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1. In isolated human placental chorionic vein segments, 5-hydroxytryptamine (5-HT; 10(-8) to 5 x 10(-5) M) elicited concentration-dependent contractions with EC50 = 5.5 (5.2-5.7) x 10(-8) M) and Emax = 93.1 +/- 7.3% of 75 mM KCl-induced contraction. 2. The agonist of 5-HT2 receptors, alpha-methyl-5-hydroxytryptamine, and the selective agonist of 5-HT1 receptors, N,N-dipropyl-5-carboxamidotryptamine and 5-carboxamidotryptamine, induced pronounced concentration-related contractions, which reached 71.1 +/- 6.0%, 53.0 +/- 5.0% and 75.0 +/- 7.8% at the highest dose tested, respectively. The agonist of 5-HT3 receptor, 2-methyl-5-hydroxytryptamine, reached a maximum averaging 36.7 +/- 5.1% of the maximal response to KCl. 3. The 5-HT1 and 5-HT3 receptor antagonists, methiothepin and metoclopramide (10(-7) to 10(-6) M) did not alter the response to 5-HT. However, ketanserin (10(-7) to 10(-6) M), a 5-HT2 receptor antagonist, induced significant inhibition of the concentration-response curve to 5-HT. 4. Contractile responses to 5-carboxamidotryptamine and 2-methyl-5-hydroxytryptamine were not affected by methiothepin and metoclopramide, respectively, whereas ketanserin significantly attenuated the contractile response to these agonists. 5. In conclusions, our study shows that 5-HT2 receptors mediate contraction of the human placental vein with no obvious role for 5-HT1-like, or 5-HT3 receptors.

Isolated human placental cotyledons from normal (NG) and preeclamptic gestants (PG) were perfused in vitro, and the effect of N omega-nitro-L-arginine (L-NA, 100 microM), methylene blue (MB, 50 microM), and indomethacin (INDO, 10 microM), on resting perfusion pressure and on the 5-hydroxytryptamine (5-HT)-induced vasoconstriction was established. In the HG, L-NA and MB increased resting perfusion pressure (p0.001) and INDO had no significant effect on resting pressure. In the PG, these agents did not significantly modify resting perfusion pressure. In the PG, 5-HT (10 microM-1 microM) caused greater maximal increases in perfusion pressure than in NG. In the NG, L-NA greatly enhanced the 5-HT-induced pressure, however INDO attenuated this effect. In the PG, L-NA did not modify significantly the 5-HT-induced response, but INDO reduced this response. These results suggest that basal release of nitric-oxide but not of vasodilator prostanoids may contribute to the low resting vascular tone in the NG and attenuates the strong vasoconstrictor effect induced by 5-HT. Impairment of action of nitric oxide could contribute to the enhanced pressor response to 5-HT observed in the PG.

Objective To examine the distribution of mast cells in human uterine tissue and to study the interactions between mast cell mediators (histamine and serotonin) and PGF2α in human myometrium contractile activity. Design Distribution of mast cells were analysed in cryostat sections of myometrium samples stained with Toluidine blue. Contractile activity was evaluated in an isolated organ bath preparation on myometrial strips obtained from women whose pregnancies ended in elective caesarean section. Setting Biological Science Laboratories at the University of Concepcion. Subjects Twenty women undergoing elective caesarean and 10 women undergoing hysterectomy at the G. Grant Hospital. Main outcome measurements Cumulative concentration-response curves for histamine and serotonin before and after the addition of subumbral concentrations of the PGF2α or serotonin were performed. Results Serotonin was more active than histamine to evoke contractions (EC50:0.20 (SE 0.02) μmol/l vs 1.5 (SE 0.2) μmol/l, respectively). Furthermore, threshold concentrations of serotonin (0.05 μmol/l) potentiated the contractile effect of histamine (EC50:0.3 (SE 0.06) μmol/l and 50% increase in Emax). PGF2α had a poor contractile effect, but threshold concentrations (0.05 and 0.10 μmol/l) enhanced the contractile effect of both serotonin and histamine. A population of mast cells was found in close apposition to smooth muscle fibres. Conclusions It is postulated that the simultaneous release of mast cell mediators (histamine and serotonin) in myometrium could be an important stimulus for evoking strong contractions in the human uterus. PGF2α may have indirect effects in myometrium by amplifying the effects of histamine and serotonin.

1. 1. The in vitro effect of progesterone on norepinephrine (NE) release and contractile activity was analyzed in uterine horns from estrogen-primed and progesterone-primed mice. 2. 2. Progesterone (6–10 nmol/ml) evoked the release of [ 3 H]NE above basal levels from uterine horns in both experimental conditions, the effect of progesterone on estrogen-primed being more important than on progesterone-primed mice uterus. 3. 3. Progesterone also increased electrically evoked [ 3 H]NE release in estrogen-primed uterine tissue, nevertheless no effect was observed in progesterone-primed ones. 4. 4. Progesterone (0.6–10 nmol/ml) inhibited uterine horn isometric contractions only in estradiol-primed mice. This effect was partially blocked in uterine horns from reserpine-treated mice and when propanolol (1 μM) was added to the preparation of estradiol-primed mice uterus.

