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Objective: Our objective was to study the involvement of adenylate and guanylate cylases in spontaneous uterine contractions and inhibition induced by the opening of potassium channels.Study Design: Uterine rings from rats at mid and term gestation and from rats at term gestation in labor were suspended in organ chambers for isometric tension recording. Concentration-response relationships to an opener of adenosine triphosphate-dependent potassium channels, levcromakalim, or to an opener of calcium-dependent potassium channels, NS 1619, were studied in the absence and presence of inhibitors of adenylate cyclase (MDL 12330 A, 2 x 10(-5) mol/L; SQ 22536, 10(-4) mol/L) or guanylate cyclase (LY 83583,3 x 10(-6) mol/L).Results: MDL 12330 A and SQ 22536 accentuated contractions in rings from rats at mid gestation but not at term gestation or at term gestation in labor. LY 83583 inhibited contractions in the rings from all 3 groups. Levcromakalim was equally effective in inhibiting contractions of rings from all 3 groups. MDL 12330 A, but not SQ 22536, decreased sensitivity and maximal inhibition induced by levcromakalim (term gestation greater than mid gestation greater than term gestation in labor). LY 83583 decreased the sensitivity to and maximal inhibition induced by levcromakalim in rings from pregnant rats at mid gestation. NS 1619 attenuated contraction of rings from rats at mid gestation and, to a lesser extent, at term gestation but accentuated contractions in rings from animals at term gestation in labor. MDL 12330 A, but not SQ 22536 or LY 83583, attenuated the changes induced by NS 1619 in rings from all 3 groups.Conclusions: (1) The influence of nucleotide cyclases on basal uterine contractility depends on gestational age. (2) The inhibition of uterine contractions that results from the opening of calcium-dependent potassium channels depends on adenylate cyclase, whereas that of adenosine triphosphate-dependent potassium channels depends on both adenylate and guanylate cyclases. 3. Activation of adenosine triphosphate-dependent potassium channels is more efficient than activation of calcium-dependent potassium channels. 4. The inhibition induced by calcium-dependent potassium channel openers, but not adenosine triphosphate-dependent potassium channel openers, decreases as pregnancy progresses, and at delivery the activation of spontaneous contractile activity is evident. [ABSTRACT FROM AUTHOR]

Objective: We sought to study the contribution of potassium channels in the effect of forskolin and 1,9-dideoxyforskolin on uterine contractility in the pregnant rat.Study Design: Rings taken from the middle portions of uterine horns from rats at 16 days of gestation were positioned in organ chambers containing physiologic salt solution bubbled with 5% carbon dioxide in air (37 degrees C, pH approximately 7.4) for isometric tension recording under 2 g passive tension. The effects of cumulative concentrations of forskolin and 1,9-dideoxyforskolin in the absence or presence of an adenylate cyclase inhibitor (MDL-12,330A, 10(-5) mol/L), a nonselective potassium channel blocker (tetrabutylammonium, 10(-4) mol/L), or an adenosine triphosphate-dependent potassium channel blocker (glibenclamide 10(-5) mol/L) were studied.Results: Both forskolin and, to a lesser extent, 1,9-dideoxyforskolin inhibit uterine contractions. Tetrabutylammonium, glibenclamide, and MDL-12, 330A attenuated the effects of forskolin, whereas glibenclamide was less effective against 1,9-dideoxyforskolin.Conclusion: Activation of adenylate cyclases, as well as adenosine triphosphate-dependent potassium channels and, to a greater extent, calcium-dependent potassium channels, is involved in the inhibitory effect of forskolin in uterine rings from rats at 16 days of gestation. Inhibition of uterine contractions by 1,9-dideoxyforskolin is less than that by forskolin and involves activation of adenylate cyclase and calcium-dependent potassium channels. Whether activation of guanylate cyclase is involved in the effect of the agents on calcium-dependent potassium channels needs further investigation. 1, 9-Dideoxyforskolin is not an inactive isomer of forskolin in rat uterine rings. