dinoprost and phorbol-12-13-didecanoate

Intracerebroventricular (icv) injection of transient receptor potential vanilloid 4 (TRPV4) agonists 4α-phorbol-12, 13-didecanoate (4α-PDD) and GSK101690A increased urinary excretion under the physiological condition. TRPV4 antagonists ruthenium red and HC-067047 significantly blocked increased urinary volume after intragastric administration of water and 4α-PDD-induced diuresis. Administration of the TRPV4 agonists did not significantly change the plasma concentration of vasopressin or atrial natriuretic factor. Pretreatment with indomethacin inhibited the diuresis induced by 4α-PDD. Moreover, icv injection of prostaglandin (PG) F

Topics: Animals; Atrial Natriuretic Factor; Dinoprost; Diuresis; Drinking; Homeostasis; Indomethacin; Male; Morpholines; Phorbol Esters; Pyrroles; Rats; Rats, Wistar; Ruthenium Red; TRPV Cation Channels; Urination; Vasopressins

We previously reported that prostaglandin F(2alpha) (PGF(2alpha)) activates both phosphoinositide-hydrolyzing phospholipase C and phosphatidylcholine-hydrolyzing phospholipase D in osteoblast-like MC3T3-E1 cells and then induces the activation of protein kinase C (PKC). In this study, we investigated the effect of PGF(2alpha) on the induction of heat shock protein 27 (HSP27), a low-molecular-weight heat shock protein, in these cells. PGF(2alpha) significantly induced the accumulation of HSP27 dose-dependently within the range of 10 nM to 10 microM. PGF(2alpha) stimulated the increase in the levels of mRNA for HSP27. A total of 10 nM 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of PKC, induced the accumulation of HSP27. The stimulative effect of PGF(2alpha) was reduced in the PKC down-regulated cells. Calphostin C, a specific inhibitor of PKC, suppressed the PGF(2alpha)-induced HSP27 accumulation as well as that induced by TPA. HSP27 induction by PGF(2alpha) was reduced by U-73122, a phospholipase C inhibitor, or propranolol, a phosphatidic acid phosphohydrolase inhibitor. PGF(2alpha) and TPA stimulated p42/p44 mitogen-activated protein (MAP) kinase. PD98059, an inhibitor of the upstream kinase that activates p42/p44 MAP kinase, suppressed the induction of HSP27 stimulated by PGF(2alpha) or TPA. PD98059 and calphostin C reduced the levels of mRNA for HSP27 increased by PGF(2alpha). These results indicate that PGF(2alpha) stimulates the induction of HSP27 via p42/p44 MAP kinase activation, which depends on upstream PKC activation in osteoblasts.

Topics: Adrenergic beta-Antagonists; Animals; Blotting, Northern; Blotting, Western; Cell Line; Dinoprost; Dose-Response Relationship, Drug; Down-Regulation; Enzyme Inhibitors; Heat-Shock Proteins; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Molecular Chaperones; Neoplasm Proteins; Osteoblasts; Oxytocics; Phorbol Esters; Phosphodiesterase Inhibitors; Protein Kinase C; RNA, Messenger; Tetradecanoylphorbol Acetate

We examined effects of phorbol 12,13-dibutyrate (PDB), which activates protein kinase C (PKC), on prostaglandin and leukotriene production in piglet cultured glia derived from cerebral cortex and white matter. Levels of prostaglandins were determined using enzyme immunoassay. Baseline levels in media for prostaglandin F2 alpha (PGF2 alpha) were 730 +/- 116 pg/ml and increased to 1,551 +/- 196 pg/ml at 10(-8) M PDB (P < 0.05) and to 2,182 +/- 190 pg/ml at 10(-6) M PDB (P < 0.05) (n = 16). Little or no 6-keto-prostaglandin F1 alpha, prostaglandin E2, or leukotrienes C4/D4 were produced. PGF2 alpha levels in media did not increase in the presence of the vehicle for PDB (dimethyl sulfoxide) or 4 alpha-phorbol 12,13-didecanoate (PDD; a phorbol ester that does not activate protein kinase C) or when indomethacin (10 micrograms/ml), quinacrine (10(-6) M), or isoquinolinylsulfonylmethyl piperazine (10(-4) M) (an inhibitor of PKC activation) was coadministered with PDB. We conclude that glia can be important contributors of prostaglandins to extracellular-cerebrospinal fluids where they could influence cerebrovascular tone, and that PDB probably increases prostaglandin production via liberation of arachidonic acid by PKC-induced activation of phospholipase A2.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Animals, Newborn; Astrocytes; Cerebral Cortex; Dinoprost; Isoquinolines; Phorbol 12,13-Dibutyrate; Phorbol Esters; Piperazines; Prostaglandin Antagonists; Prostaglandins; Protein Kinase Inhibitors; Swine

