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PubMed1990

Diets rich in n-9, n-6 and n-3 fatty acids differentially affect the generation of inositol phosphates and of thromboxane by stimulated platelets, in the rabbit.

We have studied the effects of semi-synthetic diets rich in either n-9 (olive oil, OO) or n-6 (corn oil, CO), or n-3 (fish oil, FO, as MaxEPA) fatty acids on the levels of major PUFA in platelet lipids, on the generation of inositol phosphates by [3H]inositol labelled platelets after stimulation with thrombin and of thromboxane B2 (TxB2) by platelet rich plasma (PRP) after stimulation with collagen. The predicted elevations of oleic (OA), linoleic (LA) and eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids were observed in platelet lipids of each animal group, but in the MaxEPA fed group accumulation of EPA was associated with depletion of linoleic acid (LA) rather than of arachidonic acid (AA). Basal levels of inositol-tris-phosphate (IP3) in platelets were lowest in the OO group and highest in the CO group, whereas the increment after thrombin stimulation (1 unit/ml NIH) was maximal in the OO group and minimal in the FO group. Instead, when generation of TxB2 by stimulated platelets was evaluated, no appreciable difference among the various groups could be detected, in accordance with the limited modifications of platelet AA content induced by the diets. The overall data indicate that dietary fatty acids modulate the pathway of inositol phosphate generation in rabbit platelets, independently of modifications of TxB2 production.

Animals↗
PubMed1996

Inositol phosphates in the duckweed Spirodela polyrhiza L.

We have undertaken an analysis of the inositol phosphates of Spirodela polyrhiza at a developmental stage when massive accumulation of InsP6 indicates that a large net synthesis is occurring. We have identified Ins3P, Ins(1,4)P2, Ins(3,4)P2 and possibly Ins(4,6)P2, Ins(3,4,6)P3, Ins(3,4,5,6)P4, Ins (1,3,4,5,6)P5, D- and/or L-Ins(1,2,4,5,6)P5 and InsP6 and revealed the likely presence of a second InsP3 with chromatographic properties similar to Ins(1,4,5)P3. The higher inositol phosphates identified show no obvious direct link to pathways of metabolism of second messengers purported to operate in higher plants, nor do they resemble the immediate products of plant phytase action on InsP6.

6-Phytase↗
PubMed1993

Receptor-recognized alpha 2-macroglobulin-methylamine elevates intracellular calcium, inositol phosphates and cyclic AMP in murine peritoneal macrophages.

Human plasma alpha 2-macroglobulin (alpha 2M) is a tetrameric proteinase inhibitor, which undergoes a conformational change upon reaction with either a proteinase or methylamine. As a result, a receptor recognition site is exposed on each subunit of the molecule enabling it to bind to its receptors on macrophages. We have used Fura-2-loaded murine peritoneal macrophages and digital video fluorescence microscopy to examine the effects of receptor binding on second messenger levels. alpha 2M-methylamine caused a rapid 2-4-fold increase in intracellular Ca2+ concentration ([Ca2+]i) within 5 s of binding to receptors. The agonists induced a focal increase in [Ca2+]i that spread out to other areas of the cell. The increase in [Ca2+]i was dependent on the alpha 2M-methylamine concentration and on the extracellular [Ca2+]. Both sinusoidal and transitory oscillations were observed, which varied from cell to cell. Neither alpha 2M nor boiled alpha 2M-methylamine, forms that are not recognized by the receptor, affected [Ca2+]i in peritoneal macrophages under identical conditions of incubation. The alpha 2M-methylamine-induced rise in [Ca2+]i was accompanied by a rapid and transient increase in macrophage inositol phosphates, including inositol tris- and tetrakis-phosphates. Native alpha 2M did not stimulate a rise in inositol phosphates. Finally, binding of alpha 2M-methylamine to macrophages increased cyclic AMP transiently. Thus receptor-recognized alpha-macroglobulins behave as agonists whose receptor binding causes stimulation of signal transduction pathways.

Animals↗
PubMed1985

Transmembrane signalling by the T cell antigen receptor. Perturbation of the T3-antigen receptor complex generates inositol phosphates and releases calcium ions from intracellular stores.