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this investigation was to study the effects of pharmacologic manipulation of cyclic nucleotide levels on the uterine spontaneous contractile activity and responsiveness to nitric oxide in pregnant rats at midgestation and term.Study Design: Uterine rings from pregnant rats at midgestation and term were placed in organ chambers for isometric tension recording. Concentration-response curves were obtained for phosphodiesterase and guanylate cyclase inhibitors, membrane-permeable cyclic nucleotide analogs, and forskolin. In addition, the effects of minimal inhibitory concentrations of these agents on the concentration-response relationships for diethylamine nitric oxide (a nitric oxide donor) were studied.Results: Nonselective phosphodiesterase inhibitors induced more inhibition of contractions of uterine rings from pregnant rats at term than at midgestation and zaprinast induced less. Inhibitors of guanylate cyclase and membrane-permeable analogs of cyclic guanosine monophosphate were equally effective in tissues from pregnant rats at midgestation and term. All agents attenuated the inhibitory effect of diethylamine nitric oxide at midgestation; however, dibutyryl cyclic adenosine monophosphate and papaverine increased the inhibitory effect of diethylamine nitric oxide in tissues from pregnant animals at term.Conclusions: Cyclic nucleotides modulate both spontaneous and nitric oxide-induced changes in uterine contraction during pregnancy. Application of nonselective inhibitors of phosphodiesterase, as well as membrane-permeable analogs of cyclic adenosine monophosphate, may counteract refractoriness to nitric oxide at term. [ABSTRACT FROM AUTHOR]

Objective: We sought to compare the effects of fluoxetine, imipramine, and nortriptyline on spontaneous and serotonin-activated contractile activity of the uterine rings from midterm and term pregnant rats.Study Design: Uterine rings from timed-pregnant Sprague-Dawley rats on day 14 (midgestation) and day 22 (term gestation) were used for isometric tension recording. Responses to cumulative concentrations of fluoxetine, imipramine, nortriptyline, and serotonin in the absence and presence of the monoamine reuptake inhibitors were studied.Results: Neither of the monoamine reuptake inhibitors significantly influenced spontaneous contractile activity, whereas the concentration-dependent increase in activity induced by serotonin was inhibited in rings from both midterm and term pregnant rats.Conclusions: The reported increase in preterm delivery in women receiving fluoxetine during the third trimester cannot be explained by a direct effect on uterine contractility. [ABSTRACT FROM AUTHOR]

Objective: We sought to study the effects of authentic nitric oxide and carbon monoxide on the contractile activity of pregnant human and rat myometrium.Study Design: Strips were prepared from uterine biopsy specimens of 10 pregnant, nonlaboring women at term gestation undergoing cesarean delivery. In addition, rings were prepared from the uteri of pregnant rats at midterm (day 14) and at term (day 22) gestation (n = 10-12). The tissues were mounted in organ chambers filled with Krebs-Henseleit solution continuously aerated with 5% carbon dioxide in air (37 degrees C, pH approximately 7.4) for isometric tension recording. The effects of nitric oxide and carbon monoxide gases on spontaneous contractile activity were studied. Responses to hemin (hemoxygenase substrate), which produces endogenous carbon monoxide, were also examined. Responses to nitric oxide and carbon monoxide were also studied in aortic and tail artery rings from pregnant rats after contraction with phenylephrine.Results: Nitric oxide significantly inhibited contractility of human myometrium at term (area under the concentration-response curve, 145.36 +/- 30.02 vs 40.56 +/- 22.81 in controls; P <.05) and rat myometrium at midterm gestation (264.23 +/- 47.86 vs 121.82 +/- 23.50; P <.05) but not at term. No statistically significant inhibition was induced in human or rat myometrium by carbon monoxide, whereas hemin significantly attenuated contractility in human myometrium at term and in rat myometrium at midterm gestation (P <. 05). Nitric oxide, carbon monoxide, and hemin relaxed aortic and tail artery rings.Conclusions: Authentic nitric oxide inhibits rat uterine contractile activity at midterm gestation but not at term. However, nitric oxide inhibits human myometrium activity at term. Authentic carbon monoxide does not appear to modulate uterine contractility, whereas hemin may have some inhibitory properties. [ABSTRACT FROM AUTHOR]

