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Biomedical subjects

M Maggi

Publications and source records attributed to M Maggi.

At least 91 records · Page 5Linked to original sources
PubMed1994

Receptors for and myometrial responses to oxytocin and vasopressin in preterm and term human pregnancy: effects of the oxytocin antagonist atosiban.

OBJECTIVE: Our purpose was to study myometrial oxytocin and type V1 vasopressin receptors, the in vitro contractile effects of these hormones, and the influence of an oxytocin antagonist. STUDY DESIGN: Women delivered by cesarean section preterm (n = 51) and at term (n = 71), with and without labor contractions, gave myometrium for the estimation of oxytocin and V1 vasopressin receptors. The in vitro myometrial effects of the peptides and the influence on these of the competitive oxytocin receptor blocking agent 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin were also tested. RESULTS: The median concentration of oxytocin receptors was 116 fmol/mg protein (range 15 to 372 fmol/mg protein) in patients delivered preterm not in labor, 134 fmol/mg protein (27 to 1421 fmol/mg protein) in the beginning of labor, and 46 fmol/mg protein (9 to 140 fmol/mg protein) in advanced labor. At term the corresponding concentrations were 172 (25 to 629), 223 (24 to 414), and 70 (21 to 92) fmol/mg protein. The concentration of V1 vasopressin receptors also decreased in advanced labor. In advanced labor after oxytocin infusion a reduction in the concentration of the receptor for this hormone was observed, which appeared to be related to the duration and dose of treatment. Oxytocin receptors did not vary between women with different indications for cesarean section. The oxytocin effects in vitro and the degree of inhibition by the antagonist of oxytocin responses correlated with the concentration of oxytocin receptors but not with that of V1 vasopressin receptors. No correlation was seen between the response to vasopressin and concentrations of oxytocin or V1 vasopressin receptors. CONCLUSIONS: The effect of oxytocin on the myometrium in pregnancy is mediated by an oxytocin receptor, whereas vasopressin acts on both oxytocin and vasopressin receptors. The initiation of labor both preterm and at term may be primarily related to increased release of oxytocin, which is locally produced in the uterus and not detectable in the plasma, but oxytocin and vasopressin receptors may play a role in the regulation of labor. The analog 1-deamino-2-D-Tyr(OEt)-4-Thr-8-Orn-oxytocin, which blocks both the oxytocin and the V1 vasopressin receptor, should inhibit labor both preterm and at term, the former confirming results of recent clinical studies in Sweden and the United States.

Cesarean Section↗
PubMed1994

Platelet-activating factor in human endometrium.

Platelet-activating factor (PAF) is a phospholipid actively produced by human endometrium and deeply involved in the processes of ovoimplantation and labor. We recently found that PAF represents a new autocrine growth factor for a human adenocarcinoma cell line, HEC-1A. Indeed, biologically active PAF is synthesized by HEC-1A cells, under progesterone control. In HEC-1A cells, PAF regulates intracellular calcium concentration ([Ca2+]), DNA synthesis and expression of early oncogenes. All these effects are blocked by the receptor antagonist L659,989. However, while nanomolar concentrations of PAF mobilize [Ca2+], only micromolar concentrations affect cell growth, suggesting heterogeneity of PAF receptors or signaling. Two distinct populations of PAF receptors are present in HEC-1A cells, which bind PAF in nanomolar and micromolar concentrations, respectively. Since HEC-1A cells are producing elevated concentrations of PAF and micromolar concentrations of the PAF antagonist L659,989 inhibit cell proliferation, an autocrine role for PAF is suggested in HEC-1A cells.

Adenocarcinoma↗
PubMed1994

Antagonists for the human oxytocin receptor: an in vitro study.

The oxytocin antagonist [Mpa1, D-Tyr(Et)2, Thr4, Orn8]-oxytocin has been successfully used for treating premature labour. The interactions of this antagonist with neurohypophysialhormone receptors in the human myometrium were investigated. Competition curves among [3H]oxytocin, [3H]arginine vasopressin, [3H][1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid)2-(O-methyl)-tyrosine, 8-arginine] vasopressin, the corresponding unlabelled peptides and a series of oxytocin antagonists including [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin were constructed from results taken from the myometrium of pregnant women and rabbits, and were analysed simultaneously using the computer program LIGAND. The biological activity of [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin in the human uterus was investigated by studying its effect on oxytocin-induced intracellular Ca2+ mobilization in human myometrial cells in culture that were expressing high concentrations of oxytocin receptors. The results indicate that [Mpa1,D-Tyr(Et)2,Thr4,Orn8]-oxytocin and related antagonists are selective for the oxytocin receptor in the myometrium of pregnant rabbits but not of pregnant women. In women, they bind with high affinity to the V1 vasopressin receptor. In myometrial cells [Mpa1,D-Tyr(Et)2,Thr4,Orn8]- oxytocin inhibits the oxytocin-induced increase in intracellular Ca2+ concentration in a dose-dependent fashion, with an IC50 value of 5 nmol l-1. The uterine relaxant effect of this antagonist might result not only from the block of the oxytocin receptor, but also from interaction with the V1 vasopressin receptor.