Antibodies against the T3-antigen receptor complex can activate the human T cell line, Jurkat, to produce interleukin 2 (2-5). This activation is initiated by a receptor-mediated increase in the concentration of free cytoplasmic calcium ions [Ca2+]i (3, 4). In this communication, we investigate the mechanism by which the receptor complex increases [Ca2+ )i in Jurkat cells. The initial receptor-mediated change in [Ca2+]i can occur when extracellular Ca2+ is depleted by EGTA. Perturbation of the T cell antigen receptor, therefore, generates a signal which mobilizes Ca2+ from intracellular stores. As inositol trisphosphate appears to function as such a signal for certain hormone receptors, we measured the levels of inositol trisphosphate and of the other inositol phosphate compounds in Jurkat. Antibodies to either the antigen receptor heterodimer or T3 determinants result in marked elevations of all three inositol phosphates. These changes in inositol phosphates are not secondary to the receptor-mediated increases in [Ca2+]i as demonstrated by the inability of the Ca2+ ionophore, ionomycin, to affect the levels of any of these compounds. In concentrations between 0.1 and 1 microM, purified inositol trisphosphate releases Ca2+ from permeabilized Jurkat cells. Taken together, these data indicate that, during activation, perturbation of the T3-antigen receptor complex generates inositol trisphosphate. This compound functions as an intracellular signal to release Ca2+ from intracellular stores, leading to increases in [Ca2+]i.

Aminoquinolines↗
PubMed1989

Effects of human chorionic gonadotropin, prostaglandin F2 alpha and protein kinase C activators on the cyclic AMP and inositol phosphate second messenger systems in cultured human granulosa-luteal cells.

The effects of human chorionic gonadotropin (hCG) and prostaglandin F2 alpha (PGF2 alpha) on the adenylate cyclase-cAMP and inositol phospholipid-phospholipase C-inositol trisphosphate and diacylglycerol transmembrane signalling systems were evaluated in cultured human granulosa-luteal cells. Granulosa-luteal cells obtained from patients undergoing in vitro fertilization were cultured for 72 h prior to addition of hormones. During the last 24 h of culture granulosa-luteal cells were incubated with [3H]inositol. Neither hCG nor gonadotropin-releasing hormone (GnRH) stimulated the inositol phospholipid-phospholipase C signalling system. PGF2 alpha stimulated increases in inositol mono-, bis-, and trisphosphate accumulation in 30 min incubations. NaF (20 mM) mimicked the stimulatory effect of PGF2 alpha on inositol phosphate accumulation suggesting the involvement of a guanine nucleotide regulatory protein in the activation of phospholipase C. In contrast, hCG but not PGF2 alpha or NaF stimulated cAMP accumulation in 30 min incubations. Simultaneous treatment with hCG and PGF2 alpha did not alter the stimulatory effect of PGF2 alpha on inositol phosphate accumulation but reduced (37%) the stimulatory effect of hCG on cAMP accumulation. The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA) inhibited the stimulatory effects of hCG (76%) and PGF2 alpha (62%) on cAMP and inositol phosphate accumulation, respectively. Thus, cultures of human granulosa-luteal cells possess multiple transmembrane signalling systems which may be modulated by the activation of protein kinase C.

Chorionic Gonadotropin↗
PubMed1992

The inositol phosphates in WRK1 rat mammary tumour cells.

