Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat

2007 ◽  
Vol 293 (1) ◽  
pp. R299-R305 ◽  
Author(s):  
Gerald P. McCafferty ◽  
Mark A. Pullen ◽  
Charlene Wu ◽  
Richard M. Edwards ◽  
Michael J. Allen ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Intravenous Administration ◽  
Plasma Concentrations ◽  
Oxytocin Receptor ◽  
Pregnant Rats ◽  
Uterine Contractions ◽  
Oxytocin Receptors ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Similar Affinity

Spontaneous and induced uterine contractions in the rat were found to be inhibited by a novel and selective oxytocin receptor antagonist GSK221149A (3 R,6 R)-3-Indan-2-yl-1-[(1 R)-1-(2-methyl-1,3-oxazol-4-yl)-2-morpholin-4-yl-2-oxoethyl]-6-[(1 S)-1-methylpropyl]-2,5-piperazinedione. GSK221149A displayed nanomolar affinity ( Ki = 0.65 nM) for human recombinant oxytocin receptors with >1,400-fold selectivity over human V1a, V1b, and V2 receptors. GSK221149A had similar affinity ( Ki = 4.1 nM) and selectivity for native oxytocin receptors from rat and produced a functional, competitive block of oxytocin-induced contractions in isolated rat myometrial strips with a pA2 value of 8.18. Intravenous administration of GSK221149A produced a dose-dependent decrease in oxytocin-induced uterine contractions in anesthetized rats with an ID50 = 0.27 ± 0.60 mg/kg (corresponding plasma concentrations were 88 ng/ml). Oral administration of GSK221149A (5 mg/kg) was effective in inhibiting oxytocin-induced uterine contractions after single and multiple (4-day) dosing. Spontaneous uterine contractions in late-term pregnant rats (19–21 days gestation) were significantly reduced by intravenous administration of 0.3 mg/kg of GSK221149A. These results provide further evidence that selective oxytocin receptor antagonism may offer an effective treatment for preterm labor.

Pregnancy and steroid hormones enhance the vasodilation responses to CGRP in rats

1999 ◽  
Vol 276 (1) ◽  
pp. H284-H288 ◽  
Author(s):  
P. R. R. Gangula ◽  
H. Zhao ◽  
S. Supowit ◽  
S. Wimalawansa ◽  
D. DiPette ◽  
...  
Keyword(s):  
Steroid Hormone ◽  
Sesame Oil ◽  
Pregnant Rats ◽  
Sex Steroid Hormone ◽  
Arterial Blood ◽  
Ovx Rats ◽  
Before And After ◽  
Vascular Sensitivity ◽  
Dose Dependent Decrease ◽  
Dose Dependent

We recently reported that calcitonin gene-related peptide (CGRP) reversed the hypertension induced by nitric oxide inhibition in pregnant rats and that this effect appeared to be progesterone dependent. In the present study, we examined whether the vasodilator responses to CGRP are increased during pregnancy and whether these responses are steroid hormone dependent. Three groups of ovariectomized (Ovx) rats ( n = 4–8 rats/group) were studied 3 days after daily treatment (subcutaneous injection) with progesterone (P; 2 mg/injection, twice daily for 3 days, in 0.2 ml of sesame oil), 17β-estradiol (E; 2.5 μg/injection, twice daily for 3 days, in 0.2 ml of sesame oil), or vehicle (sesame oil). A fourth group ( n = 6 rats) of pregnant rats was studied on day 19of gestation. A fifth group of adult, nonpregnant rats ( n = 6 rats), regardless of stage of estrous cycle, was also used in this study. Mean arterial blood pressure (MAP) was continuously monitored in fully awake and free-moving instrumented rats. MAP was measured before and after administration of either saline or varying bolus doses of CGRP (9–360 pmol/kg body wt). CGRP produced a dose-dependent decrease in MAP in all rats with a significant ( P < 0.05) reduction in MAP beginning with a CGRP dose of 90 pmol/kg and with maximal effects observed at 360 pmol/kg. Decreases in MAP in response to CGRP were significantly ( P < 0.05) greater in pregnant compared with nonpregnant rats. Similarly to pregnant rats, Ovx rats given both E and P treatments produced greater decreases in MAP in response to CGRP at 90, 180, and 360 pmol/kg doses compared with both ovary-intact and Ovx nonpregnant rats, which were not different from each other. In summary, these data show that 1) the hypotensive effects of CGRP are dose dependent and 2) the hypotensive effects of CGRP are enhanced during pregnancy and in Ovx rats treated with either E or P. Therefore, we suggest that the decrease in vascular tone that is seen during pregnancy may be mediated, at least in part, by a sex steroid hormone-induced increase in the vascular sensitivity to the vasodilator effects of CGRP.

