups of Charles River rats. The degree of hypertension was significantly correlated with the deleterious effects of N omega-nitro-L -arginine methyl ester on the fetuses. CONCLUSION: Within the same strain of rats the effects of long-term nitric oxide synthase inhibition on blood pressure and fetal outcome depended on the original animal colony, with animals from Harlan Sprague Dawley being more sensitive than those from Charles River Laboratories. This difference in response between animals from different suppliers is most likely caused by genetic differences inbred into the strain. In addition to explaining some of the reported inconsistencies between laboratories, these results may also provide insights into the genetic basis of preeclampsia.

Animals↗

PubMed2001

Endothelium dependence and gestational regulation of inhibition of vascular tone by magnesium sulfate in rat aorta.

OBJECTIVE: The aim of this study was to investigate the role of nitric oxide in the vasorelaxant effect of magnesium sulfate during pregnancy. STUDY DESIGN: Segments of 3 mm of the aorta, with or without intact endothelium, from 16- or 22-day-pregnant rats were mounted in organ chambers with standard Krebs solution or low-magnesium Krebs solution for measurement of isometric tension. The rings were contracted with phenylephrine, and cumulative concentration-response curves for magnesium were determined after incubation with various inhibitors. RESULTS: Magnesium relaxed the aortic rings from pregnant rats in a concentration-dependent manner. The relaxation was significantly lower on day 22 of gestation than on day 16 of gestation. Removal of the endothelium or incubation with 10(-4)-mol/L N omega-nitro-L -arginine methyl ester (a nitric oxide synthase inhibitor), 10(-5)-mol/L 6-anilino-5,8-quinolinedione (a guanylate cyclase inhibitor), or 10(-5)-mol/L indomethacin (a cyclooxygenase inhibitor) significantly decreased the relaxant effect of magnesium on aortic rings from 16-day-pregnant but not 22-day-pregnant rats. Treatment with minimally effective concentrations of a nitric oxide donor (3 x 10(-10)-mol/L sodium nitroprusside) or a cyclic guanosine monophosphate analog (10(-6)-mol/L 8-bromo-cyclic guanosine monophosphate) restored the response to magnesium. CONCLUSIONS: The relaxant effect of magnesium on rat aortic rings was dependent on both endothelium and gestational age and was lower at term than during late pregnancy. The endothelium appears to potentiate the vasorelaxant effects of magnesium through the nitric oxide-cyclic guanosine monophosphate and cyclooxygenase systems.

Aminoquinolines↗

PubMed2001

Inhibition of cyclooxygenase but not nitric oxide synthase influences effects on the human omental artery of the thromboxane A2 mimetic U46619 and 17beta-estradiol.

OBJECTIVE: These experiments were performed to study the influence of endothelial factors on the contractile effect of the thromboxane A(2) analog U46619 and on the relaxant action of 17beta-estradiol on isolated human omental arteries from nonpregnant women, women with normal pregnancies, and women with preeclampsia. STUDY DESIGN: Arterial rings (3 mm) with or without endothelium were suspended in organ chambers filled with Krebs buffer, 37 degrees C, aerated with 5% carbon dioxide in air, pH approximately 7.4, for isometric tension recording. Rings were incubated with indomethacin, N(omega)-nitro-L -arginine, or 17beta-estradiol, alone or in combination. The concentration that produced 50% of maximal effect, the area under the curve, and the maximal effect of U46619, normalized with respect to a reference contraction in response to potassium chloride, were compared. RESULTS: Neither indomethacin nor N(omega)-nitro-L -arginine changed the basal tone of omental artery rings. Neither N(omega)-nitro-L -arginine nor removal of the endothelium affected either the contractile action of U46619 or the relaxant action of 17beta-estradiol. In contrast, indomethacin potentiated the contractile effect of U46619 and abolished the inhibitory effect of 17beta-estradiol in rings from all three groups. The effects of U46619 and 17beta-estradiol were significantly less in rings from women with normal pregnancy than in those from women with preeclampsia. Tissues from women with preeclampsia demonstrated the highest contractile response to U46619. CONCLUSION: The inhibitory effect of 17beta-estradiol is not due to increased production of endothelial nitric oxide but rather involves inhibitory products of the cyclooxygenase pathway. The effect of indomethacin may result from inhibited production or release of eicosanoids or from sensitization of thromboxane A(2) receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Contractility of late pregnant rat myometrium is refractory to activation of soluble but not particulate guanylate cyclase.

OBJECTIVE: Our purpose was to compare the effects of agents activating particulate or soluble guanylate cyclases on the spontaneous contractile activity of the isolated pregnant rat uterus. STUDY DESIGN: Uterine rings from midpregnant (14-day) and late pregnant (21-day) rats were suspended in organ chambers to record spontaneous contractile activity. Concentration-response curves were obtained for the following natriuretic peptides: atrial, brain, and C-type; concentration-response curves were also obtained for diethylamine nitric oxide, 3-morpholino-sydnominine, and authentic nitric oxide. RESULTS: All 3 natriuretic peptides inhibited spontaneous uterine contractions equally at midgestation and late gestation. The inhibitory effects of the nitric oxide donors diethylamine nitric oxide, 3-morpholino-sydnominine, and authentic nitric oxide were attenuated in uterine tissues from animals in late stages of pregnancy. CONCLUSION: Agents activating either soluble or particulate guanylate cyclase inhibit contractions of uterine rings from midgestation rats, whereas the effects of soluble guanylate cyclase are attenuated at late pregnancy. Thus spontaneous uterine contractions are under the control of both soluble and particulate guanylate cyclases; the former is dependent on gestational age but the latter is not.