Objective: We sought to study the involvement of potassium channels in the inhibition by nitric oxide of spontaneous contractions in isolated uterine rings from midterm and term pregnant rats.Study Design: Uterine rings from Sprague-Dawley rats at midterm and term gestation were used for isometric tension recording. The inhibition of spontaneous contractile activity by potassium channel openers and nitric oxide was studied in the absence and presence of potassium channel inhibitors.Results: The adenosine triphosphate-dependent potassium channel opener levcromakalim inhibited spontaneous contractions in rings from both midterm and term pregnant rats in a concentration-dependent manner, and the effects were significantly attenuated by pretreatment with selective inhibitor of the adenosine triphosphate-dependent potassium channel inhibitor glibenclamide. The opener of calcium-dependent potassium channel NS 1619 inhibited spontaneous contractions in rings from midterm but significantly less so in rings from term pregnant rats in a concentration-dependent manner, and the effect was significantly attenuated by pretreatment with potassium channel inhibitors tetraethylammonium and tetrabutylammonium but not with glibenclamide. Rings from midterm and term pregnant rats were more sensitive to the inhibitory effect of levcromakalim compared with NS 1619. Nitric oxide donor diethylamine-nitric oxide inhibited spontaneous contractions in rings from midterm but significantly less in rings from term pregnant rats in a concentration-dependent manner, and the effect was attenuated by tetraethylammonium and tetrabutylammonium but not by glibenclamide.Conclusions: There is gestational age-dependent refractoriness to calcium-dependent potassium but not adenosine triphosphate-dependent potassium channel opener-induced inhibition of spontaneous contractile activity of isolated rat uterine rings. Nitric oxide inhibits uterine contractions by opening of calcium-dependent potassium channels in pregnant rat myometrium. Refractoriness to nitric oxide toward term may result from decreased probability to open or number of calcium-dependent potassium channels. [ABSTRACT FROM AUTHOR]

Objective: This study was intended to test the hypothesis that glycosylated hemoglobin adversely affects endothelium-dependent vascular relaxation during pregnancy.Study Design: Omental artery rings (3 mm) obtained from patients undergoing cesarean delivery at term were suspended in organ chambers for isometric tension recording in Krebs bicarbonate solution. They were bubbled with 5% carbon dioxide in air (37 degrees C, pH 7.4). After equilibration at 1-g passive tension and contraction with endothelin 1, concentration-relaxation curves in response to bradykinin were determined in the presence or absence of oxyhemoglobin, glycosylated hemoglobin, or nitric oxide synthase inhibitors (N(omega)-nitro-L-arginine methyl ester or N(omega)-nitro-L-arginine).Results: Oxyhemoglobin and glycosylated hemoglobin attenuated the endothelium-dependent relaxation induced by bradykinin. The inhibition did not differ significantly between the 2 nitric oxide scavengers and was of the same magnitude as that noted with the nitric oxide synthase inhibitors.Conclusion: Glycosylation of hemoglobin does not change its effect on endothelium-dependent relaxation in human omental vessels during pregnancy. These data do not support the hypothesis that glycosylated hemoglobin may be the reason for abnormal endothelial function in diabetes. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to compare the effects of agents stimulating particulate and soluble guanylate cyclase with spontaneous rat uterine contractions at midgestation and term.Study Design: Uterine rings from midgestation (day 13) and term nonlaboring (day 22) rats were positioned in organ chambers for isometric force recording. Rings were treated with increasing concentrations of atrial natriuretic peptide, permeable analogs of cyclic guanosine monophosphate, and diethylamine/nitric oxide.Results: Atrial natriuretic peptide was more effective in inhibition of uterine contractions than diethylamine/nitric oxide. The 50% inhibitory concentrations were -7.4 +/- 0.12 and -7.38 +/- 0.11 for atrial natriuretic peptide and -5.68 +/- 0.09 and -4.23 +/- 0.12 for diethylamine/nitric oxide at midgestation and term, respectively. Pretreatment of uterine rings with atrial natriuretic peptide significantly attenuated inhibition of spontaneous contractions by diethylamine/nitric oxide at midgestation.Conclusions: Uterine spontaneous contractions are influenced by both soluble and particulate guanylate cyclase; the former, but not latter, is gestational age dependent. [ABSTRACT FROM AUTHOR]

Objectives: Our purpose was to study the effects of corticotropin-releasing factor on (1) maternal blood pressure, (2) uterine vasculature, and (3) parturition in pregnant rats.Study Design: Infusion minipumps containing vehicle, corticotropin-releasing factor, or alpha-helical corticotropin-releasing factor 9-41 (corticotropin-releasing factor receptor antagonist) were inserted subcutaneously in timed pregnant rats on day 16 of gestation. Systolic blood pressure was measured daily by the tail-cuff method. The time of onset of labor was determined and the newborn pups were weighed. Circulating levels of corticotropin-releasing factor were measured in untreated controls by radioimmunoassay. Relaxant responses to corticotropin-releasing factor were studied in