Effects of cyclophosphamide treatment before implantation on the development of rat embryos after implantation

Development ◽  
1977 ◽  
Vol 41 (1) ◽  
pp. 65-78
Author(s):  
Horst Spielmann ◽  
Hans-Georg Eibs ◽  
Hans-Joachim Merker
Keyword(s):  
Early Stage ◽  
Subsequent Development ◽  
Cell Number ◽  
Pregnant Rats ◽  
Cyclophosphamide Treatment ◽  
Wet Weight ◽  
Dose Dependent Decrease ◽  
Decidual Reaction ◽  
Dose Dependent

After treatment of pregnant rats 24 h before implantation with a single injection of cyclophosphamide (20–80 mg/kg), a dose-dependent increase in resorption was observed at term but no malformed fetuses could be found. The lowest cyclophosphamide dose that caused 100 % resorption was 60 mg/kg. Somite number and wet weight indicated retardation of about 24 h during organogenesis. Determination of the time of implantation revealed that the developmental retardation in treated embryos was not due to delayed implantation. At implantation, 24 h after cyclophosphamide treatment, a significant and dose-dependent decrease of the cell number of blastocysts was found. Embryo transplantation experiments showed that early cyclophosphamide treatment interfered with the subsequent development of both the embryo and the mother. The decidual reaction seemed to be more affected by the treatment than the embryos. Most teratologists hold that mouse embryos after treatment in the preimplantation period either die before implantation or survive to term without being malformed. The present study, however, proves that the reaction of drugs at this early stage of pregnancy is more complex than is generally assumed.

Influence of ovarian steroids on myometrial sensitivity and tolerance to relaxin in the rat in vivo: lack of cross-tolerance between relaxin, salbutamol and cromakalim

1992 ◽  
Vol 135 (1) ◽  
pp. 17-28 ◽  
Author(s):  
S. J. Downing ◽  
M. Hollingsworth
Keyword(s):  
Dependent Manner ◽  
Cross Tolerance ◽  
Pregnant Rats ◽  
Uterine Contractions ◽  
Adrenoceptor Agonist ◽  
Fold Reduction ◽  
Oestradiol Benzoate ◽  
Relaxin 2 ◽  
Dose Dependent

ABSTRACT The influence of oestradiol benzoate and progesterone on uterine sensitivity and development of tolerance to relaxin was investigated in bilaterally ovariectomized non-pregnant rats in vivo. Bolus doses of relaxin (2–20 μg/kg i.v.) produced rapid and reversible inhibition of uterine contractions in a dose-dependent manner. Treatment with oestradiol benzoate or oestradiol benzoate plus progesterone significantly increased uterine sensitivity to relaxin over 48 h by 2·4- to 8·5-fold. Tolerance to relaxin developed during continuous infusion of the hormone at 20 μg/kg per h for 40 h. A 7·8- to 17·4-fold reduction in sensitivity to relaxin was observed in relaxin-infused rats, whereas no change in sensitivity was observed in saline-infused rats. Infusion of relaxin at 50 μg/kg per h for 40 h produced a 131·8-fold reduction in uterine sensitivity to relaxin. The uterus remained tolerant to relaxin for up to 24 h after cessation of infusion. Treatment with oestradiol benzoate and/or progesterone did not influence the extent of tolerance development, but a more rapid recovery of uterine sensitivity to relaxin was observed in rats treated with oestradiol benzoate plus progesterone. Cross-tolerance with other uterine relaxant drugs was measured to investigate possible common mechanisms of action and sites of tolerance between relaxin and a β-adrenoceptor agonist (salbutamol) and potassium channel openers (cromakalim and minoxidil sulphate). No cross-tolerance was observed between relaxin and salbutamol, or relaxin and cromakalim or minoxidil sulphate. Cross-tolerance between cromakalim and minoxidil sulphate was seen. Journal of Endocrinology (1992) 135, 17–28

scholarly journals Selectivity of d[Cha4 ]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b /oxytocin receptor antagonist

