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At least 19 recordsLinked to original sources
PubMed1992

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.

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 micrograms/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 micrograms/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 micrograms/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 beta-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.

Albuterol↗
PubMed1975

Development of a radioimmunoassay for porcine relaxin using 125I-labeled polytyrosyl-relaxin.

Tyrosine was incorporated into highly purified porcine relaxin employing the reagent N-carboxy-L-tyrosine anhydride. The resulting polytyrosyl-relaxin contained 1.67 mol of tyrosine per mol of relaxin, retained its original biological activity, and was readily radioiodinated to specific activities ranging from 80 to 100 muCi per mug. High affinity antibodies applicable in final dilutions ranging from 1:50,000 to 1:200,000 were developed in rabbits against unconjugated highly purified porcine relaxin. A double antibody radioimmunoassay for porcine relaxin sufficiently sensitive to routinely measure from 32 to 1000 pg of pig relaxin was developed. Using this radioimmunoassay, peripheral serum concentrations of porcine relaxin were found to be less than 1 ng/ml during early pregnancy. Serum concentrations of porcine relaxin were high during late pregnancy. The mean concentration of porcine relaxin one day before parturition was 38 ng per ml. Within a day following parturition relaxin concentrations fell to a mean concentration of 2.1 ng per ml.

Animals↗
PubMed1976

Radioimmunoassay (RIA) of relaxin in sera of various species using an antiserum to porcine relaxin.

We have investigated the application of a RIA for porcine relaxin to the assay of relaxinlike substances in the blood of various other mammalian species. The cross-reactivity between antiporcine relaxin antibody and the relaxinlike substances in the blood of other mammals during pregnancy was sufficiently high to permit the assay of 0.1-0.5 ml of serum or plasma samples. Nonspecific reactivity was controlled by adding similar volumes of serum or plasma obtained from ovariectomized female or intact male subjects to RIA tubes containing known porcine standards. RIA relaxin levels rose markedly during the last third of pregnancy in rats, mice, and guinea pigs. RIA relaxin was also found in late pregnancy in dog, rhesus and java monkeys, and human beings. The apparent blood levels of hormone found in each species will depend upon their degree of cross-reactivity with the antiporcine relaxin antibody as well as upon their actual concentration. Thus, absolute blood level values should not be taken literally. However, the fluctuations in RIA relaxin observed during the course of gestation in any given species would appear to reflect accurately the relative blood concentrations of the hormone.

Animals↗
PubMed1978

Target tissues for relaxin identified in vitro with 125I-labelled porcine relaxin.

Various tissues from the mouse, rat and guinea-pig were used to examine the binding of a biologically active, esterified and 125I-labelled porcine relaxin. Binding to mouse symphysial homogenates was time- and temperature-dependent. Other peptide hormones did not complete with relaxin for binding. Mouse uterine tissue displayed similar binding characteristics. Fractionated mammary tissue from 15- and 20-day-pregnant rats exhibited significant relaxin binding activity, as did homogenates of the guinea-pig public symphysis and cervix. Under the conditions used, no relaxin receptors were noted in the liver, spleen or heart from any of the species investigated.

Animals↗
PubMed1977

Production of antisera against electrophoretically separated relaxin and immunofluorescent localization of relaxin in the porcine corpus luteum.

Antisera to porcine relaxin were produced in rabbits injected with different fractions that had been separated by polyacrylamide gel electrophoresis (PAGE). Analyses by agar double immunodiffusion demonstrated that the different fractions of relaxin separated by PAGE have similar antigenic sites and the individual fractions are indistinguishable from one another by this procedure. Antiserum to porcine relaxin inhibited the interpubic ligament forming ability of the hormone in vivo. Indrict fluorescent antibody studies demonstrated that the hormone was localized only in the corpus luteum of the pregnant sow ovary. Large ovoid or polyhedral cells, assumed to be granulosa lutein cells, exhibited the heaviest fluorescence.

Animals↗
PubMed1992

Purification and sequence determination of canine relaxin.

