FP receptor; prostaglandin F (PGF) receptor; Endogenous Metabolite

Dinoprost tromethamine salt (prostaglandin F2α tromethamine salt; 1 μM; for 24 hours) induces endoplasmic reticulum stress, autophagy, and apoptosis in goat luteal cells [1]. Dinoprost tromethamine salt (1 μM; for 24 hours) significantly increases the expression of GRP78 and UPR sensors [1]. Apoptosis analysis [1] Cell line: goat luteal cells Concentration: 1 μM Incubation time: 24 hours Results: Apoptosis rate increased significantly (15.62±3.12%). Autophagy detection [1] Cell line: goat luteal cells Concentration: 1 μM Incubation time: 24 hours Results: There is extensive overlap between LC3 and LAMP1 in luteal cells, and autophagic lysosomes are formed in goat luteal cells. Western Blot Analysis[1] Cell line: Goat luteal cells Concentration: 1 μM Incubation time: 24 hours Results: Expression of GRP78 and UPR sensors, including cleaved ATF6, phospho-EIF2S1, EIF2S1, ATF4, phospho-IRE1, autologous Phagocytosis-related intracellular protein LC3-II and pro-apoptotic factor cleaved Caspase3 were significantly increased.

Using two PGF(2α) treatments 14 days apart as a way to enhance estrus detection rate following the 2nd treatment is a reproductive management tool that continues to be used on large dairy farms. In one study, in cows with a functional CL and a dominant follicle, treatment with cloprostenol vs. dinoprost resulted in greater peripheral estradiol concentrations. The objective of the present study was to determine if cloprostenol could enhance pregnancy rates of cows in a large dairy herd using a PGF(2α) program for 1st artificial insemination (AI). Lactating dairy cows (n = 4549) were randomly assigned to receive two treatments of either 500 μg cloprostenol or 25 mg dinoprost 14 days apart, with the 2nd treatment on the 1st day of the voluntary waiting period (57 DIM). Cows detected in estrus within 5 days after the 2nd treatment were inseminated. There was no effect of treatment on day of estrus detection, with 78% of cows inseminated on Days 3 or 4 following treatment. Cloprostenol increased (P < 0.01) estrus detection rates in 1st parity cows compared to dinoprost, 42.4 vs. 34.0%. In cows inseminated on Days 3 or 4 after treatment, cloprostenol increased (P = 0.05) conception rates compared to dinoprost, 38.3 vs. 34.4%. When treatments and parities were combined, conception rates increased (P < 0.02) with interval after treatment (27.0, 36.4, and 44.5% for Days 1 or 2, Days 3 or 4, and Day 5, respectively). Cloprostenol increased (P = 0.02) overall pregnancy rate compared to dinoprost, 14.4 vs. 12.2%. In summary, cloprostenol increased fertility in 1st parity cows inseminated on Days 3 or 4 following treatment and subsequently enhanced pregnancy rates of 1st parity lactating dairy cows compared to dinoprost. Fertility appeared greater in cows expected to have had a young antral ovarian follicle at treatment[3].

The ET-1-induced (10(-8) M) contraction in isolated BTM was inhibited by PGF2alpha (10(-6) M) and fluprostenol (10(-6) M). This effect was blocked by FP receptor antagonists. Carbachol-induced contraction or baseline tension was not affected by PGF2alpha or fluprostenol. In cultured TM cells, ET-1 caused a transient increase in [Ca2+]i that was reduced by PGF2alpha. No reduction occurred in the presence of the FP receptor antagonist Al-8810. Western blot analysis revealed the expression of the FP receptor in native and cultured TM. Conclusions: FP receptor agonists operate by direct interaction with ET-1-induced contractility of TM. This effect is mediated by the FP receptor. Thus, FP receptor agonists may decrease IOP by enhancing aqueous humor outflow through the TM by inhibiting ET-1-dependent mechanisms.[1]

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Corpus luteum (CL) is a transient endocrine tissue that produces progesterone for maintaining pregnancy in mammals. In addition, the regression of CL is necessary for the initiation of the estrous cycle. Extensive research has shown that the prostaglandin F2α (PGF2α) induces the regression of CL in ruminants. However, the mechanisms of endoplasmic reticulum (ER) stress and autophagy in the regression of goat CL induced by PGF2α are still unclear. In this study, ovaries of dioestrus goats and goats that were 3 months pregnant were collected to detect the location of the ER stress-related protein GRP78. The relationship between the different stages of the luteal phase of goat CL during the estrous cycle and changes in the expression of ER stress-related proteins and autophagy-related proteins was confirmed by western blot analysis. The results showed that both ER stress and autophagy were activated in the late luteal phase of the goat CL. To reveal the function of ER stress and autophagy in the CL regression process induced by PGF2α, we used 4-phenyl butyric acid (4-PBA) and chloroquine (CQ) for inhibiting ER stress and autophagy, respectively. Through the apoptotic rate detected by the flow cytometry and the expression of ER stress- and autophagy-related proteins detected by western blotting, we demonstrated that ER stress promoted goat luteal cell apoptosis and autophagy, and that apoptosis can be enhanced by the inhibition of autophagy. In addition, knockdown of EIF2S1, which blocked the PERK pathway activation, promoted apoptosis by reducing autophagy in goat luteal cells treated with PGF2α. In conclusion, our study indicates that ER stress promotes goat luteal cell apoptosis to regulate the regression of CL and activates autophagy to inhibit the goat luteal cell apoptosis via PERK signaling pathway.[2]