1. A detailed structural survey has been made of the inositol phosphates of unstimulated and vasopressin-stimulated WRK-1 rat mammary tumour cells. Inositol phosphate peaks were separated by h.p.l.c., and structural assignments were made for more than 20 compounds by combinations of: (a) co-chromatography with labelled standards; (b) site-specific enzymic dephosphorylation; (c) complete and partial periodate oxidation, followed by h.p.l.c. of polyols and their stereospecific oxidation by dehydrogenases; and (d) ammoniacal hydrolysis. 2. The 'inositol monophosphates' fraction from unstimulated cells included an uncharacterized peak, probably containing some glycerophosphoinositol, and Ins(1:2-cyclic)P. Stimulation provoked accumulation of both Ins1P and Ins3P, of Ins2P, and of Ins5P and/or the enantiomers Ins4P and Ins6P. The proportions of Ins1P and Ins3P were determined by partial periodate oxidation and enantiomeric identification of the resulting glucitols. 3. Three inositol bisphosphate peaks were detected in unstimulated cells: Ins(1,4)P2 [this was distinguished chemically from its enantiomer Ins(3,6)P2], Ins(3,4)P2 and/or Ins(1,6)P2, and Ins(4,5)P2 and/or Ins(5,6)P2. On stimulation, Ins(1,4)P2 and Ins(3,4)P2 [and/or Ins(1,6)P2] levels increased, and Ins(1:2-cyclic,4)P2 and Ins(1,3)P2 were also formed. 4. Three inositol trisphosphate peaks were obtained from unstimulated cells: all increased during stimulation. These were Ins(1,3,4)P3 [with some Ins(1:2-cyclic,4,5)P3], Ins(1,4,5)P3 and Ins(3,4,5)P3 [and/or Ins(1,5,6)P3]. During stimulation, another compound, probably Ins(1,4,6)P3, appeared in the 'Ins(1,4,5)P3 peak'. The 'Ins(3,4,5)P3 peak' contained a second trisphosphate, probably Ins(2,4,5)P3. 5. Three inositol tetrakisphosphates, namely Ins(1,3,4,6)P4, Ins(1,3,4,5)P4, were present in unstimulated cells, and all accumulated during stimulation. 6. Ins(1,3,4,5,6)P5, which is the most abundant inositol polyphosphate in these cells, a less abundant inositol pentakisphosphate and inositol hexakisphosphate were all unresponsive to stimulation.

Animals↗
PubMed1989

Subacute and chronic in vivo lithium treatment inhibits agonist- and sodium fluoride-stimulated inositol phosphate production in rat cortex.

We have investigated the effects of in vivo lithium treatment on cerebral inositol phospholipid metabolism. Twice-daily treatment of rats with LiCl (3 mEq/kg) for 3 or 16 days resulted in a 25-40% reduction in agonist-stimulated inositol phosphate production, compared with NaCl-treated controls, in cortical slices prelabelled with [3H]inositol. A small effect was also seen with 5-hydroxytryptamine (5-HT) 24 h after a single dose of LiCl (10 mEq/kg). Dose-response curves to carbachol and 5-HT showed that lithium treatment reduced the maximal agonist response without altering the EC50 value. This inhibition was not affected by the concentration of LiCl in the assay buffer. Stimulation of inositol phosphate formation by 10 mM NaF in membranes prepared from cortex of 3-day lithium-treated rats was also inhibited, by 35% compared with NaCl-treated controls. Lithium treatment did not alter the kinetic profile of inositol polyphosphate formation in cortical slices stimulated with carbachol. Muscarinic cholinergic and 5-HT2 bindings were unaltered by lithium, as was cortical phospholipase C activity and isoproterenol-stimulated cyclic AMP formation. [3H]Inositol labelling of phosphatidylinositol 4,5-bisphosphate was significantly enhanced by 3-day lithium treatment. The results, therefore, indicate that subacute or chronic in vivo lithium treatment reduces agonist-stimulated inositol phospholipid metabolism in cerebral cortex; this persistent inhibition appears to be at the level of G-protein-phospholipase C coupling.

Animals↗
PubMed1993

Inositol phosphates modulate binding of thyroid hormone to human red cell membranes in vitro.

D-Myo-inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and D-myo-inositol 4,5-bisphosphate (10(-6) mol/L) displaced specifically bound L-[125I] T4 from human erythrocyte membranes in vitro by up to 80%. D-Myo-inositol 1,3,4,5-tetrakisphosphate, D-myo-inositol 1-monophosphate, and D-myo-inositol 1,4-bisphosphate were ineffective in decreasing thyroid hormone binding to membranes. The effect of Ins(1,4,5)P3 on high affinity binding reflected a change in Kd (5.8 x 10(-11) vs. 1.5 x 10(-11) mol/L) and binding capacity (15 vs. 2 fmol/mg membrane protein) in the absence and presence of Ins(1,4,5)P3, respectively. Ins(1,4,5)P3 also displaced T3 from red cell membranes. Thus, selected inositol phosphates regulate the abundance of sites available for binding of thyroid hormone by human red cell membranes. This stereospecific action of inositol phosphates is among several plasma membrane effects recently described for these members of the signal-transducing phosphoinositide pathway.