Relaxin immunological activity has been observed in the plasma of pregnant bitches, and preliminary studies in our laboratory indicated that the highest relaxin concentrations were found in placentas. Therefore, canine placentas were collected at term and also from spay and relaxin was purified by methods developed for equine relaxin. Tissue was prepared by homogenization and purification on a C18 column. The preparation was further purified by stepwise elution ion-exchange chromatography, gel filtration, and gradient elution ion-exchange chromatography. One predominant peak in relaxin immunoactivity was collected. Canine relaxin was found to be larger than either porcine or equine relaxin as determined by SDS-PAGE. It migrated faster under reducing conditions, indicating a subunit structure. Purified canine relaxin was used for tracer and standard in a canine radioimmunoassay (RIA) using an antiporcine relaxin antibody. Concentrations of relaxin immunoactivity using the canine assay were up to 300-fold higher in placental preparations than those measured in the porcine relaxin assay. Sequence analysis of canine relaxin revealed a structure similar to other relaxins in the presence and placement of cystine residues.

Amino Acid Sequence↗
PubMed1992

Relaxin binding in the rat heart atrium.

Relaxin is a member of the insulin family of polypeptides that is best known as a reproductive hormone. In an effort to elucidate the mechanism of action of relaxin we previously localized the specific binding sites of a 32P-labeled relaxin in the rat uterus and brain. These studies suggested that, in addition to its classical role in pregnancy, relaxin might have other physiological functions. In the present paper we describe the specific and high-affinity binding of relaxin to the cardiac atrium of both male and female rats. The relaxin binding could not be displaced by peptides belonging to the same family [insulin, insulin-like growth factor I (IGF-I)] or by peptides that were identified in the atrium or were known to have cardiovascular functions (atrial natriuretic peptide, angiotensin II). The dissociation constant for relaxin in the atrium was estimated to be 1.4 nM, which was similar to that found in the uterus (1.3 nM) and the brain (1.4 nM). In view of the close association of relaxin with reproduction, an experiment was also performed to compare the relaxin binding in the uterus and heart after gonadectomy and sex steroid treatment. It was found that the relaxin binding in the rat uterus was diminished by 53% overall following ovariectomy but was restored to 90% of normal levels when treated with estrogen (but not with testosterone). In contrast, the relaxin binding in the rat heart was not affected by castration or sex steroid treatment. We conclude that specific and high-affinity relaxin receptors exist in the atrium of both the male and female rat heart and that these are regulated differently than the relaxin receptors in the uterus.

Amino Acid Sequence↗
PubMed1979

In vitro analysis of antisera to relaxin.

This article describes the development of an in vitro assay to quantitate the ability of antisera to inhibit the biological action of the pregnancy hormone, relaxin. The procedure employed a modification of the in vitro assay for the ability of relaxin to inhibit spontaneous uterine contractions as initially described by Kroc et al. (1959). Several antisera were tested that showed inhibition of relaxin activity. Tests of cross-reactivity demonstrated that antiserum produced against porcine relaxin effectively inhibited the activity in relaxin preparations from cows and rabbits but was much less effective in inhibiting the activity in rat relaxin preparations. Agar double-immunodiffusion studies supported the cross-reactivity studies in that cow and rabbit relaxin preparations gave reactions of identity with the porcine relaxin while the rat relaxin preparation did not produce a precipitin line with the anti-porcine relaxin antiserum.

Animals↗
PubMed1979

Specificity of radioimmunoassays for relaxin.

The specificities of two radioimmunoassays (RIA) for relaxin, based upon crude porcine relaxin (NIH-R-P1; RIA I) and a highly purified porcine relaxin (RIA II) have been studied concurrently using purified hormones and plasma samples. A labelled fraction, selected from radio-iodinated NIH-R-P1 and used in that RIA, was also bound to antiserum raised to the highly purified relaxin. Hence a third RIA was possible in which both the crude and the purified relaxins inhibited in the ng/ml range. Porcine insulin and the connecting peptide of porcine proinsulin did not inhibit any of the assay systems whereas porcine proinsulin did inhibit in each assay at the microgram/ml range. Concurrent measurements by assays I and II have been made in sheep plasma obtained during both delivery of the lamb and suckling. The peak values obtained by assays I and II are 3 and 6 min out of phase during suckling and delivery respectively; the NIH-R-P1 relaxin immunoactivity appearing first. The plasma inhibition curves of both appear to be the sum of individual contributions from relaxin and relaxin-like peptides, such as prorelaxin and its fragments, as seen by different antisera. Both assays, however, give qualitatively similar indices of relaxin immunoactivity. The RIA developed for the more purified peptide would be expected to yield a better quantitative estimate of relaxin secretion but this, like specificity, cannot be shown absolutely.

