Effects of 4-hydroxyandrostenedione and hyperstimulation with pregnant mare serum gonadotrophin on early embryonic development in rats

2001 ◽  
Vol 79 (9) ◽  
pp. 744-753 ◽  
Author(s):  
Terry Y.Y Tong ◽  
Victor H.H Goh
Keyword(s):  
Embryonic Development ◽  
Early Embryonic Development ◽  
Female Rats ◽  
High Dose ◽  
Negative Effects ◽  
Embryo Survival ◽  
High Doses ◽  
Higher Doses ◽  
Pregnant Mare Serum Gonadotrophin

A possible role of high oestradiol levels in mediating the adverse effects of hyperstimulation with pregnant mare serum gonadotrophin (PMSG) on early embryonic development in the rat was investigated using an aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA), to inhibit endogenous oestradiol production. Three experiments were conducted in this study. In the first, varying doses of 4-OHA were administered either concurrently with human chorionic gonadotropin (hCG) to pro-oestrus female rats hyperstimulated at early di-oestrus stage with 20 IU PMSG or alone into nonhyperstimulated pro-oestrus females. At high doses of 1000, 2000, or 5000 µg/rat, 4-OHA substantially improved the survival of embryos in hyperstimulated females, while low doses of 100 and 500 µg/rat were ineffective. The protective effect of 4-OHA on embryo count was optimum at 2000 µg. When administered alone, only the highest dose of 5000 µg/rat 4-OHA increased embryo count. In the second experiment, higher doses of PMSG were studied (30 or 40 IU), with or without 5000 µg/rat 4-OHA given at the time of hCG injection. PMSG proved to be more detrimental with increasing dose, and 5000 µg/rat 4-OHA was able to rescue embryos from death in the 30, but not 40, PMSG group. In the third experiment, the influence of the timing of 4-OHA treatment on its ability to improve the embryo count in hyperstimulated females was examined by introducing 4-OHA 24 h earlier, rather than at the time of hCG treatment. The results showed the importance of timing of 4-OHA administration, as 5000 µg/rat 4-OHA was able to restore embryo survival in the 40 PMSG hyperstimulated group only when it was administered 24 h before hCG injection. Together, these results highlighted that 4-OHA, when administered at the appropriate time and dose, could reverse the negative effects of hyperstimulation from PMSG on early embryonic development. This may be due to its potent aromatase inhibiting properties that lead to the suppression of oestrogen production, thereby alleviating the supraphysiological level of oestradiol, which is typically present in PMSG-treated females. Interestingly, 4-OHA treatment on its own was able to positively influence embryo count when given at a high dose of 5000 µg/rat, and this may be associated with its weak androgenic properties. In conclusion, this study supports the hypothesis that excessive oestradiol is responsible for the negative effects of hyperstimulation with PMSG on early embryonic development.Key words: 4-hydroxyandrostenedione, embryonic development, PMSG, rat.

Arachidonic acid mediates dual effect of TNF-α on Ca2+ transients and contraction of adult rat cardiomyocytes

2002 ◽  
Vol 282 (6) ◽  
pp. C1339-C1347 ◽  
Author(s):  
Aïssata Amadou ◽  
Artur Nawrocki ◽  
Martin Best-Belpomme ◽  
Catherine Pavoine ◽  
Françoise Pecker
Keyword(s):  
Arachidonic Acid ◽  
Cyclooxygenase Inhibitors ◽  
High Dose ◽  
Negative Effects ◽  
Dual Effect ◽  
Rat Cardiomyocytes ◽  
Adult Rat ◽  
Tnf Α ◽  
Biphasic Effect

Tumor necrosis factor (TNF)-α has a biphasic effect on heart contractility and stimulates phospholipase A2 (PLA2) in cardiomyocytes. Because arachidonic acid (AA) exerts a dual effect on intracellular Ca2+ concentration ([Ca2+]i) transients, we investigated the possible role of AA as a mediator of TNF-α on [Ca2+]i transients and contraction with electrically stimulated adult rat cardiac myocytes. At a low concentration (10 ng/ml) TNF-α produced a 40% increase in the amplitude of both [Ca2+]i transients and contraction within 40 min. At a high concentration (50 ng/ml) TNF-α evoked a biphasic effect comprising an initial positive effect peaking at 5 min, followed by a sustained negative effect leading to 50–40% decreases in [Ca2+]i transients and contraction after 30 min. Both the positive and negative effects of TNF-α were reproduced by AA and blocked by arachidonyltrifluoromethyl ketone (AACOCF3), an inhibitor of cytosolic PLA2. Lipoxygenase and cyclooxygenase inhibitors reproduced the high-dose effects of TNF-α and AA. The negative effects of TNF-α and AA were also reproduced by sphingosine and were abrogated by the ceramidase inhibitor n-oleoylethanolamine. These results point out the key role of the cytosolic PLA2/AA pathway in mediating the contractile effects of TNF-α.

