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PubMed1988

Chronic exposure to high glucose decreases myo-inositol in cultured cerebral microvascular pericytes but not in endothelium.

It has been proposed that the development of diabetic complications may involve a depletion of cellular myo-inositol due to an increase in polyol (sorbitol) formation. We therefore initially examined the effect of diabetes on levels of these metabolites in isolated cerebral microvessels. Compared with microvessels from control rats, microvessels from diabetic animals showed no detectable alteration in myo-inositol levels and a small increase in sorbitol content. To assess whether myo-inositol depletion might occur in only certain microvascular cells, cultured bovine cerebral microvascular pericytes and endothelium were grown for 3 or 18-20 days at 1.1, 5.5, or 22.2 mmol/l glucose. Increased medium glucose concentration resulted in increased sorbitol content in both cell types after both periods of incubation (p less than 0.05). In contrast, a significant decrease in myo-inositol content (22%, p less than 0.01) was observed only in pericytes grown for 18-20 days in the high glucose medium. Neither the adenosine 5'-triphosphate content nor the adenosine 5'-triphosphate/adenosine 5'-diphosphate (ATP/ADP) ratio of the pericytes was affected by the medium glucose concentration, indicating that the decrease in myo-inositol was not caused by a deficiency in the cellular energy state affecting the active transport of myo-inositol. These data suggest that myo-inositol depletion occurs selectively in the pericyte, a cell type known to be the site of early morphological changes in diabetes. Furthermore, the depletion apparently requires prolonged exposure to high glucose and is not due to a change in energy state.

Adenosine Diphosphate↗
PubMed1993

Restoration of brain myo-inositol levels in rats increases latency to lithium-pilocarpine seizures.

Lithium pretreatment in rats potentiates the epileptogenic effects of pilocarpine and other cholinergic agonists. In order to determine if this effect of lithium could be reversed by myo-inositol, rats were pretreated with intracerebroventricular (ICV) injections of myoinositol, artificial CSF or L-chiro-inositol. Lithium chloride, 3 meq/kg was administered intraperitoneally 20-24 h prior to the subcutaneous injection of pilocarpine, 20 or 30 mg/kg. In both experiments, myo-inositol significantly prolonged the latency to the appearance of clonic seizures and lowered the pilocarpine seizure score. myo-Inositol prevented the development of clonic seizures in 50% of the rats receiving pilocarpine, 20 mg/kg. The levels of cortical myo-inositol in rats injected with myo-inositol were approximately double those of the CSF and L-chiro-inositol groups.

Animals↗
PubMed1998

Augmentation of lithium's behavioral effect by inositol uptake inhibitors.

Lithium inhibits the enzyme inositol monophosphatase and thus obstructs the enzymatic degradation of inositol triphosphate (IP3) to inositol in the phosphate-phosphoinositide (PIP) cycle. This inhibition may result in reduced availability of the second messengers IP3 and DAG that are derivates of the PIP cycle, and this action is currently a leading hypothesis regarding lithium's therapeutic and prophylactic effect in affective disorders. Inositol is also available to the cell by uptake from the intercellular matrix, and therefore it is possible that compounds that block the uptake may have lithium-like effects. To test this hypothesis, the present study evaluates the effects of two inositol uptake inhibitors, the carbohydrate L-fucose and the cyclodepsipeptide nordidemnin, in a behavioral model of pilocarpine-induced seizures known to be enhanced by lithium. We tested the possibility that L-fucose produces lithium-like effects, or that L-fucose or nordidemnin augment lithium's behavioral effects. Results indicate that acute ICV treatment with L-fucose did not by itself have a lithium-like effect in the behavioral model, but significantly augmented lithium's effect when combined with lithium treatment. Nordidemnin treatment showed similar effects. The results suggest that when inositol monophosphatase is inhibited by lithium, further restriction of cellular inositol availability may result in an augmentation of lithium's behavioral effects. It is possible that such manipulations may be applicable in the treatment of patients with affective disorders, especially patients who are poor responders to lithium monotherapy.

Animals↗
PubMed1988

Gradient ion chromatography of inositol phosphates.