Animals↗
PubMed1994

Endothelin in the human uterus during pregnancy.

In this study we report the immunolocalization, binding and biological activity of endothelins in the human uterus. Since, in previous studies in the rabbit, sex steroids greatly affected uterine endothelin-1 (ET-1) immunolocalization and binding, we sought to compare results obtained in a relatively steroid-deprived uterus (postmenopausal women) with those obtained in late pregnancy. Two classes of ET receptors were identified in human pregnant and non-pregnant myometrium. One site (ETB) was a low capacity site (0.3 pM/mg protein) that bound with high affinity (0.1 nM), yet no selectivity, ET-1, ET-2, ET-3, sarafotoxin (SRTX) and vasoactive intestinal contractor (VIC). The second site (ETA) was six fold more concentrated than the former (1.9 pM/mg protein) and was relatively selective for ET-1, ET-2 and VIC but showed lower affinity for ET-3 and SRTX. Studies with human myometrial cells indicated that the ETA receptor mediates an increase in intracellular calcium, while the physiological function of the ETB receptor is still unclear. Homologous competition curves for ET-1 were used in order to study the ET receptor density (ETA+ETB) in individual myometrial samples. We found that the concentration of ET receptors did not change during different stages of labour or in postmenopausal women. We identified cells with intense positivity for ET-1 in human decidua. Similar cells were also present in pregnant myometrium, intimately associated with smooth muscle cells. Conversely, no staining for ET-1 was observed in non-pregnant myometrium. A paracrine role for ET-1 in the human uterus is suggested.

Adult↗
PubMed1993

Effects of endothelin-1 on bovine parathyroid cells.

Endothelin-1 (ET-1) is synthesized and released by parathyroid epithelium. The effects of endothelin isopeptides were studied in clonal bovine parathyroid endothelial (BPE) cells. BPE cells did not produce ET-1, but showed ETA receptors (Kd = 0.1 +/- 0.02 nM, mean +/- SE). ET-1 (10(-8)10(-11)M) increased the intracellular calcium ion concentration ([Ca2+]i) in BPE cells, while endothelin-3 (ET-3) was ineffective. The increase in [Ca2+]i was less sustained in the absence of extracellular Ca2+ ions. Moreover ET-1 induced phospholipase C (PLC) activation, as demonstrated by the increase in inositol trisphosphate. Cell growth was not affected by ET-1 in a wide range of concentrations. The present findings demonstrate: 1) BPE cells possess ETA receptors; 2) the peptide activates PLC and increases cytosolic [Ca2+]i via both a release of Ca2+ ions from intracellular calcium pool(s) and an influx of the cation from the extracellular milieu. A possible role of ET-1 as a paracrine factor in parathyroid tissue can be hypothesized.

Animals↗
PubMed1993

Endothelin-1: a new autocrine/paracrine factor in rat testis.

Cultured Sertoli cells of 20-day-old rats were found to produce and release endothelin-1-like immunoreactivity (ET-1-LI) under follicle-stimulating hormone control. The elution profile of ET-1-LI from extracts of spent Sertoli cell culture medium corresponds to that of synthetic ET-1, suggesting a testicular production of authentic ET-1. In contrast, the conditioned medium from rat Leydig cells did not contain ET-1-LI. Immunohistochemical studies confirmed that, in 20-day-old rats, the positive staining was confined to some Sertoli cells, whereas interstitial cells were negative. In the adult rat testis the positivity was not limited to the tubular compartment (Sertoli cells) but was also present in the interstitium. A high concentration (13 pmol/mg protein) of high-affinity (dissociation constant = 0.6 nM) 125I-labeled ET-1 binding sites was present in Leydig cells. These sites bind ET-1 and ET-2 with 1,000-fold higher affinity than ET-3, suggesting that they correspond to the subtype ETA of the ET receptors. Specific 125I-ET-1 binding sites are present also in Sertoli cells but are 50-fold less concentrated than in Leydig cells. Our results suggest an autocrine/paracrine role for ET-1 in rat testis.