Prostaglandin F2 alpha (PGF2 alpha) release from the uterus causes luteolysis in ruminants, and oxytocin is thought to be a regulator of this release. In the present study, we have examined the mechanisms involved in oxytocin stimulation of PGF2 alpha secretion by bovine endometrium in vitro. Endometrial tissue explants, obtained from heifers at Day 19 or 20 (n = 3) and Day 0 (estrus, n = 5) of the estrous cycle, were incubated for 2 h and 6 h, and PGF2 alpha concentration in the medium was determined by radioimmunoassay (RIA). Basal PGF2 alpha release increased for up to 6 h and was significantly stimulated after 2 h of incubation with 100 microU and 1000 microU of oxytocin at Day 0 but not at Day 19 or 20. Secretion of PGF2 alpha was not affected by cholera toxin (10 ng/ml) or the cyclic nucleotide analogs dibutyryl cyclic adenosine 3',5'-monophosphate and dibutyryl cyclic guanosine 3',5'-monophosphate at a concentration of 1 mM. A protein kinase A inhibitor (500 microM) had no effect on the oxytocin-induced release of PGF2 alpha. Both the phorbol ester, 12-myristate-13-acetate (100 mM), and the non-phorbol stimulator of protein kinase C, 1-octanoyl-2-acetylglycerol (500 microM), significantly stimulated PGF2 alpha secretion to the same extent as oxytocin. Neither basal nor stimulated PGF2 alpha release was affected by the calcium ionophore A23187 (0.1-5.0 microM). However, PGF2 alpha secretion was sensitive to cycloheximide (1 microgram/ml) suggesting that protein synthesis may be involved. In conclusion, these data suggest that the stimulation of PGF2 alpha by oxytocin is via the protein kinase C effector pathway.

Topics: Animals; Arachidonic Acids; Bucladesine; Calcimycin; Carcinogens; Cattle; Cholera Toxin; Cycloheximide; Dibutyryl Cyclic GMP; Diglycerides; Dinoprost; Endometrium; Female; Nucleotides, Cyclic; Oxytocin; Phorbol Esters; Protein Kinase Inhibitors; Tetradecanoylphorbol Acetate; Uterus

To explore the possible role of protein kinase C and calcium in the luteolytic process, we treated luteal cells with a protein kinase C activator, the phorbol ester, phorbol 12-myristate 13-acetate (PMA), and with the calcium ionophore, A23187. Lower concentrations of PMA could clearly mimic the inhibitory, luteolytic effects of prostaglandin F2 alpha (PGF2 alpha) on LH-induced cAMP and progesterone production. A nontumor promoting phorbol ester, 4 alpha-phorbol 12,13-didecanoate, had no inhibitory effect, indicating a specific PMA effect. The calcium ionophore, A23187, also gave a marked inhibition of LH-induced cAMP and progesterone production. Hormone-stimulated adenylate cyclase activity was markedly impaired after preincubation of the cells with PGF2 alpha, PMA, or A23187, but no effect was seen when the substances were added to isolated membranes. In addition, the stimulation of progesterone production in the luteal cells with the cAMP analogs, 8-bromo-cAMP and (Bu)2cAMP, was almost totally abolished when PMA or A23187 was present. We conclude that PMA and A23187 in many ways mimic the effect of PGF2 alpha in luteal cells. The inhibition of steroidogenesis is partly dependent on depressed activity of the hormone-sensitive adenylate cyclase, but also obtained by inhibiting steps distal to cAMP formation. Both points of action seem to be calcium and/or protein kinase C dependent. In contrast, higher concentrations of PMA markedly stimulated steroidogenesis without affecting the cAMP level, a stimulation not seen after incubation with 4 alpha-phorbol 12,13-didecanoate, suggesting again a specific PMA effect. The stimulation of steroidogenesis by higher concentrations of PMA seems to be specific, but the interpretation of this finding is unclear at present. In conclusion, PMA and A23187 mimic some of the luteolytic properties of PGF2 alpha, not only inhibiting the luteal cAMP system, but also by inducing lesions in the steroidogenic steps beyond the cAMP system.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Adenylyl Cyclases; Animals; Calcimycin; Corpus Luteum; Cyclic AMP; Dinoprost; Female; In Vitro Techniques; Kinetics; Luteinizing Hormone; Phorbol Esters; Progesterone; Prostaglandins F; Rats; Rats, Inbred Strains; Tetradecanoylphorbol Acetate