This study characterizes the reactivity of human chorionic plate vein in full-term (39.4+/-0.3 weeks of gestation) and preterm (34.4+/-0.6 weeks of gestation) pregnancy to endothelin-1 (ET-1) and attempts to characterize ET-1 receptor subtype, and the contribution of nitric oxide and cyclooxygenase products in these responses. In placental veins from full-term and preterm pregnant women, cumulative addition of ET-1 (10(-10)-10(-6) M) caused marked and long-lasting concentration-dependent contractile responses. The mean EC(50) and E(max) values for ET-1-induced venoconstriction did not differ between the full-term and preterm pregnancy groups. In the veins from preterm placental preparations, the ET(A) receptor-selective antagonist cyclo(D-alpha-aspartyl-L-propyl-D-valyl-L-leucyl-D-tryptophyl (BQ123) reduced the ET-1-induced contraction by 28.6+/-2.4%, compared to a decline in tension of 51.2+/-4.2% in the full-term placental vessels. The ET(B) receptor-selective antagonist, N-[N-[N-[2,6-dimethyl-1piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(methoxycarbonyl)-D-tryptophyl]-D-norleucinemonosodium (BQ788), did not influence ET-1-induced contraction in placental vein from both pregnancy groups in terms of maximal contraction and sensitivity. Pretreatment with the cyclooxygenase inhibitor, indomethacin (1 microM) and the nitric oxide synthase inhibitor N(w)-nitro-L-arginine (NOLA, 100 microM) did not significantly affect either the EC(50) or the maximum contraction to ET-1 in veins from normal full-term and preterm preparations. The results of this study suggest that there is no correlation between ET-1-induced vasoconstriction and gestational age and that this vasoconstriction is mediated predominantly via ET(A) receptor subtype in both groups of pregnant women, independent of NO and eicosanoids.

Pharmacologic and methodologic advances over the last decade have resulted in a body of information implicating serotonin as a mediator in the genesis of preeclamptic hypertension. Platelets contain the largest storage of serotonin in peripheral blood and have the ability to take up this amine from sourroundings, store and release it by several mechanisms. Plasma and platelet serotonin concentrations and platelet serotonin uptake have been measured in 8 non-pregnant women, 12 normal pregnant women and 8 women with severe pre-eclampsia. Plasma serotonin concentration was significantly higher in severely preeclamptic women, compared with age and gestation matched normal pregnant women. In addition, plasma serotonin concentration was directly related to systolic and diastolic blood pressure with severity of the syndrome. Furthermore, platelet serotonin concentration in women with pre-eclampsia was significantly higher than in non-pregnant controls, but it was not significantly different from the normal pregnant women. Moreover, serotonin is effectively taken up by platelets through a saturable transport process. The calculated apparent Km for serotonin uptake process did not differ significantly among non-pregnant women, normal pregnant women and women with pre-eclampsia. However, Vmax values were significantly higher in women with pre-eclampsia than in the normotensi ve pregnant women. As the actions of serotonin in the periphery could be terminated primarily by active uptake system by platelets and placenta, significant alterations in the rate of transport could result in physiologically significant changes in serotonin levels. These data raise the possibility that abnormal regulation of transporter function is involved in the etiology of pre-eclampsia.

1. 1. The ability of prostaglandin F 2α (PGF 2α ), histamine and serotonin to induce and/or potentiate contractions in mouse uterine horns was studied in an attempt to analyze whether uterine mast cells degranulation could favor contractions during labor. 2. 2. PGF 2α was the most potent of the three compounds (EC 50 = μ M), being followed by serotonin (EC 50 = 1.2 μ M) and histamine. Between 10 and 100 μM histamine only evoked weak contractions, not higher than 50% of maximal amplitude of contractions. 3. 3. Serotoin (0.1 μM) potentiated the contractile effect of both histamine and PGF 2α when added simultaneously with the corresponding compound to the isolated organ bath. Also, histamine at threshold contractile concentration (3 μM) was able to potentiate the contractile effect of both serotonin and PGF 2α . 4. 4. The potentiating effect of PGF 2α on both histamine and serotonin evoked contractions was recorded after treating the preparation with 10 μM of the compound for at least 10 min before the corresponding concentration-effect curves were performed. 5. 5. It is postulated that the simultaneous presence of these mast cells mediators in myometrium could be an important stimulus for both to trigger and/or to maintain contractions during labor.

The effect of isoproterenol (ISO), norepinephrine (NE) and phenylephrine (PHE) on electrically-induced contractions of mice uterine horns was studied during pregnancy. At the different times of gestation adrenergic agonists always inhibited uterine contractions in the following rank order of potency: ISO greater than NE greater than PHE. Cumulative dose-response curves constructed for the effect of these amines during diestrous, and at days 3-7, 10-15, 17-21 of gestation, showed that EC50 values increased gradually as term approached, which could imply a lower capacity of the uterus to respond to adrenergic drugs. Some likely explanations for this phenomenon are proposed. It is suggested that this lower response to catecholamines at the end of pregnancy could be a cause for the reduced success of beta 2-adrenergic drugs to stop premature labor.

Correlation between contractile activity and norepinephrine (NE) release induced by electrical stimulation or by high K+ depolarization has been analyzed in isolated preparations of mouse uterus throughout the different stages of the estrous cycle. Both the contractile activity induced by electrical stimulation and the capacity to maintain contracture, after changing the physiological bathing solution by high K+ solution, followed the same pattern: estrous greater than proestrous greater than diestrous greater than metestrous. High-K+ induced 3H-NE release was also different according to the stage of the estrous cycle. 3H-NE release was significantly less in estrous than in diestrous uterine horns. EC50 values for inhibiting contractile response, for isoprenaline, norepinephrine and phenylephrine were significantly greater in metestrous than in other stages of the estrous cycle. On the other hand, reserpinized mouse uteri showed an increase in EC50 values in the stages tested. The data support the hypothesis that in a mouse uterus, sex steroid hormones could affect beta-adrenergic receptor function indirectly, perhaps through an action on adrenergic neurons by a mechanism affecting NE release from sympathetic terminals.