Animals↗
PubMed1992

Suramin inhibits the growth of human rhabdomyosarcoma by interrupting the insulin-like growth factor II autocrine growth loop.

Suramin is a polysulfonated naphthyl-urea with antineoplastic activity that binds various peptide growth factors. Since we previously demonstrated that insulin-like growth factor II (IGF-II) is an autocrine growth factor in human rhabdomyosarcoma (RMS), we studied the effect of suramin on the growth of human RMS cells. Suramin caused a dose-dependent decrease of RMS cell number grown either in 10% fetal bovine serum or in serum-free medium (half-maximal effective dose in mitogenic assays, 1.6 x 10(-4) and 9 x 10(-5) M, respectively). IGF-II and IGF-I added to RMS cells in the presence of suramin reversed the suramin-induced inhibition of cell growth. Since IGF-II exerts its mitogenic effects on RMS cells by binding to the type I receptor, we performed radioreceptor assays using 125I-IGF-I and found that suramin displaced 125I-IGF-I from the type I IGF receptor. There was an excellent correlation between the doses of suramin effective in inhibiting the growth of RMS cells and those that displaced the binding of IGF-I. Our data indicate that suramin exerts its effect on RMS cell growth by interfering with the binding of IGF-II to the type I IGF receptor, thereby interrupting the IGF-II autocrine growth in these cells. Disrupting autonomous growth of RMS may be a promising novel therapeutic approach.

Antineoplastic Agents↗
PubMed1992

Frequency of prolactin pulsatile release in normal men and in agonadal patients is neither coupled to LH release nor influenced by androgen modulation.

OBJECTIVE: We wished to examine and characterize the prolactin pulsatile secretory pattern in both normal and agonadal males in order to assess whether there was any concordance with LH secretion. DESIGN: Patients were sampled every 5 minutes for 12 hours. PATIENTS: We studied five normal and four agonadal men, the latter group before and on testosterone enanthate (TE) (200 mg i.m. every 15 days) treatment. MEASUREMENTS: Prolactin and luteinizing hormone plasma levels were determined using commercial RIA systems. Pulse detection was performed using the DETECT program and the degree of concordance between luteinizing hormone and prolactin was established computing the specific concordance index. RESULTS: We demonstrated the presence of a frequent PRL secretory pattern in normal men (22.8 +/- 1.8 peaks/12h; mean +/- SEM) and in agonadal patients, both in basal conditions and during testosterone treatment (20.5 +/- 2.8 and 18 +/- 1.6 peaks/12h, respectively). The testosterone treatment in agonadal men significantly reduced luteinizing hormone pulse frequency (baseline: 27.5 +/- 2, testosterone administration: 18 +/- 1.3 peaks/12h, P < 0.01) but did not affect pulsatile prolactin release. Using a 10 and 15 minute sampling protocol, we observed that prolactin pulse frequency significantly decreased (P < 0.01) and was similar to the frequencies estimated in previous reports. When luteinizing hormone and prolactin time series were studied to evaluate the possible presence of a specific concordance (SC) between the secretory events of the two hormones, no significant degree of concomitancy was observed neither using the specific concordance index or the cross-correlation analysis. CONCLUSIONS: This report demonstrates (a) the presence of frequent pulsatile release of prolactin in both controls and agonadal patients (baseline and on testosterone enanthate), (b) the use of an appropriate sampling interval (5 minutes) to unmask the prolactin pulsatile release, (c) that in men, luteinizing hormone secretory events are not temporally linked to prolactin secretion, and (d) that androgens, even if reducing luteinizing hormone pulse frequency in agonadal patients, do not significantly affect prolactin pulsatile secretion, suggesting that testosterone and its metabolites do not affect lactotroph activity.

Adult↗
PubMed1992

Endothelin in rabbit uterus during pregnancy.