Erythrocyte Membrane↗
PubMed1993

Beryllium competitively inhibits brain myo-inositol monophosphatase, but unlike lithium does not enhance agonist-induced inositol phosphate accumulation.

Despite limiting side-effects, lithium is the drug of choice for the treatment of bipolar depression. Its action may be due, in part, to its ability to dampen phosphatidylinositol turnover by inhibiting myo-inositol monophosphatase. Beryllium has been identified as a potent inhibitor of partially purified myo-inositol monophosphatase isolated from rat brain (Ki = 150 nM), bovine brain (Ki = 35 nM), and from the human neuroblastoma cell line SK-N-SH (Ki = 85 nM). It is over three orders of magnitude more potent than LiCl (Ki = 0.5-1.2 mM). Kinetic analysis reveals that beryllium is a competitive inhibitor of myo-inositol monophosphatase, in contrast with lithium which is an uncompetitive inhibitor. Inhibition of exogenous [3H]inositol phosphate hydrolysis by beryllium (IC50 = 250-300 nM) was observed to the same maximal extent as that seen with lithium in permeabilized SK-N-SH cells, reflecting inhibition of cellular myo-inositol monophosphatase. However, in contrast with that observed with lithium, agonist-induced accumulation of inositol phosphate was not observed with beryllium in permeabilized and non-permeabilized SK-N-SH cells and in rat brain slices. Similar results were obtained in permeabilized SK-N-SH cells when GTP-gamma-S was used as an alternative stimulator of inositol phosphate accumulation. The disparity in the actions of beryllium and lithium suggest that either (1) selective inhibition of myo-inositol monophosphatase does not completely explain the action of lithium on the phosphatidylinositol cycle, or (2) that uncompetitive inhibition of myo-inositol monophosphatase is a necessary requirement to observe functional lithium mimetic activity.

Animals↗
PubMed1993

Anion-exchange high-performance liquid chromatography with post-column detection for the analysis of phytic acid and other inositol phosphates.

The use of gradient anion-exchange HPLC, with a simple post-column detection system, is described for the separation of myo-inositol phosphates, including "phytic acid" (myo-inositol hexaphosphate). Hexa-, penta-, tetra-, tri- and diphosphate members of this homologous series are clearly resolved within 30 min. This method should facilitate analysis and quantitation of "phytic acid" and other inositol phosphates in plant, food, and soil samples.

Chromatography, High Pressure Liquid↗
PubMed1988

Inositol phosphates: proliferation, metabolism and function.

After the initial discovery of receptor-linked generation of inositol(1,4,5)trisphosphate (Ins(1,4,5)P3) it was generally assumed that Ins(1,4,5)P3 and its proposed breakdown products inositol(1,4)bisphosphate (Ins(1,4)P2) and Ins1P, along with cyclic inositol monophosphate, were the only inositol phosphates found in significant amounts in animal cells. Since then, three levels of complexity have been introduced. Firstly, Ins(1,4,5)P3 can be phosphorylated to Ins(1,3,4,5)P4, and the subsequent metabolism of these two compounds has been found to be intricate and probably different between various tissues. The functions of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 are almost certainly to regulate cytosolic Ca2+ concentrations, but the reasons for the labyrinth of the metabolic pathways after their deactivation by a specific 5-phosphatase remain obscure. Secondly, inositol pentakis- and hexakisphosphates have been found in many animal cells other than avian erythrocytes. It has been shown that their synthesis pathway is entirely separate from the inositol phosphates discussed above, both in terms of many of the isomers involved and probably in the subcellular localization; some possible functions of InsP5 and InsP6 are discussed here. Thirdly, cyclic inositol polyphosphates have been reported in stimulated tissues; the evidence for their occurrence in vivo and their possible physiological significance are also discussed.