Animals↗
PubMed1992

Monoclonal antibodies specific for rat relaxin. VII. Passive immunization with monoclonal antibodies throughout the second half of pregnancy prevents development of normal mammary nipple morphology and function in rats.

We recently demonstrated that relaxin-dependent development of the mammary nipples during the second half of pregnancy is required for pup survival during lactation in the rat. The two related objectives of this investigation were to 1) characterize the effects of endogenous relaxin on the histological modifications that normally occur in the mammary nipples, and 2) test the hypothesis that the cause of lactational failure in relaxin-deficient rats is attributable to failure of the nipples to grow and develop during the second half of pregnancy. Endogenous relaxin was neutralized by daily iv injection of a highly purified monoclonal antibody specific for rat relaxin (MCA1) to intact rats from days 12-22 of pregnancy. Mammary nipples were collected on day 22 of pregnancy and routinely prepared for light microscopy. Tissue cross-sections (6 microns) obtained from the midpoint of mammary nipples were stained with either Gomori's trichrome stain (to visualize collagen) or orcein (to visualize elastin). Nipple size as well as histological characteristics of nipple cross sections were determined by morphometric analysis. MCA1-treated rats were significantly different from controls with the following parameters: shorter length of the nipples; smaller cross-sectional areas of the entire nipple, lactiferous duct lumen, and blood vessels; greater percentage of the analysis field composed of collagen; lower percentage of the analysis field composed of amorphous ground substance; and longer elastin fibers. To test the hypothesis that the cause of lactational failure in relaxin-deficient rats is attributable to the failure of nipples to grow and develop, MCA1 and control rats were cesarean sectioned between 2100-2400 h on day 22 of pregnancy, and lactation was examined using normal foster pups from intact donor females. Unlike pups fostered to controls, pups fostered to MCA1-treated dams failed to grasp the nipples, stimulate PRL release, or have milk in their abdomens. This study demonstrates that endogenous relaxin promotes not only growth, but also modifications of the histological characteristics of the nipple that are consistent with relaxin's effects on the cervix and mammary glands. Additionally, this study provides evidence that lactational failure in relaxin-deficient rats is attributable to the small size and different histology of the mammary nipples, which results in the inability of the pups to attach to the nipple, stimulate PRL release, and obtain milk from the dams.

Animals↗
PubMed1992

Synergistic effects of insulin-like growth factor I and gonadotrophins on relaxin and progesterone secretion by ageing corpora lutea of pigs.

Insulin-like growth factor I (IGF-I) is involved in paracrine/autocrine regulation of gonadal steroidogenesis and peptide hormone biosynthesis. This study was designed to determine whether IGF-I alone, or an interaction of IGF-I, is involved in augmenting the actions of luteinizing hormone (LH) and prolactin in controlling relaxin and progesterone secretion from ageing corpora lutea of hysterectomized gilts at days 110, 113 and 116 after oestrus. Luteal tissue slices were incubated for 8 h with IGF-I (0, 50, 300 ng ml-1), LH (0, 100, 1000 ng ml-1), and prolactin (0, 100, 1000 ng ml-1) alone or in combination. Progesterone and relaxin concentrations were determined by radioimmunoassay of spent medium and of homogenates from luteal tissue slices before and after incubation. Porcine luteal tissue from day 110 had a net output of 25 ng progesterone and 26 ng relaxin in the control and of 65 ng progesterone and 2125 ng relaxin in the combined IGF-I, LH and prolactin treatment mg-1 of luteal tissue, respectively. IGF-I, LH and prolactin alone or in combination significantly increased (P < 0.01) progesterone production by luteal tissue from day 110, but they were partially effective at day 113 and ineffective at day 116. By contrast, the same hormone treatments increased relaxin production by luteal tissue from days 110 and 113. Even at day 116, prolactin alone or with LH or IGF-I continued to stimulate relaxin production. In conclusion, IGF-I augments the ability of prolactin and LH to increase relaxin production by ageing corpora lutea; however, a decrease in progesterone secretion and an increase in relaxin secretion at day 113 indicate that different mechanisms control progesterone and relaxin secretion in pigs.