isolated segments of uterine artery from late (day 18) and term (day 22) pregnant rats mounted in a wire myograph.Results: The blood pressure was decreased by corticotropin-releasing factor and increased by alpha-helical corticotropin-releasing factor 9-41 (p < 0.05). The time of onset of labor was not affected by either treatment. Pup weight was decreased by corticotropin-releasing factor (p < 0.05). Circulating levels of corticotropin-releasing factor (immunoreactive) were not changed in pregnancy. In vitro, corticotropin-releasing factor caused relaxation of the uterine artery in a concentration-dependent manner and the relaxation was decreased at term compared with late pregnancy (p < 0.05).Conclusions: Endogenously produced corticotropin-releasing factor lowers blood pressure during pregnancy in rats. It is a relaxant of uterine vasculature and this effect is decreased at term. It does not play an essential role in the initiation of labor in rats. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to examine the hypothesis that the relaxant response to corticotropin-releasing factor is endothelium dependent and changes during pregnancy.Study Design: Relaxant responses to cumulative concentrations of corticotropin-releasing hormone were measured in rings of thoracic aorta, precontracted with phenylephrine, from pregnant and nonpregnant female rats. Each group consisted of 5 to 10 rats.Results: The relaxation induced by corticotropin-releasing factor in aortic rings from nonpregnant rats decreased after deendothelization and treatment with N omega-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), LY-83,583 (a guanylate cyclase inhibitor), or alpha-helical corticotropin-releasing factor 9-41 (a corticotropin-releasing factor antagonist). The percent decrease in relaxation at 1 nmol/L of corticotropin-releasing factor was about 88% with deendothelization, 100% with N omega-nitro-L-arginine methyl ester, 76% with LY-83,583, and 100% with alpha-helical corticotropin-releasing factor 9-41. The responses to corticotropin-releasing factor in intact rings from rats in early pregnancy were not significantly different from those in the nonpregnant female rats, but the responses were decreased during the later stages of gestation (percent decrease in relaxation at 1 nmol/L of corticotropin-releasing factor about 71% at day 20 and 98% at term). The relaxation induced by corticotropin-releasing factor during pregnancy was also inhibited by deendothelization, N omega-nitro-L-arginine methyl ester, or LY-83,583.Conclusions: The relaxant response to corticotropin-releasing factor in the rat aorta is endothelium dependent and is mediated by the nitric oxide-cyclic guanosine monophosphate pathway. The receptor involved in this effect is alpha-helical corticotropin-releasing factor 9-41 sensitive. This inhibitory response is unchanged during early pregnancy but reduced toward the end of gestation. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to study the mechanism by which 17 beta-estradiol modulates contractile activity in isolated rings of omental artery from nonpregnant and pregnant patients.Study Design: Rings of omental artery with intact endothelium from nonpregnant and pregnant women were mounted in organ chambers for isometric tension recording. The concentration-relaxation relationship to 17 beta-estradiol (10(-7) mol/L to 3 x 10(-5) mol/L) was studied in rings contracted with 60 mmol/L potassium chloride (in both the absence and the presence of tamoxifen, 10(-6) mol/L). The effect of 17 beta-estradiol (10(-5) mol/L) on the contraction induced by 60 mmol/L potassium chloride and on the concentration-contraction relationships to both norepinephrine (10(-9) mol/L to 10(-5) mol/L) and calcium ion (0.05 mmol/L to 2.5 mmol/L in calcium-free depolarizing solution) were studied in the presence and absence of tamoxifen (10(-6) mol/L). The maximal contraction, negative logarithm of the concentration producing 50% relaxation or 50% contraction to the reference 60 mmol/L potassium chloride contraction, and the area under the curve were calculated. Data analysis was by one-way analysis of variance, Newman-Keuls test, and two-sample tests as appropriate. Probability values less than 0.05 in a two-tailed test were considered statistically significant.Results: 17 beta-Estradiol relaxed omental arteries contracted with 60 mmol/L potassium chloride, and this effect was potentiated by tamoxifen in both groups. Incubation of the omental arteries with 17 beta-estradiol inhibited contractions induced by 60 mmol/L potassium chloride in rings from both groups of patients, and tamoxifen did not antagonize this effect in either group. Rings of omental artery from the nonpregnant patients (expressed as percentage of the reference potassium chloride contraction) showed greater contraction than rings from the pregnant women when exposed to norepinephrine, a statistically significant difference. 