Inositol phosphates including phytic acid were separated in 30 min by gradient ion chromatography with postcolumn derivatization. All four pentakisphosphates were resolved, while four tetrakisphosphate peaks were detected. The limits of detection for all polyphosphates, including tris- and bisphosphates, were between 1 and 2 nmol. The method was used to compare nonenzymatic dephosphorylation of inositol hexakisphosphate at pH 4.0 versus pH 10.8. The only pentakisphosphate detected in calf brains was identified as myo-inositol 1,3,4,5,6-pentakisphosphate. The major pentakisphosphate in raw soybean seeds was myo-inositol 1,2,4,5,6-pentakisphosphate of unknown enantiomeric composition, while lesser amounts of myo-inositol 1,2,3,4,5-pentakisphosphate of unknown enantiomeric composition, myo-inositol 1,2,3,4,6-pentakisphosphate, and myo-inositol 1,3,4,5,6-pentakisphosphate were also present.

Animals↗
PubMed1989

The separation of [32P]inositol phosphates by ion-pair chromatography: optimization of the method and biological applications.

We have developed an ion-pair reverse-phase HPLC method to measure inositol phosphates in 32P-labeled cells. The different chromatographic parameters were analyzed to optimize the resolution of the 32P-labeled metabolites. Analysis of inositol phosphates in biological samples was improved by a single charcoal pretreatment which eliminated interfering nucleotides without removing inositol phosphates. The kinetics of production of inositol phosphates in calcium-activated erythrocytes, vasopressin-stimulated hepatocytes, and thrombin-activated platelets were analyzed. Original data on the activation of phosphoinositide phospholipase C were obtained in intact erythrocytes by direct measurement of inositol (1,4,5)P3. Data from agonist-stimulated hepatocytes and platelets were consistent with those from previous studies. In conclusion, this technique offers many advantages over the methodologies currently employed involving anion-exchange chromatography and [3H]inositol labeling: (i) 32P labeling is less expensive and more efficient than 3H labeling and can be used with all types of cells without permeabilization treatments and (ii) ion-pair HPLC gives good resolution of inositol phosphates from nucleotides with shorter retention times, and long reequilibration periods are not required.

Blood Platelets↗
PubMed1979

A defect of the myo-inositol maintenance mechanism in the lens of hereditary cataract mice.

The myo-inositol uptake system was studied in lenses of normal and hereditary cataract mouse. The normal mouse was able to accumulate myo-inositol continuously from medium and keep it in a high concentration. The specific myo-inositol uptake was dependent on temperature and it decreased in Ca(2+)-free medium. In contrast, specific uptake of myo-inositol reached a plateau after 15 min in the cataract mouse lens although initial incorporation was more rapid than that in normal mouse lens. This uptake system was not affected by temperature or Ca(2+) in the medium. The rate of myo-inositol efflux into the medium was more rapid in the cataract lens than that of the normal lens. It was shown that the low level of myo-inositol in the lens of hereditary cataract mouse was due to the defect of myo-inositol transport system and the enhanced efflux rate. These results suggest a dysfunction of the lens membrane.

Animals↗
PubMed1991

myo-inositol transport in rat intestinal brush border membrane vesicles, and its inhibition by D-glucose.

The uptake of myo-inositol into rat intestinal brush border membrane vesicles (BBMV) has been investigated. It is demonstrated that myo-inositol is transported into the vesicles by a secondary active process, specifically using the sodium gradient as the driving force. In the absence of sodium gradient, the transport reaction is still sodium dependent, and rheogenic, indicating that a myo-inositol/sodium cotransport is likely to occur. A kinetic analysis shows an hyperbolic saturation process with a Km of 0.16 +/- 0.02 mM with respect to myo-inositol and Vmax of 68.5 +/- 21.2 pmol/min per mg protein. The transport is inhibited by D-glucose, phloridzin and few other sugars. The mechanism of D-glucose inhibition appears to be of the mixed type. Finally, the myo-inositol transport is trans-activated by myo-inositol itself, but not by D-glucose. It is concluded that myo-inositol is transported into rat intestine BBMV by a specific transport system, which is also able to bind D-glucose, but not efficiently transport it across the membrane.

Animals↗
PubMed1995

Sodium-independent carrier-mediated inositol transport in cultured renal epithelial (LLC-PK1) cells.