Animals↗
PubMed1999

Enzyme-assisted total synthesis of the optical antipodes D-myo-inositol 3,4,5-trisphosphate and D-myo-inositol 1,5, 6-trisphosphate: aspects of their structure-activity relationship to biologically active inositol phosphates.

Unambiguous total syntheses of both optical antipodes of the enantiomeric pair D-myo-inositol 3,4,5-trisphosphate (Ins(3,4,5)P3) and D-myo-inositol 1,5,6-trisphosphate (Ins(1,5,6)P3) are described. The ring system characteristic of myo-inositol was constructed de novo from p-benzoquinone. X-ray data for the enzymatically resolved (1S,2R,3R,4S)-1,4-diacetoxy-2,3-dibromocyclohex-5-ene enabled the unequivocal assignment of the absolute configuration. Subsequent transformations under stereocontrolled conditions led to enantiopure C2-symmetrical 1,4-(di-O-benzyldiphospho)conduritol B derivatives. Their synthetic potential was exploited to prepare Ins(3,4,5,6)P4 and Ins(1,4,5,6)P4 in three steps. With a recently identified and partially purified InsP5/InsP4 phosphohydrolase from Dictyostelium discoideum, these enantiomers could be converted to the target compounds, Ins(3,4,5)P3 and Ins(1,5,6)P3, on a preparative scale. An HPLC system employed for both purification of the inositol phosphates and analytical runs ensured that the products were isomerically homogeneous. The sensitivity of detection achieved by a complexometric postcolumn derivatization method indicates that the complexation properties of Ins(3,4,5)P3/Ins(1,5,6)P3 resemble those of Ins(1,2,3)P3, a compound with antioxidant potential. The set of inositol phosphates synthesized was used to clarify structural motifs important for molecular recognition by p42(IP4), a high-affinity Ins(1,3,4,5)P4/PtdIns(3,4,5)P3-specific binding protein from pig cerebellum.

Acid Anhydride Hydrolases↗
PubMed1992

Effects of ovine conceptus secretory proteins and progesterone on oxytocin-stimulated endometrial production of prostaglandin and turnover of inositol phosphate in ovariectomized ewes.

This study examined the effects of progesterone and intrauterine injection of ovine conceptus secretory proteins (oCSP) on endometrial responsiveness to oxytocin. Twelve ewes were ovariectomized on day 4 of the cycle (oestrus = day 0) and assigned in a 2 x 2 factorial arrangement, to receive either 1.5 mg ovine serum proteins (SP) or oCSP containing 25 micrograms ovine trophoblast protein 1 (oTP-1) (by radioimmunoassay) in 1.5 mg total protein into each uterine horn, via catheters, twice a day on days 11, 12, 13 and 14. Ewes received 200 mg progesterone per day (i.m.) from day 4 to day 10 or 15. Oxytocin-induced prostaglandin F2 alpha was measured as 13,14-dihydro-15-keto-prostaglandin F2 alpha (PGFM) on days 11, 12, 13 and 14 in plasma from three integrated, 10 min (10 ml) blood samples (0-10, 10-20, 20-30 min) obtained after intravenous injection of 20 iu oxytocin, and in a pre-oxytocin (-10 to 0 min) sample collected via an indwelling jugular catheter. The pre-oxytocin samples were also assayed for progesterone. Oxytocin-induced turnover of inositol phosphate was determined in endometrium on day 15 after hysterectomy. In ewes receiving progesterone to day 10, plasma progesterone decreased from about 12 to 2 ng ml-1 (SEM +/- 2.6) during the treatment period (days 11-14), but remained high (12-20 +/- 2.6 ng ml-1) in ewes that received progesterone to day 15. Intrauterine injection of oCSP resulted in high basal concentrations of PGFM on days 12 and 13 compared with SP-treated ewes (P less than 0.01). Treatments with progesterone did not affect basal PGFM concentrations. Treatment with oCSP abolished oxytocin-induced endometrial secretion of prostaglandin only if progesterone was maintained to day 15 (P less than 0.01); in ewes receiving such treatment, oCSP inhibited (P less than 0.01), but SP did not inhibit, oxytocin-induced endometrial turnover of inositol phosphate (P less than 0.06), which was greater in ewes treated with progesterone to day 10 than in those treated to day 15 (P less than 0.05). Ewes that responded to oxytocin with increased PGFM exhibited increased oxytocin-stimulated turnover of inositol phosphate on day 15. These results indicate that the antiluteolytic action oTP-1 exerts on the endometrium requires progesterone and that this mechanism involves inhibition of oxytocin-stimulated turnover of inositol phosphate.