Animals↗
PubMed1992

Transforming growth factor-beta is a potent inhibitor of basal and stimulated relaxin release by porcine luteal cells maintained in monolayer culture.

The effect of transforming growth factor-beta (TGF-beta) on relaxin release by porcine large luteal cells (LLC) was examined by use of a reverse haemolytic plaque assay. In this assay, mixed luteal cells were co-cultured in monolayers with protein A-coupled sheep erythrocytes. In the presence of complement and porcine relaxin antiserum, a zone of haemolysis (a plaque) developed around relaxin-releasing LLCs. The rate of plaque development in time-course experiments and the average size of plaque areas were used to monitor the rate of relaxin release and cumulative amounts of hormone respectively. Monolayers were bathed in medium containing TGF-beta alone, or in the co-presence of a stimulatory secretagogue (prostaglandin E2; PGE2). Exposure of luteal cell-containing monolayers to TGF-beta (1 ng/1-100 micrograms/1) elicited a dose-related inhibition in the rate of basal relaxin release. Minimal and maximal concentrations were approximately 10 ng/1 and 10 micrograms/1 respectively. Treatment with 1 microgram TGF-beta/1 reduced the cumulative amount of relaxin released to 63 +/- 6% of control values (mean +/- S.D., P < 0.05, n = 6; averaged over the whole course of the experimental incubation). Exposure of monolayers treated with TGF-beta to the relaxin-stimulatory secretagogue PGE2 (0.1 mumol) resulted in a significant (P < 0.05) increase in the amount of relaxin released by TGF-beta-suppressed LLCs, and restored rates of hormone release to control levels. This is evidence that TGF-beta and PGE2 interact antagonistically in the modulation of relaxin. The effect of TGF-beta was strictly time-dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Relaxin alone and in conjunction with interferon-gamma decreases collagen synthesis by cultured human scleroderma fibroblasts.

Fibroblasts derived from the involved skin of scleroderma patients frequently display a phenotype of supernormal collagen expression when cultured. Fibroblasts displaying this phenotype derived from seven patients were treated with relaxin (1-100 ng/ml) and interferon-gamma (1-100 U/ml), individually and in combination, to assess the relative abilities of these cytokines to down-modulate collagen synthesis and secretion. Scleroderma fibroblasts displayed varying sensitivities to both relaxin and interferon-gamma. Relaxin (100 ng/ml) decreased expression of collagen by six of seven lines tested from 8 to 59% compared to untreated cultures. Interferon-gamma (100 U/ml) depressed collagen secretion by all seven lines in a range from 7 to 89%. When relaxin and interferon-gamma were used in combination, relaxin augmented IFN-gamma-induced decreases in collagen secretion in four of seven lines. In three of these lines, the use of relaxin in conjunction with suboptimal doses of interferon-gamma resulted in decreases equivalent to or greater than that seen with a tenfold higher concentration of interferon-gamma. This study demonstrates the ability of relaxin to directly alter the excessive collagen-producing phenotype of scleroderma fibroblasts. In addition, in some cases, combining relaxin and interferon-gamma resulted in a cooperative effect in decreasing collagen expression by scleroderma cells in vitro.

Cells, Cultured↗
PubMed1979

Development of a homologous radioimmunoassay for rat relaxin.