In addition to the concentrative, Na(+)-dependent inositol transport system demonstrated in many cell types, carrier-mediated, Na(+)-independent inositol transport is also shown to exist in LLC-PK1 renal epithelia. Inhibition of inositol uptake in Na(+)-free saline by 0.1 mM phloretin, and self-inhibition by net concentrations of inositol exceeding 10 mM, demonstrate the carrier-mediation of the Na(+)-independent uptake and distinguish it from flux through anion channels. The Na(+)-dependent uptake exhibits higher affinity for inositol, as seen by the stronger self-inhibition at lower inositol concentrations in Na+ saline. Kinetic analyses indicate a Km of 178 microM and a Vmax of 2447 pmol/min per microgram DNA for the Na(+)-dependent system, whereas the lower affinity, lower capacity Na(+)-independent system manifests a Km of 5.2 mM and a Vmax of 249 pmol/min per microgram DNA. the Na(+)-independent uptake further differs from the Na(+)-dependent transport by the lack of inhibitory effect of 10 microM glucose, and the greater relative inhibition of phloretin compared to that of phlorizin. Both types of uptake appear to localize predominantly to the basal-lateral cell surface. The Na(+)-independent transport is bidirectional, functioning in efflux as well as influx of inositol.

Animals↗
PubMed1989

Differences in the metabolism of inositol and phosphoinositides by cultured cells of neuronal and glial origin.

Phosphoinositide and inositol metabolism was compared in glioma (C6), neuroblastoma (N1E-115) and neuroblastoma X glioma hybrid (NG 108-15) cells. All cell lines had similar proportions of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), and phosphatidylinositol 4,5-bisphosphate (PIP2). Neuroblastoma and hybrid cells had almost identical phospholipid and phosphoinositide compositions and similar activities for the enzymes metabolizing polyphosphoinositides (PI kinase, PIP phosphatase, PIP kinase, PIP2 phosphatase, PIP2 phosphodiesterase). Glioma cells differed by having greater proportions of ethanolamine plasmalogen and sphingomyelin, lower PIP kinase, 3-5-fold higher PIP phosphatase activity and 10-15-fold greater PIP2 phosphodiesterase activity. Higher PIP phosphatase and PIP2 diesterase activities appear to be characteristic of cells of glial origin, since similar activities were found in primary cultures of astroglia. Glioma cells also metabolize inositol differently. In pulse and pulse-chase experiments, glioma cells transported inositol into a much larger water-soluble intracellular pool and maintained a concentration gradient 30-times greater than neuroblastoma cells. Label in intracellular inositol was less than in phosphoinositides in neuroblastoma and exchanged rapidly with extracellular inositol. In glioma, labeling of intracellular inositol greatly exceeded that of phosphoinositides. As a consequence, radioactivity in prelabeled phosphoinositides could not be effectively chased from glioma cells by excess unlabeled inositol. Such differences between cells of neuronal and glial origin suggest different and possibly supportive roles for these two cell types in maintaining functions regulated through phosphoinositide-linked signalling systems in the central nervous system.

1-Phosphatidylinositol 4-Kinase↗
PubMed1985

Specific binding of concanavalin A to free inositol and liposomes containing phosphatidylinositol.

We previously reported that concanavalin A could bind specifically to liposomes containing phospholipids and lacking glycoconjugates (Biochem. Biophys. Res. Comm. 74, 208, 1977). In the present study we show that the binding of concanavalin A to the liposomes was greatly increased (up to 5 fold) by the presence of phosphatidylinositol in the liposomes. Furthermore, the binding of concanavalin A to phosphatidylinositol-liposomes was specific and could be inhibited by either alpha-methyl mannoside or by myo-inositol. We also found that concanavalin A-induced lymphocyte mitogenesis could be inhibited either by alpha-methyl mannoside or by myo-inositol. Simultaneous addition of both inhibitors to concanavalin A and liposomes showed that inhibition was non-competitive: alpha-methyl mannoside was more inhibitory to liposomes lacking phosphatidylinositol, and myo-inositol was more inhibitory to liposomes containing phosphatidylinositol. This suggests that the binding site for inositol might be different than that for mannose. Equilibrium dialysis and Scatchard plots revealed 4 binding sites each for inositol and mannose at neutral pH. The binding constants of concanavalin A were 0.13 X 10(4) and 0.25 X 10(4) liters/mole respectively for inositol and mannose. We conclude that concanavalin A binds specifically to the inositol portion of phosphatidylinositol.

Animals↗
PubMed1985

Manganese stimulates incorporation of [3H]inositol into an agonist-insensitive pool of phosphatidylinositol in brain membranes.

In a particulate preparation from rat brain, manganese ions stimulate the incorporation of [3H]inositol into inositol phospholipids in a concentration-dependent manner. Incubation with CDP-diacylglycerol (0.5 mM) alone had no effect on the incorporation of [3H]inositol but potentiated the stimulatory effect of manganese. Despite the increase in [3H]inositol incorporation into phosphatidylinositol, the carbachol-induced accumulation of [3H]inositol-1-phosphate was unaltered in membranes preincubated with manganese but when coincubated with CDP-diacylglycerol the carbachol-induced accumulation of [3H]inositol-1-phosphate was increased. These data suggest that manganese stimulates the incorporation of [3H]inositol into an agonist-insensitive pool of phosphatidylinositol.