Animals↗

PubMed2001

Inhibition of cervical ripening by local application of cyclooxygenase 2 inhibitor.

OBJECTIVE: Our goal was to test the hypothesis that the previously demonstrated progesterone-independent prolongation of pregnancy in rats treated with cervical application of the cyclooxygenase 2 inhibitor nimesulide is the result of inhibition of cervical ripening. STUDY DESIGN: Timed-pregnant Sprague-Dawley rats were randomly allocated to treatment with 50 mg nimesulide or vehicle, applied daily on the cervix for 5 days (days 14-18). On day 19 the animals were humanely killed and the cervices were removed. In the first series of experiments the cervices of animals treated with nimesulide (n = 10) or vehicle (n = 10) were examined with a cervimeter, which stretches the cervical tissues in incremental steps of 0.2 mm at 1-minute intervals. A steeper slope through the linear portion of the resulting force-versus-displacement curve indicates more resistance to stretch. In the second series of experiments the cervices of animals treated with nimesulide (n = 11) or vehicle (n = 11) were examined with the Collascope optical device. The cervical content of cross-linked collagen was measured with light-induced fluorescence. The fluorescence spectrum at 390 nm (peak wavelength of the collagen spectrum) was determined. For standardization, the ratio of counts of collagen peak over reference counts was used in the final analyses as an indicator of cross-linked collagen content. RESULTS: Animals treated with cervical application of nimesulide had significantly higher resistance to stretch than controls (slope: 0.2564 +/- 0.1213 vs 0.1387 +/- 0.0652; P =.019). The cervical content of cross-linked collagen was not significantly different between nimesulide-treated animals and controls (light-induced fluorescence ratios: 3.2134 +/- 0.7390 vs 2.7892 +/- 0.8518; P =.227). CONCLUSIONS: Treatment with cervical application of the cyclooxygenase 2 inhibitor nimesulide prevents the physiologic process of cervical ripening in late pregnancy. The inhibition is not the result of changes in cross-linked collagen content. Inhibition of cervical ripening with locally administered cyclooxygenase 2 inhibitor may be a potentially valuable treatment for patients at risk for preterm delivery.

Administration, Topical↗

PubMed2001

The effects of cervical application of inhibitors of inducible nitric oxide synthase, cyclooxygenase-1, and cyclooxygenase-2 on delivery in rats.

OBJECTIVE: To investigate the effect of cervical application of nonselective and selective inhibitors of nitric oxide synthases--N-nitro-L-arginine methyl ester, L-N-iminoethyl-lysine, and aminoguanidine--as well as inhibitors of cyclooxygenases--indomethacin, and nimesulide--on timing of delivery and fetal death and disease in pregnant rats. STUDY DESIGN: In a series of experimental protocols, timed-pregnant Sprague-Dawley rats (length of pregnancy, 22 days) were randomly allocated to daily cervical applications of (1) 0.04 mg (n = 6), 0.4 mg (n = 6), 4 mg (n = 6), or 40 mg (n = 6) L-N-iminoethyl-lysine or vehicle (n = 12) on days 19 to 22 of pregnancy; (2) 50 mg aminoguanidine (n = 6), 150 mg aminoguanidine (n = 6), or vehicle (n = 10) on days 19 to 22 of pregnancy; (3) 3 mg indomethacin (n = 6) or vehicle (n = 6) on days 19 to 22 of pregnancy; (4) 12.5 mg/kg nimesulide (n = 8), 25 mg/kg nimesulide (n = 8), 50 mg/kg nimesulide (n = 12), or vehicle (n = 12) on days 19 to 22 of pregnancy and 50 mg/kg nimesulide (n = 23) or vehicle (n = 23) on days 14 to 22 of pregnancy; (5) 50 mg/kg nimesulide (n = 10), 50 mg aminoguanidine plus 50 mg/kg nimesulide (n = 10), 50 mg aminoguanidine (n = 10), or vehicle (n = 10) on days 14 to 22 of pregnancy. The following variables were evaluated: proportion of animals that were delivered on day 23, time to delivery of the first pup (midnight on day 22 was considered to be 0 hour), number of stillborn pups, and average pup weight of each litter. RESULTS: Unlike L-N-iminoethyl-lysine, aminoguanidine, and indomethacin, 50 mg/kg nimesulide applied on the cervix daily for 8 days significantly increased the proportion of animals that were delivered on day 23 (18 of 23 versus 7 of 23; P =.003) and the time to delivery of the first pup by a mean of 10.8 hours (P <.001). Shorter treatment with nimesulide for 4 days increased only the time to delivery of the first pup at the 25-mg/kg dosage (P =.008). Simultaneous application of aminoguanidine and nimesulide significantly (P =.008) prolonged pregnancy to a degree similar to nimesulide alone. The experiment with N-nitro-L-arginine methyl ester was aborted because of severe maternal side effects. Unlike pups in the L-N-iminoethyl-lysine, aminoguanidine, and nimesulide groups, significantly more pups in the indomethacin group died in utero compared with the control group (36.1% versus 3.1%; P <.001), and the surviving pups had lower birth weights (P <.001). CONCLUSIONS: In an animal model, nimesulide was effective in delaying the onset of labor, was well tolerated during pregnancy, and affected cervical ripening directly independent of progesterone withdrawal. Conversely, cervical application of nitric oxide synthase and nonselective cyclooxygenase inhibitors do not extend the duration of pregnancy in the dosages studied, and some are associated with significant adverse effects in the mothers and fetuses.

Administration, Topical↗