17 beta-Estradiol decreased the norepinephrine-induced contraction in omental arteries from nonpregnant but not pregnant women in a statistically significant way. Tamoxifen did not influence the effect of norepinephrine for either group. 17 beta-Estradiol inhibited calcium ion-induced contraction similarly in rings of omental artery from both nonpregnant and pregnant patients. Tamoxifen potentiated estradiol-induced inhibition in arteries from pregnant patients.Conclusions: 17 beta-Estradiol inhibits norepinephrine-induced contractions in omental arteries from nonpregnant but no pregnant patients. The inhibition of the ter sion developed after exposure to potassium chloride, norepinephrine, and calcium ion is caused by a calcium channel blocking action. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to compare the responsiveness of omental resistance arteries from nonpregnant women and from normotensive and preeclamptic pregnant women to selected contractile agonists.Study Design: Omental artery rings with intact endothelium from normotensive premenopausal nonpregnant women and from normal and preeclamptic pregnant women were mounted in Krebs-bicarbonate solution in organ baths for isometric tension recording. After the presence of endothelium was confirmed, cumulative concentrations of norepinephrine, serotonin, U46619, and endothelin-1 were added. Concentration-response curves were constructed and expressed as percentage of a reference 60 mmol/L potassium chloride contraction. Data analysis was by repeated-measures analysis of variance. Newman-Keuls test, and paired or unpaired Student t test, as appropriate. Statistical significance was by two-tailed p<0.05.Results: Endothelin-1 and U46619 increased tension similarly in all three groups. Norepinephrine increased tension in nonpregnant vessels to a greater extent than in either preeclamptic or pregnant vessels (nonpregnant 114.3 +/- 5.42% vs pregnant 65.2 +/- 10.5%, p<0.05). Nonpregnant omental artery developed significantly greater tension than did pregnant tissue at three concentrations of norepinephrine (10(-5) mol/L, 3 x 10(-5) mol/L, 10(-4) mol/L), and preeclamptic vessels developed more tension than that from normal pregnant vessels at 3 x 10(-6) mol/L (p=0.06) and 10(-5) mol/L (p<0.05). There was a negligible change in tension with increasing concentrations of serotonin in the vessels from nonpregnant women; serotonin-induced contraction in the omental arteries from normotensive pregnant women and preeclamptic patients was <6% of the potassium chloride reference contraction, but this was significantly (p<0.05) different from that of the nonpregnant women.Conclusions: Omental artery segments from nonpregnant, normotensive pregnant and preeclamptic women contract similarly to endothelin-1 and U46619 but exhibit variable responses to norepinephrine and serotonin. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to study the direct vascular effects of estradiol-17 beta and progesterone on isolated omental artery from premenopausal nonpregnant women and from normotensive and preeclamptic pregnant women.Study Design: Omental artery rings from normotensive premenopausal nonpregnant women and from normal and preeclamptic pregnant women were mounted in Krebs-bicarbonate solution in organ baths for isometric tension recording. The endothelium was removed from some of the rings, and all were contracted with potassium chloride (60 mmol/L) and then exposed to cumulative concentrations of estradiol-17 beta and progesterone. Concentration response curves were constructed and relaxation was expressed as percent change from the reference 60 mmol/L potassium chloride contraction. Data analysis was by repeated-measures analysis of variance, Newman-Keuls test, and the unpaired Student t test as appropriate. A two-tailed p < 0.05 was considered statistically significant.Results: Both hormones studied caused vasorelaxation in omental arteries from all three groups of patients. Of the two, estradiol-17 beta was more effective, regardless of the presence or absence of endothelium. Removal of the endothelium shifted the estradiol-17 beta concentration-response curve to the right in the normal pregnant artery but not in nonpregnant or preeclamptic vessels. Removal of the endothelium shifted the progesterone concentration-response curve to the left in arteries from preeclamptic patients.Conclusions: Estradiol-17 beta and progesterone have direct in vitro vasodilator activity that appears to be linked, in part, to the endothelium in human omental artery from normal and hypertensive women in different hormonal states. [ABSTRACT FROM AUTHOR]