Animals↗
PubMed1990

Autocrine motility factor stimulates a three-fold increase in inositol trisphosphate in human melanoma cells.

The biochemical pathways through which tumor cell locomotion is mediated are poorly understood. Autocrine motility factor (AMF), which is produced by and stimulates motility in A2058 human melanoma cells, was used to characterize phosphoinositide (PtdIns) metabolism activated in association with tumor cell motility. AMF stimulated up to a 400% increase in de novo incorporation of 3H-myo-inositol into cellular lipids beginning 40 minutes after exposure. In cells prelabeled with 3H-myo-inositol, AMF stimulated a 200% increase in total inositol phosphates (inositol monophosphate, InsP1; inositol bisphosphate, InsP2; inositol trisphosphate, InsP3) after 90 minutes of exposure, with a 300% maximal increase in InsP3 at 120 minutes. InsP1 and InsP2 were maximally increased 130% of control values. Treatment with AMF stimulated a parallel dose-dependent increase in both motility and PtdIns levels. We have shown previously that the A2058 motile response to AMF is inhibited markedly by cell pretreatment with pertussis toxin (PT). Inositol phosphate production was inhibited by a 2-hour pretreatment of cells with PT (0.5 microgram/ml). PT treatment of A2058 membranes was associated with ADP-ribosylation of a 40-kDa protein consistent with the presence of an alpha subunit of a guanine nucleotide-binding protein (G protein). These data indicate that AMF elicits increases in cell motility and phosphoinositide metabolism via a PT-sensitive G protein signal transduction pathway.

Adenosine Diphosphate Ribose↗
PubMed1985

Relationship between stimulated inositol lipid hydrolysis and contractility in guinea-pig visceral longitudinal smooth muscle.

Carbamylcholine caused a marked, concentration-dependent stimulation of [3H]Ins P, [3H] InsP2 and to a lesser extent [3H]InsP3 production in guinea-pig longitudinal smooth muscle prelabelled with myo-[3H]inositol. Accumulation of these three inositol phosphates showed differential sensitivity to LiCl. Muscle contraction was apparent at lower concentrations of carbamylcholine. Both responses were mediated via muscarinic-type receptors. An association of inositol phosphate production and contractility was also observed in response to substance P, histamine and noradrenaline, the latter via an alpha-adrenergic mechanism. The Ca2+-channel agonist CGP 28392 failed to stimulate inositol phosphate production despite inducing a contractile response. Carbamylcholine -induced inositol phosphate production persisted in the presence of D600 or Mn2+ despite loss of contractile activity. However, both responses showed a similar, marked dependence on the presence of Ca2+ in the extracellular medium. Mn2+ could restore basal and stimulated inositol phosphate production in low Ca2+ solutions but could not substitute for Ca2+ in restoring contractility. The results suggest that stimulated inositol lipid hydrolysis in longitudinal smooth muscle does not result from Ca2+ entry into the tissue, although the response does depend on the concentration of divalent cations in the extracellular medium. This dependency may be related to the maintenance of membrane potential and possibly phospholipid conformation.

Animals↗
PubMed1989

Long-term lithium treatment selectively reduces receptor-coupled inositol phospholipid hydrolysis in rat brain.

Rats were treated with dietary lithium for 30 days, followed by assessment of the activity of the receptor-coupled inositol phospholipid second messenger-producing system in three brain regions. The major effect of long-term lithium treatment was a significant reduction of the response to norepinephrine in all three brain regions that were examined: the cerebral cortex, the hippocampus, and the striatum. After long-term lithium treatment, the response to serotonin was reduced in the hippocampus and striatum, but not the cortex, and the carbachol-induced response was only reduced in the striatum. Lithium treatment did not alter the incorporation of [3H]inositol into phospholipids, the in vitro lithium concentration-dependent accumulation of [3H]inositol monophosphate, or the stimulation by NaF of inositol phospholipid hydrolysis. These results indicate that the decreased responses to agonists after long-term lithium treatment are not likely to be due to depletion of inositol phospholipids or to altered activity of myo-inositol-1-phosphatase, phospholipase C, or the guanine nucleotide-binding protein. It is suggested that long-term lithium treatment may alter receptor number or receptor coupling, perhaps by phosphorylation, thereby selectively lowering the agonist-induced generation of second messengers by the inositol phospholipid system.