Animals↗
PubMed1988

Formation and metabolism of [3H]inositol phosphates in AR42J pancreatoma cells. Substance P-induced Ca2+ mobilization in the apparent absence of inositol 1,4,5-trisphosphate 3-kinase activity.

After 2 days of incubation of AR42J pancreatoma cells with 400 microM [3H]inositol, the specific radioactivity of [3H]phosphatidylinositol 4,5-bisphosphate and the specific radioactivity of [3H]inositol were similar, indicating that isotopic equilibrium had been achieved. The inositol 1,4,5-trisphosphate (1,4,5-IP3) level in cells was estimated to be approximately 2 microM and was increased by substance P receptor activation to about 25 microM. HPLC analysis of [3H]inositol phosphates indicated that only 1,4,5-IP3, inositol 1,4-bisphosphate, and inositol 4-monophosphate were increased upon receptor activation. There was no increase in inositol 1,3,4,5-tetrakisphosphate (1,3,4,5-IP4), or in any of its metabolites. Incubation of [3H]1,4,5-IP3 with a cell homogenate did not result in the formation of [3H]1,3,4,5-IP4. Therefore, it appears that 1,4,5-IP3 3-kinase is either not present or not functional under these assay conditions. Substance P increased cytosolic calcium levels in fura-2-loaded cells from about 600 nM to 2.5 microM. This increase in Ca2+ was partially attenuated in the absence of extracellular calcium, indicating that in AR42J cells, substance P stimulation appears to activate calcium signaling through both Ca2+ entry and intracellular Ca2+ release. These modes of Ca2+ mobilization occur without an increase in 1,3,4,5-IP4 or any of its metabolites.

Animals↗
PubMed1991

The inhibition of agonist- or depolarisation-evoked formation of inositol phosphate by excitatory amino acids in rat cerebral cortex is due to the neurotoxic action of this class of neurotransmitter and is mediated by sodium influx.

Previous work has shown that excitatory amino acids inhibit agonist or depolarisation evoked formation of inositol phosphate in brain. In this paper, possible mechanisms by which this may be occurring have been investigated. The inhibition of carbachol-stimulated formation of inositol phosphate by kainic acid (KA) was abolished if the tissue was incubated in a sodium-free medium. The sodium channel activator, veratridine (10 microM) and the sodium ionophore, monensin (3 microM), also inhibited the response of inositol phosphate to carbachol; tetrodotoxin (300 nM) reversed the effect of veratridine but not monensin or KA. Incubation with cadmium (0.3 mM) or removal of extracellular calcium did not alter the effects of KA, monensin or veratridine. The effects of KA were significantly reduced with the Na+/K(+)-ATPase inhibitor, ouabain (10-100 microM). Inhibition by KA was still observed in tissue that had been prestimulated with KA and then washed to remove the agonist. Incorporation of [3H]inositol into inositol lipids was significantly reduced by KA, in the absence or presence of carbachol. It is suggested that the inhibition of the turnover of stimulated phosphoinositide, by excitatory amino acids, is related to the neurotoxic actions of these transmitters and is mediated by Na+ influx, with a consequent activation of Na+/K(+)-ATPase, depletion of cellular ATP and reduction in synthesis of inositol lipid.

Animals↗
PubMed1990

The effect of dopamine D1 and D2 receptor agonists on inositol phosphate turnover in rat striatal slices.