Highly purified rat relaxin has been radioiodinated to specific activities of approximately 100 micro Ci/microgram with the Bolton and Hunter reagent [N-succinimidyl 3-(4-hydroxy-5-[125I]iodophenyl) propionate]. A rabbit antirat relaxin serum, applicable in a final dilution of 1:100,000, was developed in a rabbit using unconjugated highly purified rat relaxin. A specific and precise double antibody RIA for rat relaxin sufficiently sensitive to routinely measure from 32--2000 pg rat relaxin was developed. Using this RIA, relaxin immunoactivity levels in extracts of pregnant rat ovaries were found to rise from 0.8 microgram/geq ovarian fresh tissue on day 8 of pregnancy to 723 microgram/geq ovarian fresh tissue on day 20 of pregnancy and then to drop precipitously to 6 microgram/geq ovarian fresh tissue on day 1 of lactation. Consistent with the occurrence and relative levels of relaxin in the ovarian extracts, levels of relaxin in pregnant rat serum were less than 2 ng/ml on day 10 of pregnancy, approximately 150 ng/ml on days 20 and 22 of pregnancy, and 12 ng/ml on day 2 of lactation.

Animals↗
PubMed1992

Evidence for immunoreactive relaxin in boar seminal vesicles using combined light and electron microscope immunocytochemistry.

Light-microscope immunocytochemistry using the peroxidase-antiperoxidase technique and a polyclonal rabbit antiserum raised against purified porcine relaxin showed that cytoplasmic immunostaining for relaxin could be visualized in the epithelial cells of the seminal vesicle. No relaxin immunoreactivity was seen in the testis, epididymis, ductus deferens, prostate or bulbo-urethral gland. A ten times higher concentration of porcine relaxin antiserum was necessary to achieve immunostaining in the seminal vesicle comparable to that in the corpora lutea of pregnant sows. Ultrastructural examination showed that the epithelial cells of the boar seminal vesicle resembled typical protein-secreting cells with prominent rough endoplasmic reticulum and well-developed Golgi apparatus. The most striking feature of these cells was the accumulation of granules with a limiting membrane, which ranged from 200 to 600 nm in diameter and contained flocculent material of moderate electron density. Electron-microscope immunocytochemistry using the protein A-gold technique and relaxin antiserum demonstrated that the granules were the only intracellular organelles that showed immunoreactivity for relaxin. These results indicate that a relaxin-like substance is present in boar seminal vesicles and that the subcellular site of its localization is the granules, suggesting that the seminal vesicle produces and stores a relaxin-like substance, but that it is present at much lower concentrations than in the corpora lutea of pregnant sows.

Animals↗
PubMed1992

Interaction between myometrial relaxants and oxytocin: a comparison between relaxin, cromakalim and salbutamol.

The influence of treatment with oestradiol on the effects of the uterine relaxants, relaxin, salbutamol (an agonist at beta 2-adrenoceptors) and cromakalim (a potassium channel opener) and their interactions with the uterine stimulant oxytocin were investigated in vivo in the ovariectomized rat. Oestradiol benzoate (0.4 micrograms/kg per day) significantly increased sensitivity to cromakalim as an inhibitor of spontaneous uterine contractions compared with vehicle-treated rats by approximately threefold. The same dose of oestradiol benzoate had no effect on uterine sensitivity to salbutamol. Previous studies have shown that this dose of oestradiol benzoate produces a twofold increase in uterine sensitivity to relaxin as an inhibitor of spontaneous contractions. Oestradiol influenced the ability of relaxin to inhibit oxytocin-stimulated uterine contractions. In corn oil-treated rats, uterine responses to relaxin were markedly reduced during oxytocin infusion compared with responses to relaxin before oxytocin; the maximum obtainable response to relaxin was less than 50% inhibition. In oestradiol-treated rats, uterine sensitivity to relaxin during oxytocin infusion was similar to that observed against spontaneous contractions. Cromakalim was able to inhibit uterine contractions during oxytocin infusion in both corn oil- and oestradiol-treated rats, uterine sensitivity to cromakalim being similar in the absence and presence of oxytocin for both hormone treatment groups. Salbutamol was also able to inhibit uterine contractions during oxytocin infusion in both corn oil- and oestradiol-treated rats. Oestradiol treatment increased the potency of salbutamol as an inhibitor of oxytocin-stimulated uterine contractions compared with corn oil treatment by 3.5-fold. The interaction of oestradiol and relaxin during late pregnancy may be important for attenuation of the myometrial response to stimulants.

Albuterol↗