Animals↗
PubMed1992

The preparation of intermediates for the synthesis of 1D-myo-inositol 1,4,5-trisphosphate, a second messenger for signal transduction in cells.

Racemic 1,2,4-tri-O-benzyl-5,6-O-isopropylidene-myo-inositol was prepared by a new route involving crotyl (but-2-enyl) ethers and converted into the (-)-omega-camphanates to give the pure crystalline 1L-diastereoisomer and the chirally impure, syrupy 1D-diastereoisomer. The latter was converted via the 1-O-allyl or 1-O-p-methoxybenzyl ethers into chirally pure 1D-2,3,6-tri-O-benzyl-myo-inositol [required as an intermediate for the synthesis of 1D-myo-inositol 1,4,5-trisphosphate (1,4,5-IP3)], which was also prepared by de-p-methoxybenzylation of 1D-2,3,6-tri-O-benzyl-1,5-di-O-p-methoxybenzyl-myo-inositol. Racemic 2,4-di-O-benzyl-5,6-O-isopropylidene-1-O-p-methoxybenzyl-myo-inositol was prepared in a similar way to the analogous tribenzyl ether (using crotyl ethers) and the omega-camphanate esters behaved similarly, allowing efficient resolution by crystallisation of the (-)- and (+)-omega-camphanates. Racemic 1,2,4-tri-O-allyl-3-O-(but-2-enyl)-myo-inositol was resolved via the (-)-omega-camphanates and was also converted into 1,2,4-tri-O-(cis-prop-1-enyl)-myo-inositol, an alternative intermediate for the synthesis of 1,4,5-IP3.

Animals↗
PubMed1991

Inositol 1,4,5-triphosphate phosphatase activity in membranes isolated from amphibian skeletal muscle [corrected].

The hydrolysis of [3H]inositol 1,4,5-trisphosphate by a soluble fraction and by isolated transverse tubule and sarcoplasmic reticulum membranes from frog skeletal muscle was studied. Transverse tubule membranes displayed rates of hydrolysis several-fold higher than those of sacroplasmic reticulum and soluble fraction; Km and Vmax were 25.2 microM and 44.1 nmol/mg/min, respectively. Transverse tubule membranes sequentially hydrolyzed inositol trisphosphate to inositol bisphosphate, inositol 1-phosphate and inositol, indicating that these membranes have inositol bis- and monophosphatases in addition to inositol trisphosphatase.

Animals↗
PubMed1992

Production of inositol phosphates and reactive oxygen metabolites in quartz-dust-stimulated human polymorphonuclear leukocytes.

The present paper explores phosphoinositide turnover in quartz-stimulated human polymorphonuclear leukocytes. Separation of inositol phosphates was carried out with a new ion-pair, reverse-phase high performance liquid chromatographic method applying a gentle tetrabutyl ammonium phosphate buffer gradient. The method separates inositol monophosphates, inositol 1,4-bisphosphate, inositol trisphosphates and inositol 1,3,4,5-tetrakisphosphate. Reactive oxygen metabolites, indices for leukocyte activation, were measured with a luminometric assay. Quartz increased the production of reactive oxygen metabolites, preceded by facilitated inositol phosphate turnover. This finding provides evidence that inositol phosphate second messengers may be involved in quartz-induced leukocyte activation and subsequent production of reactive oxygen metabolites.

Chromatography, High Pressure Liquid↗
PubMed1982

myo-inositol in the reproductive tract of the female rat.

1. myo-Inositol concentrations in oviduct, ovary and uterus were many-fold those of blood serum during all four stages of the estrous cycle of the female rat. 2. Inositol concentration was higher in oviduct than in ovary or uterus and was lower in uterine fluid than in uterus. 3. Estrus uteri had higher inositol concentrations than uteri in other phases of the cycle. 4. In order to measure dynamic aspects of the distribution of inositol, the distribution of radioactivity among organs of the reproductive tract of mature female rats was measured 45 min after i.p. injection of [2-3H]myo-inositol. 5. These organs concentrated inositol from the blood, and the tissue radioactivity (expressed as dpm/mg wet wt of tissue) increased in the sequence: vagina less than cervix less than uterus less than ovary less than oviduct. 6. The uterus and ovary concentrated myo-inositol more strongly during proestrus than during metestrus, diestrus of estrus. 7. The contents of proestrus follicles were more highly radioactive than was the ovary itself, whereas proestrus uterine fluid was less radioactive than the uterine tissue.

Animals↗