There is a lot of controversy in the literature about the role of dopamine D1 and D2 receptor stimulation on the turnover of phosphoinositols, and phosphoinositols are one of the important second messenger. In order to resolve this controversy, the effect of dopamine receptor stimulation on turnover of phosphoinositols was studied by estimation of the accumulation of individual labelled inositols in rat striatal slices which were prelabelled with [3H]myoinositol. Incubation of the prelabelled striatal slices with 1 microM of quinpirole, D2 specific agonist or with 1 microM of SKF-38393, D1 specific agonist, did not affect the accumulation of basal level of either inositol monophosphate, or inositol biphosphate, or inositol triphosphate. In addition, in conclusion of D1 specific antagonist cis-flupentixol or D2 specific antagonist sulpiride did not affect the basal levels of inositol phosphates. The activity of enzyme phospholipase-C which produces these inositol phosphates was also measured in rat striatal membrane. Incubation of rat striatal membrane with either agonist quinpirole or SKF-38393 did not change the basal level of phospholipase C. Our data thus indicate that occupation of dopamine receptors did not affect the inositol phosphate system in rat striatum.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Progesterone increases basal 3',5'-cyclic adenosine monophosphate formation and down-regulates the agonist-induced inositol phosphates generation in human term placenta.

Whether the placenta is a target tissue for estrogens and progesterone, and their putative mechanism of action, is still a controversial question in the literature. The effect of progesterone and estradiol on 3',5'-cyclic adenosine monophosphate (cAMP) and inositol phosphates generation in human term placenta was investigated. Placental explants were incubated in vitro for up to 48 h in the absence and in the presence of estradiol, progesterone or both steroids (0.1 mumol/l final concentration in all cases), and were stimulated with terbutaline, a beta-adrenergic agonist, (0.1 mmol/l) or angiotensin II (1 mumol/l). The cAMP content was measured by a competitive protein binding assay, and the generation of labelled inositol phosphates formation in explants prelabelled with 3H-myo-inositol was measured by anion exchange chromatography. Progesterone increased significantly basal cAMP concentrations in comparison with control or estradiol-treated tissues (169 +/- 13, 72 +/- 8, and 69 +/- 2 pmol/g wet wt tissue, mean +/- SEM, respectively). However, following terbutaline stimulation cAMP levels (mean +/- SEM) increased to similar values under all conditions (182 +/- 33, 197 +/- 36, and 237 +/- 17 pmol/g wet wt tissue for control, estradiol-, and progesterone-treated tissues, respectively). Angiotensin II stimulated inositol phosphates generation in placental explants by an average of fivefold, but this increase was significantly reduced in the presence of progesterone (5.2 +/- 0.7, 3.7 +/- 0.4, and 2.2 +/- 0.3 fold increase vs non-angiotensin-stimulated tissues, for control, estradiol-, and progesterone-treated placenta, mean- +/- SEM, respectively). These data suggest that progesterone modulates the formation of second messengers in human placenta at term.

Angiotensin II↗
PubMed1993

Alpha 1-adrenoceptor subtypes and inositol phosphates production in heart ventricles of spontaneously hypertensive rats.

To study potential cardiac alpha 1-adrenoceptor changes in the stage of established hypertension, [3H]prazosin binding characteristics and norepinephrine (NE) stimulated production of inositol phosphates in the ventricular tissue of spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto control rats (WKY) were determined. The maximum number of cardiac [3H]prazosin binding sites was significantly reduced in SHR as compared with WKY rats, but the Kd values were similar in both groups of animals. Distribution of the [3H]prazosin-labeled high- and low-affinity binding sites for WB 4101 was similar in SHR and WKY rats. Pretreatment of ventricular heart membranes with the irreversible alpha 1B-adrenoceptor-selective antagonist chloroethylclonidine resulted in the same percentage of loss of specific [3H]prazosin binding in both groups of rats. Together, these results showed a similar ratio of alpha and alpha 1B-adrenoceptor subtypes in SHR and WKY rats. In addition, [3H]inositol phosphate accumulation in response to cardiac alpha 1-adrenoceptor stimulation by NE was significantly reduced in SHR as compared with WKY rats although the EC50 values were not significantly different in the two strains of animals. Thus, we conclude that in an established stage of hypertension there is a specific loss in the number of cardiac alpha 1-adrenoceptors with consequently reduced inositol phosphate turnover. These results are compatible with the reported decrease in the positive inotropic effect mediated through myocardial alpha 1-adrenoceptors in spontaneous hypertension.

Adrenergic alpha-Antagonists↗