Specific immunostaining for endothelin-1 (ET-1) was observed in the uterine mucosa of pregnant and nonpregnant rabbits. During gestation, giant cells immunopositive for ET-1 were identified in either endometrium or myometrium. In the latter, they were located in close proximity to the muscular fibers. High-affinity (dissociation constant = 0.25 nM) high-capacity [maximal binding (Bmax) = 7 pmol/mg protein] receptors for ET-1 were present in myometrial membranes of estrous rabbits. During pregnancy the concentration of ET-1 receptors progressively decreased (Bmax on day 29 = 4 pmol/mg protein), rising again at the time of spontaneous delivery. Conversely, ET-1 receptors in the aorta did not change during pregnancy and parturition. The presence of giant cells immunopositive for ET-1 in close proximity to the myometrial cells, together with the evidence of an increase in ET-1 receptors in myometrium of parturient rabbits, suggests a paracrine role for endometrial ET-1 during delivery. Because we previously demonstrated that oxytocin releases ET-1 from endometrial cells in primary culture and that endometrial and myometrial oxytocin receptors abruptly rise at the time of parturition, we propose that ET-1 might participate in the complex cell-to-cell interactions that occur during labor.

Animals↗
PubMed1992

Sex steroid modulation of neurohypophysial hormone receptors in human nonpregnant myometrium.

Neurohypophysial hormone receptors were studied in myometrial specimens obtained from nonpregnant women using binding and in vitro contractility studies. The mathematical modeling of self- and cross-competition curves among [3H]oxytocin (OT), [3H]arginine vasopressin, the V1 vasopressin (VP) antagonist [3H]d(CH2)5TyrMeAVP, the corresponding unlabeled peptides, and the OT agonist [Thr4, Gly7] OT strongly indicates the presence of multiple classes of OT and arginine vasopressin receptors. The latter show the same pharmacological characteristics as the neurohypophysial hormone receptors described by our group for the human pregnant myometrium; in addition, they regulate the contractility of uterine strips. Blocking experiments were performed to evaluate the relative OT and V1 VP receptor distribution in 30 uterine specimens obtained from normal cycling and postmenopausal women. The glucuronoconjugate metabolites of 17 beta-estradiol and progesterone were also measured in 16 patients in early morning urine samples taken the same day as surgery. Our results show that V1 VP receptors are not only present but also biologically active in all the uterine specimens studied with virtually equal density in normal cycling and postmenopausal women. However, their concentrations do not correlate with either estrogen or progesterone urinary levels. The lowest OT receptor density was found at mid-cycle and in menopause, independently of any correlation with the urinary estrogens. Conversely, OT receptors rise sharply in the late luteal phase and during menstruation. In addition they show a positive relationship with glucuronoconjugate metabolites of progesterone levels. These results indicate that progesterone does not inhibit the expression of uterine OT receptors in the human uterus. Furthermore, they imply that neurohypophysial hormones are involved in the control of uterine activity during the menstrual cycle.

Adult↗
PubMed1991

Natriuretic peptide receptors regulate endothelin synthesis and release from parathyroid cells.

Cloned rat parathyroid cells (PTr cell line) that produce parathyroid hormone-related peptide plus endothelin 1 and primary cultures of human parathyroid cells were tested for growth and differentiation responses to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). High- and low-affinity binding sites for ANP were found on PTr cells; BNP appeared to bind to the same receptors with similar affinities. Either ANP or BNP stimulated production of cGMP and caused a 30% decrease in Na(+)-K(+)-Cl- cotransport. Each peptide increased synthesis and secretion of endothelin 1 by PTr cells in a dose-dependent fashion, but cell growth was not affected. Human parathyroid cells (normal and pathological) also responded to ANP or BNP with an increase in cGMP production. The finding of receptors for natriuretic hormones on parathyroid cells with consequent effects on release of endothelin 1 might be of relevance in understanding the clinical association between hyperparathyroidism and hypertension.

Animals↗
PubMed1991

Endothelin as an autocrine factor in the regulation of parathyroid cells.

Endothelin, originally purified from porcine aortic endothelial cells, is widely distributed in tissues and is recognized as a product of epithelial cells, glial cells, and neurons in addition to endothelial cells. We found evidence by mRNA content and immunoreactivity that this peptide is synthesized in rat parathyroid epithelial cells (PT-r cells) and bovine parathyroid chief cells. The peptide synthesized by PT-r cells comigrated with synthetic endothelin 1 in reverse-phase HPLC and was diluted out in radioimmunoassay in parallel with the synthetic peptide. Bovine parathyroid endothelial cells (BPE-1 cells) did not express this peptide. Preproendothelin 1 mRNA expression by PT-r cells and endothelin 1 peptide production were regulated by calcium. Shifts in extracellular calcium either from high to low concentrations or vice versa elicited similar evanescent increases in expression of mRNA with a peak at 1 h. Synthesis of the peptide seems to be controlled by mRNA expression, and peptide in the medium appears to be continuously degraded or taken up by cells because its concentration in the medium showed a time course similar to that of mRNA expression. PT-r cells also bear a single class of receptors highly specific for endothelin 1, suggesting an autocrine regulation by endothelin 1 of the parathyroid. The facile regulation of endothelin concentrations in the medium by shifts in extracellular calcium concentration and possible autocrine regulation by endothelin 1 suggest that this peptide may mediate, at least in part, effects of calcium on the parathyroid system.