2005 ◽  
Vol 146 (5) ◽  
pp. 744-751 ◽  
Author(s):  
Cristiana Griffante ◽  
Andrew Green ◽  
Ornella Curcuruto ◽  
Carl P Haslam ◽  
Bryony A Dickinson ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Oxytocin Receptor ◽  
Oxytocin Receptors

Norepinephrine effects on fetal cardiovascular and endocrine systems

1988 ◽  
Vol 254 (4) ◽  
pp. H734-H741 ◽  
Author(s):  
C. Y. Cheung ◽  
R. A. Brace
Keyword(s):  
Blood Volume ◽  
Venous Pressure ◽  
Plasma Concentrations ◽  
Plasma Renin ◽  
Fold Increase ◽  
Dependent Manner ◽  
Vasoactive Hormones ◽  
Near Term ◽  
Dose Dependent Decrease ◽  
Dose Dependent

Norepinephrine (NE) was infused intravenously into near-term chronically catheterized sheep fetuses for 30 min. Infusions of 0.39, 1.2, 3.9, 12, and 39 micrograms/min caused a 1- to 300-fold increase in plasma NE concentration. Fetal arterial pressure increased in a dose-dependent manner up to a maximum of 72 +/- 5% above basal levels at 6-7 min and gradually declined thereafter. Venous pressure increased during the four highest infusion rates to a maximum at 6-7 min followed by a return toward normal. Fetal blood volume underwent a rapid dose-dependent decrease by a maximum of 12 +/- 1% during 39-micrograms/min infusions of NE. Heart rate initially decreased by up to 40 beats/min during the 3.9-, 12-, and 39-micrograms/min infusions, returned to normal within 10 min, and increased to 50 beats/min above control by the end of the 30-min infusion. Plasma concentrations of arginine vasopressin, epinephrine, and plasma renin activity did not change during or after the four lowest infusion rates. Thus fetal vascular pressures and blood volume are altered in a dose-dependent manner over a broad range of plasma NE concentrations. In addition, NE does not appear to affect other circulating vasoactive hormones within its physiological range of concentrations.

Effect of IL-1 receptor antagonist and antiserum to TNF-alpha on LPS-induced plasma ACTH and corticosterone rise in rats

1994 ◽  
Vol 266 (6) ◽  
pp. E986-E992 ◽  
Author(s):  
O. Ebisui ◽  
J. Fukata ◽  
N. Murakami ◽  
H. Kobayashi ◽  
H. Segawa ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Intravenous Administration ◽  
Rabbit Antiserum ◽  
Plasma Corticosterone ◽  
Tnf Alpha ◽  
Dependent Manner ◽  
Plasma Acth ◽  
Series Of Experiments ◽  
Dose Dependent ◽  
Necrosis Factor

Using an antiserum against tumor necrosis factor (TNF)-alpha and an interleukin (IL-1) receptor antagonist, we studied putative roles of these cytokines in mediating the endotoxin-induced elevation of plasma adrenocorticotropic hormone (ACTH) and corticosterone levels in freely moving rats. Intravenous administration of Escherichia coli lipopolysaccharide (LPS) increased plasma ACTH and corticosterone levels in a dose-dependent manner. The plasma corticosterone reached to its highest level among a series of experiments after the administration of even the smallest dose (0.03 microgram/kg) tested. Plasma ACTH and corticosterone levels in these rats were completely inhibited by the intravenous administration of anti-murine TNF-alpha-rabbit antiserum (anti-TNFAS) after the administration of LPS but not by the intravenous administration of IL-1 receptor antagonist (IL-1RA). On the other hand, both recombinant human IL-1RA and anti-TNFAS significantly inhibited plasma ACTH increase stimulated with 10 micrograms/kg LPS. These findings indicate that 1) when the plasma corticosterone increase induced by intravenous LPS remains below its maximum, the effect is exclusively mediated by TNF-alpha, and 2) when a larger amount of LPS is administered, both IL-1 beta and TNF-alpha participate at least in part in the hypothalamic-pituitary-adrenal axis activation.