Role of High-Dose Intravenous Frusemide Therapy in the Management of Chronic Renal Failure

1975 ◽  
Vol 3 (4) ◽  
pp. 245-250
Author(s):  
Mam Chandra ◽  
M K Mitra ◽  
N N Gupta
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Side Effects ◽  
Treated Group ◽  
Fixed Dose ◽  
High Dose ◽  
Dose Regime ◽  
Diuretic Response ◽  
High Doses

The results of using high doses of intravenous frusemide in the management of 28 patients suffering from chronic renal failure are presented. The results are compared with those obtained from 14 patients also suffering from chronic renal failure, who received identical ‘conservative management’ but were not treated with diuretics. Large doses of intravenous frusemide produced a satisfactory diuretic response in a higher percentage of treated patients (71%) compared with controls (36%). It was also observed that in the treated group of patients a significant diuretic response could be obtained in patients with a creatinine clearance below 4 ml per minute. The study also demonstrated that in the group of patients receiving frusemide the response was better in those who were given a progressive-dose regime; 88% of patients improved with this regime compared with 68% of patients who were treated with a fixed dose of frusemide. Transient deafness with tinnitus and vertigo were the only side-effects observed. However these effects were only seen in patients who received 1000 mg or more frusemide in one day, administered over a period of one to two hours. It is concluded that all patients suffering from chronic renal failure should be given a trial of large doses of intravenous frusemide therapy, along with other conventional measures, particularly where facilities for dialysis are not immediately available.

Renal ammoniagenic response to chronic acid loading: role of glucocorticoids

1988 ◽  
Vol 254 (1) ◽  
pp. F134-F138 ◽  
Author(s):  
T. C. Welbourne ◽  
G. Givens ◽  
S. Joshi
Keyword(s):  
Production Rate ◽  
Low Dose ◽  
High Dose ◽  
Ammonium Excretion ◽  
Ammonia Production ◽  
Total Ammonia ◽  
High Doses ◽  
Reduced Rate ◽  
Acid Loading

Adrenalectomized (ADX) animals exhibit a blunted renal response to chronic acid loading. To determine whether this response truly reflects impaired renal ammoniagenesis from glutamine, urinary ammonium excretion was compared with acid intake in ADX, intact, and ADX rats supplemented with either a low dose (4 micrograms.100 g-1.day-1) or a high dose (40 micrograms.100 g-1.day-1) of triamcinolone. ADX rats consumed similar amounts of acid as did intact controls yet excreted only 37% of the load as ammonium; in contrast intact controls returned 86% and triamcinolone-supplemented animals returned 98 and 88% for low and high doses, respectively. Nor could the reduced ammonium excretion be attributed to increased renal venous release, since total ammonia production, the sum of renal venous and urine ammonium, was reduced to 49% of the intact controls; low- and high-dose triamcinolone restored and markedly increased the production rate. Underlying the impaired ammonia production rate in ADX rats was a reduced rate of glutamine extraction, 350 +/- 49 vs. 896 +/- 102 and 1,260 +/- 247 and 1,448 +/- 112 nmol.min-1.100 g-1 for intact and low and high doses, respectively. Unlike intact acidotic and glucocorticoid-supplemented ADX acidotic rats, glutamine extraction was disassociated from the delivered glutamine load consonant with the role of glucocorticoid in coupling cellular glutamine transport to its metabolic utilization.

scholarly journals Dose-response effects of equine chorionic gonadotrophin (eCG) and human chorionic gonadotrophin (hCG) on early embryonic development and viable pregnancy rate in rats

Reproduction ◽  
2001 ◽  
pp. 283-287 ◽  
Author(s):  
CF Tain ◽  
HH Goh ◽  
SC Ng
Keyword(s):  
Embryonic Development ◽  
Pregnancy Rate ◽  
Dose Response ◽  
Early Embryo ◽  
Chorionic Gonadotrophin ◽  
Early Embryonic Development ◽  
Embryo Yield ◽  
Female Wistar Rats ◽  
High Doses

The present study examined the dose-response effects of eCG treatment alone and in combination with various doses of hCG on early embryonic development in vivo and viable pregnancy rate in rats. Mated female Wistar rats were treated with eCG alone (0, 10, 20 or 40 iu), or with 20 iu eCG in combination with various doses of hCG (10, 20, 40 or 80 iu) administered 48 h later. The animals were killed on days 2, 3, 4, 5 or 14 of pregnancy and the numbers of embryos and fetuses recovered were scored. All rats treated with 0 or 10 iu eCG were pregnant. The pregnancy rate was reduced from 62.5% on day 2 to 25% on day 14 and from 31% on day 2 to 10% on day 14 in the groups treated with 20 and 40 iu eCG, respectively. The reduction in pregnancy rate induced by 20 iu eCG was negated by the increasing doses of hCG used. A 100% pregnancy rate was noted on days 2 and 3 in the groups treated with doses of hCG between 10 and 80 iu and from day 2 to day 4 in the groups treated with doses of hCG between 20 and 80 iu. However, a higher viable pregnancy rate was observed only in the group treated with 10 iu hCG compared with the group treated with 20 iu eCG and 0 iu hCG. These results imply that hyperstimulation of rats with high doses of eCG compromises pregnancy rate and markedly reduces litter size and that the addition of hCG is required for complete ovulation, which results in higher embryo yield and a delay in early embryo demise.