Animals↗
PubMed1991

Steroid modulation of oxytocin/vasopressin receptors in the uterus.

Oxytocin (OT) and V1 vasopressin (VP) receptors are present simultaneously in several tissues, including the uterus. In myometrium these receptors mediate contractility, while in endometrium they mediate the release of other uterotonic substances as endothelin (ET). In rabbit myometrium, estrogens increase, while progesterone blunts neurohypophysial hormone receptors. However, the action of sex steroids on OT and V1 VP receptors differs in terms of the ED50 and maximal effect. Therefore, at parturition, only OT receptors show a dramatic rise, while V1 VP receptors do not change, suggesting a major role for OT in labor. ET is a potent stimulator of uterine activity acting through specific receptors present on myometrial cells. These receptors as well as the endometrial localization of ET are modulated by sex steroids, indicating that ET might represent a paracrine regulator of uterine activity. In humans, OT but not V1 VP receptors increase as pregnancy progresses, confirming the primary relevance of OT in timing delivery.

Animals↗
PubMed1991

Immunolocalization, binding, and biological activity of endothelin in rabbit uterus: effect of ovarian steroids.

Specific immunostaining for endothelin 1 (ET-1) was observed in the endometrium but not myometrium of rabbits. The staining was dramatically affected by subacute treatment with ovarian steroids: epithelial cells were predominantly positive in immature rabbits, whereas, in sex steroid-primed rabbits, ET-1 was mainly localized in the stromal compartment. Binding studies were performed in myometrium of estrogen-treated rabbits using labeled ET-1 and ET-3, the corresponding unlabeled peptides, and sarafotoxin b (SRTX). Mathematical modeling of experimental results indicates that two populations of sites are present in myometrium. One site (R1 = 1 pmol/mg protein) shows approximately the same affinity for ET-1, ET-3, and SRTX [dissociation constant (Kd) 100 pM], whereas the second site (R2 = 10 pmol/mg protein) selectively binds ET-1 (Kd 400 pM). According to binding studies, ET-1 was more potent than SRTX in stimulating uterine contraction "in vitro." The subacute administration of increasing concentrations of 17 beta-estradiol (0.2-200 micrograms/kg for 4 days), but not 17 beta-estradiol (200 micrograms/kg for 4 days) plus progesterone (5 mg/kg for 4 days), stimulates a dose-dependent increase in endothelin receptors in myometrium (half-maximal effective dose = 0.7 micrograms/kg for 4 days). However, estrogen treatment does not affect the concentration of endothelin receptors in myometrial cells in primary culture. Conversely, divalent ions like calcium and magnesium enhance the binding of ET-1 to both uterine membranes and cells. Our results indicate that in rabbit uterus endothelin is present in the endometrium, whereas specific receptors are located in myometrium.

Animals↗
PubMed1991

Oxytocin and V1 vasopressin receptors in rabbit endometrium during pregnancy.

Neurohypophysial hormone receptors were identified and characterized in rabbit endometrium and decidua by radioligand binding methods. The results strongly support the presence of a heterogeneity of sites in the decidua of parturient rabbits. The oxytocin site (R1) binds oxytocin and oxytocin analogues ([Thr4, Gly7]oxytocin and OTA) with high affinity, whereas the AVP site (R2) was selective for the V1 AVP analogues, [Phe2, Orn8]VT and d(CH2)5TyrMeAVP. The concentration of oxytocin receptors was low (50-100 fmol/mg protein) at oestrus (Day 0) and on Day 29 of pregnancy, but increased significantly (about 8-fold, P less than 0.05) during parturition. Conversely, V1 AVP receptors were more concentrated than the oxytocin sites at the end of pregnancy (150 fmol/mg protein) but did not change during parturition. These results indicate that neurohypophysial hormones have specific receptors not only in the myometrium but also in the uterine mucosa and we suggest that these receptors may participate in the regulation of uterine activity during pregnancy.

Animals↗