Functional expression of the oxytocin receptor in Xenopus laevis oocytes primed with mRNA from bovine endometrium

1988 ◽  
Vol 1 (1) ◽  
pp. 77-81 ◽  
Author(s):  
S. D. Morley ◽  
W. Meyerhof ◽  
J. Schwarz ◽  
D. Richter
Keyword(s):  
Xenopus Laevis ◽  
Receptor Antagonist ◽  
Voltage Clamp ◽  
Functional Expression ◽  
Oxytocin Receptor ◽  
Xenopus Laevis Oocytes ◽  
Induced Membrane ◽  
Membrane Changes ◽  
Dose Dependent ◽  
Voltage Clamp Method

ABSTRACT Synthesis of the uterine receptor for the hypothalamic hormone oxytocin has been induced in oocytes from Xenopus laevis previously primed with bovine endometrium mRNA. The injected oocytes responded to oxytocin by showing dose-dependent oscillations in membrane currents as recorded by the voltage-clamp method. The response was specific in that it was not elicited by several other peptides tested. The oxytocin-induced membrane changes were suppressed when oocytes were pretreated with an oxytocin receptor antagonist.

scholarly journals Up-regulation of oxytocin receptors in non-pregnant rat myometrium by isoproterenol: effects of steroids

1999 ◽  
Vol 161 (3) ◽  
pp. 403-411 ◽  
Author(s):  
T Engstrom ◽  
P Bratholm ◽  
NJ Christensen ◽  
H Vilhardt
Keyword(s):  
Gene Expression ◽  
Plasma Membranes ◽  
Contractile Response ◽  
Oxytocin Receptor ◽  
Gonadal Steroids ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Oxytocin Receptors ◽  
Important Regulator ◽  
Isoproterenol Infusion

The objective of the present study was to further elucidate our previous observation that beta2-adrenoceptor activation induces oxytocin receptor (OTR) expression in rat myometrium. We wanted to investigate whether the mechanism behind this effect was under the influence of gonadal steroids. Ovariectomized non-pregnant rats were treated with estrogen, progesterone or a combination of both for 3 days. Some rats were concomitantly treated with isoproterenol. Estrogen treatment increased both OTR mRNA production and maximal binding of [3H]-oxytocin to isolated myometrial plasma membranes, but it did not affect contractility of isolated uterine strips challenged with oxytocin. When the estrogen regimen was combined with isoproterenol treatment, an augmented maximal contractile response (Emax) to oxytocin was observed although no further increase in OTR mRNA and binding was seen. Progesterone treatment did not in itself alter OTR mRNA, OTR binding or Emax. However, OTRs were induced at the level of gene expression when progesterone was supplemented with isoproterenol infusion. Finally, progesterone suppressed the effect of estrogen on OTR mRNA production and binding when the two compounds were administered together. However, when isoproterenol treatment was added this effect was abolished and Emax was enhanced more than that seen following treatment with estrogen alone. These data suggest that beta2-adrenoceptor activation represents an important regulator of OTR expression/function in estrogen- and progesterone-dominated rat myometrium.

The Measurement of Heparin and Other Therapeutic Sufphated Polysaccharides in Plasma, Serum and Urine

1985 ◽  
Vol 54 (03) ◽  
pp. 630-634 ◽  
Author(s):  
J Dawes ◽  
C V Prowse ◽  
D D Pepper
Keyword(s):  
Biological Fluids ◽  
Anticoagulant Activity ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Heparin Therapy ◽  
Competitive Binding Assay ◽  
First Order Kinetics ◽  
Activity Measurements ◽  
Heparin Activity ◽  
Dose Dependent

SummaryThe competitive binding assay described will specifically and accurately measure concentrations of administered heparin in biological fluids with a sensitivity of 60 ng ml-1. Neither endogenous glycosaminoglycans, nor plasma proteins such as ATIII and PF4 interfere in the assay. Semi-synthetic highly sulphated heparinoids and LMW heparin can also be measured. Using this assay heparin clearance followed simple first-order kinetics over the dose range 100-5,000 units, but the half-life was strongly dose-dependent. There was good correlation with heparin activity measurements by APTT and anti-Xa clotting assays. Plasma concentrations were measurable for at least 5 h following subcutaneous injection of 10,000 units of heparin. Excretion in the urine could be followed after all but the lowest intravenous dose. This assay, used in conjunction with measurements of heparin anticoagulant activity, will be valuable in the elucidation of mechanisms of action of heparin and the heparinoids, and in the assessment and management of problems related to heparin therapy.

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