Goat ovaries were collected from sexually mature healthy goats and from goats that were pregnant for 3 months in a local abattoir within 10–20 min of slaughter. The duration of pregnancy was determined by the size and morphological characteristics of the fetus. Fresh ovaries stored on ice were taken back to our laboratory within 30 min for subsequent sampling. The complete CL was exfoliated during the estrous cycle from the non-pregnant goats’ ovaries on ice, and each CL was divided into two equal parts. These CL tissues were frozen in liquid nitrogen and stored at −80°C until RNA and protein extraction. Based on the detection of morphological characteristics and the levels of marker genes’ expression, such as STAR, 3βHSD, LH-R, and CYP19A1, in these goat CLs as previously described (Farin et al., 1986), the stages of the luteal phase of the CLs were categorized into five main groups [i.e., early (1–3 day after ovulation), mid1 (4–7 day after ovulation), mid2 (8–12 day after ovulation), mid3 (13–16 day post-ovulation), and late (17–20 post-ovulation)] (Figures 1B,C). For one independent experiment, we exfoliated goat CLs from at least three ovaries in each luteal stage (n = 3 ovaries per stage). All other ovaries fixed in paraformaldehyde (4%) for immunohistochemistry analysis were collected from three dioestrus goats and three pregnant goats.[2]

Absorption, Distribution and Excretion
Slowly absorbed from the amniotic fluid into systemic circulation.

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Metabolism / Metabolites
Enzymatic dehydrogenation primarily in the maternal lungs and also in the liver.

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Biological Half-Life
The half-life of dinoprost in amniotic fluid is 3 to 6 hours. The plasma half-life of dinoprost after intravenous administration is reported to be less than 1 minute.

[1]. Invest Ophthalmol Vis Sci. 2006 Mar;47(3):938-45.

[2]. Front Physiol. 2020 Sep 11:11:868.

[3]. Compared to dinoprost tromethamine, cloprostenol sodium increased rates of estrus detection, conception and pregnancy in lactating dairy cows on a large commercial dairy. Theriogenology. 2012 Sep 1;78(4):823-9.

Dinoprost tromethamine is an organic molecular entity.
The tromethamine (THAM) salt of the naturally occurring prostaglandin F2 alpha, dinoprost tromethamine occurs as a white to off-white, very hygroscopic, crystalline powder. Dinoprost tromethamine may also be known as dinoprost trometamol, PGF2 alpha THAM, or prostaglandin F2 alpha tromethamine.
Dinoprost Tromethamine is a synthetic analogue of the naturally occurring prostaglandin F2 alpha. Prostaglandin F2 alpha stimulates myometrial activity, relaxes the cervix, inhibits corpus luteal steroidogenesis, and induces luteolysis by direct action on the corpus luteum. (NCI04)
See also: Dinoprost (has active moiety).

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Drug Indication
Used for aborting second-trimester pregnancy (between the twelfth to eighteenth week of gestation) and in incomplete abortion or for therapeutic abortion in cases of intrauterine fetal death and congenital abnormalities incompatible with life. Also used at low-doses for medically indicated induction of labor at term. Also injected intra-arterially for use as a vasodilator to assist in angiography.

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Mechanism of Action
Dinoprost tromethamine appears to act directly on the myometrium, but this has not been completely established. Dinoprost stimulates myometrial contractions (via its interaction with the prostaglandin receptors) in the gravid uterus that are similar to the contractions that occur in the term uterus during labor. These contractions are usually sufficient to cause abortion. Uterine response to prostaglandins increases gradually throughout pregnancy. Dinoprost also facilitates cervical dilatation and softening.

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Pharmacodynamics
Dinoprost tromethamine is the tromethamine (THAM) salt of the naturally occurring prostaglandin F2_alpha. Prostaglandin F2_alpha has several pharmacologic effects on the female reproductive system, including stimulation of myometrial activity, relaxation of the cervix, inhibition of steroidogenesis by corpora lutea, and can potentially lyse corpora lutea.

C24H45NO8

475.6160

475.314

C, 60.61; H, 9.54; N, 2.94; O, 26.91

38562-01-5

Dinoprost; 551-11-1; Dinoprost-d4; 34210-11-2

5282415

White to off-white solid powder

531ºC at 760 mmHg

25-35ºC

289ºC

1.404

8

9

15

33

486

5

O([H])[C@@]1([H])C([H])([H])[C@]([H])([C@]([H])(C([H])=C([H])[C@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])O[H])[C@]1([H])C([H])([H])C([H])=C([H])C([H])([H])C([H])([H])C([H])([H])C(=O)O[H])O[H].O([H])C([H])([H])C(C([H])([H])O[H])(C([H])([H])O[H])N([H])[H]

IYGXEHDCSOYNKY-RZHHZEQLSA-N

InChI=1S/C20H34O5.C4H11NO3/c1-2-3-6-9-15(21)12-13-17-16(18(22)14-19(17)23)10-7-4-5-8-11-20(24)25;5-4(1-6,2-7)3-8/h4,7,12-13,15-19,21-23H,2-3,5-6,8-11,14H2,1H3,(H,24,25);6-8H,1-3,5H2/b7-4-,13-12+;/t15-,16+,17+,18-,19+;/m0./s1

2-amino-2-(hydroxymethyl)propane-1,3-diol;(Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]cyclopentyl]hept-5-enoic acid

U 14585; U14585; U-14585; Dinoprost; Tromethamine; Dinoprost; Trometamol; Zinoprost; PGF2alpha THAM; Lutalyse; PGF2-alpha tham; Prostamate;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~95 mg/mL (~199.7 mM)
Water: ~95 mg/mL
Ethanol: ~95 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.26 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 50 mg/mL (105.13 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)