scholarly journals The role of apoptosis in early embryonic development of the adenohypophysis in rats

2008 ◽  
Vol 4 (1) ◽  
Author(s):  
Jens Weingärtner ◽  
Kristina Lotz ◽  
Andreas Faltermeier ◽  
Oliver Driemel ◽  
Johannes Kleinheinz ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Early Embryonic Development

scholarly journals Role of bone morphogenetic protein signaling in bovine early embryonic development and stage specific embryotropic actions of follistatin†

2020 ◽  
Vol 102 (4) ◽  
pp. 795-805 ◽  
Author(s):  
Sandeep K Rajput ◽  
Chunyan Yang ◽  
Mohamed Ashry ◽  
Joseph K Folger ◽  
Jason G Knott ◽  
...  
Keyword(s):  
Embryonic Development ◽  
Bone Morphogenetic Proteins ◽  
Mammalian Species ◽  
Cell Lineage ◽  
Bmp Signaling ◽  
Early Embryonic Development ◽  
Protein Signaling ◽  
Bovine Embryos ◽  
Embryonic Genome

Abstract Characterization of the molecular factors regulating early embryonic development and their functional mechanisms is critical for understanding the causes of early pregnancy loss in monotocous species (cattle, human). We previously characterized a stage specific functional role of follistatin, a TGF-beta superfamily binding protein, in promoting early embryonic development in cattle. The mechanism by which follistatin mediates this embryotropic effect is not precisely known as follistatin actions in cattle embryos are independent of its classically known activin inhibition activity. Apart from activin, follistatin is known to bind and modulate the activity of the bone morphogenetic proteins (BMPs), which signal through SMAD1/5 pathway and regulate several aspects of early embryogenesis in other mammalian species. Present study was designed to characterize the activity and functional requirement of BMP signaling during bovine early embryonic development and to investigate if follistatin involves BMP signaling for its stage specific embryotropic actions. Immunostaining and western blot analysis demonstrated that SMAD1/5 signaling is activated after embryonic genome activation in bovine embryos. However, days 1–3 follistatin treatment reduced the abundance of phosphorylated SMAD1/5 in cultured embryos. Inhibition of active SMAD1/5 signaling (8–16 cell to blastocyst) using pharmacological inhibitors and/or lentiviral-mediated inhibitory SMAD6 overexpression showed that SMAD1/5 signaling is required for blastocyst production, first cell lineage determination as well as mRNA and protein regulation of TE (CDX2) cell markers. SMAD1/5 signaling was also found to be essential for embryotropic actions of follistatin during days 4–7 but not days 1–3 of embryo development suggesting a role for follistatin in regulation of SMAD1/5 signaling in bovine embryos.

Loperamide and cardiac events: Is high-dose use still safe for chemotherapy-induced diarrhea?

2017 ◽  
Vol 24 (8) ◽  
pp. 634-636 ◽  
Author(s):  
Mário L de Lemos ◽  
Jolene Guenter ◽  
Victoria Kletas
Keyword(s):  
Daily Intake ◽  
Extended Period ◽  
Torsades De Pointes ◽  
Serum Levels ◽  
Cardiac Risk ◽  
High Dose ◽  
Cardiac Events ◽  
The Us ◽  
High Doses ◽  
Higher Doses

High-dose loperamide is often used for the acute management of chemotherapy-induced diarrhea, with a maximum daily dosing of up to 24 mg. Recently, the US Food and Drug Administration has issued a warning that loperamide can cause rare serious cardiac events, including QT prolongation, torsades de pointes, cardiac arrest and death. Most events were reported in patients taking very high doses for an extended period of time. Daily intake ranged from 64 mg to 1600 mg, often continuously for weeks or months. In addition, the reported serum levels of loperamide ranged from 22 ng/mL to 210 ng/mL, which is likely significantly higher than that expected from patients taking the recommended doses for chemotherapy-induced diarrhea. Overall, the incidence of serious cardiac events associated with loperamide remains low. In balance, the risk of uncontrolled complications from chemotherapy-induced diarrhea is likely greater than the rare cardiac risk associated with the chronic misuse of much higher doses of loperamide.

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