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PubMed1989

Inositol lipid metabolism in vasopressin stimulated hepatocytes from rats infused with tumor necrosis factor.

We studied the effect of i.v. infusion of human recombinant tumor necrosis factor alpha (rHuTNF alpha, Cetus, 15 micrograms/100 g bw over 3 h) on vasopressin (VP)-stimulated 32P-inositol lipid turnover and the release of 3H-inositol phosphates in isolated rat hepatocytes. The early VP-induced decrease (within 30 s) in 32P-phosphatidylinositol 4-phosphate and 32P-phosphatidylinositol 4,5-bisphosphate labeling was significantly reduced (-40%) and at the same time the uptake of 32P into phosphatidic acid was 50% lower than in saline-infused (matched control) rats. Within 5 min of VP-stimulation, lower 32P phosphatidylinositol (-40%) and higher 32P-phosphatidic acid (+30%) labeling were observed in rHuTNF alpha-infused rats. Infusion of rHuTNF alpha also affected the VP-induced release of 3H-inositol phosphates. The accumulation of 3H-inositol-labeled water soluble products was decreased by 25% and 17% at 30 s and 10 min, respectively. These data show that rHuTNF alpha mimics early perturbations induced by Escherichia coli endotoxin infusion in VP-stimulated inositol lipid metabolism in rat hepatocytes.

Animals↗
PubMed1989

Accumulation of cAMP in the cells of Candida tropicalis at an early stage of ethanol-induced filamentous growth and its prevention by myo-inositol.

Phosphatidylinositol metabolism is enhanced in the cells of Candida tropicalis Pk 233 at an early stage of filamentous growth caused by ethanol, and myo-inositol prevents the ethanol-induced changes in the metabolism and morphology [Uejima et al. (1987) FEBS Lett. 214, 127-129]. The accumulation of cAMP and an increase in adenylate cyclase activity were observed in the cells grown with ethanol to the mid-log phase. Myo-inositol abolished these effects of ethanol also. The activity of cAMP phosphodiesterase was affected by neither ethanol nor myo-inositol. These results suggest that the inositol phospholipid-linked and cAMP-linked signaling pathways may be involved in the mechanism of ethanol-induced filamentous growth of this yeast and also that myo-inositol would affect morphogenesis by controlling these pathways.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1990

Cyclic GMP stimulates inositol phosphate production in cultured pituitary cells: possible implication to signal transduction.

Addition of the stable and permeable analog 8-bromo cyclic GMP (8-BR-cGMP) to myo-[2-3H]inositol prelabeled cultured rat pituitary cells results in enhanced formation of [3H]-myo-inositol monophosphate (IP1). The stimulatory effect of the cyclic nucleotide analog is additive to the effect of Li+, which accumulates IP1 via inhibition of inositol 1-monophosphatase, and also to the effect of gonadotropin releasing hormone (GnRH) which stimulates the formation of IP1, as well as that of inositol 1,4-bisphosphate (IP2) and inositol 1,4,5-trisphosphate (IP3) via enhanced hydrolysis of polyphosphoinositides. Many Ca2(+)-mobilizing hormones acting via phosphoinosite turnover also stimulate cGMP formation. The cyclic nucleotide might then serve as a modulator by further hydrolysis of phosphoinositides needed for protein kinase C activation.

Animals↗
PubMed1990

Hemoglobin causes release of inositol trisphosphate from vascular smooth muscle.

To test the hypothesis that oxyhemoglobin causes contraction of vascular smooth muscle by production of inositol 1,4,5-trisphosphate which results in a release of intracellular calcium, smooth muscle cells were exposed to oxyhemoglobin and inositol trisphosphate was measured. Oxyhemoglobin, but not methemoglobin which has much less contractile action, stimulated inositol trisphosphate production. The time course was consistent with an early role for this compound in the contraction produced by hemoglobin. The increase in production of inositol trisphosphate was inhibited by pertussis toxin and also by neomycin, an inhibitor of phospholipase C, although the actions of the latter compound cannot be attributed only to an inhibition of the enzyme responsible for the production of inositol trisphosphate.

Animals↗
PubMed1990

Nafenopin, a hypolipidemic and non-genotoxic hepatocarcinogen increases intracellular calcium and transiently decreases intracellular pH in hepatocytes without generation of inositol phosphates.

Addition of nafenopin (30-300 microM to 45Ca2+ preloaded cultured hepatocytes caused a rapid and concentration-dependent increase in 45Ca2+ efflux in a manner similar to vasopressin, as evidenced by the loss of radioactivity from the cells. In contrast to vasopressin, addition of nafenopin to [3H]inositol prelabelled hepatocytes in culture did not increase [3H]inositol phosphate production. When added simultaneously with vasopressin, nafenopin inhibited the vasopressin-stimulated [3H]inositol phosphate production. In hepatocyte suspensions isolated from rats treated for 1 week with a carcinogenic dose of nafenopin (1000 ppm in their daily food) the incorporation of [3H]inositol into the phosphoinositide fraction, particularly phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate, was much less than that in hepatocytes isolated from untreated rats. The vasopressin-stimulated [3H]inositol phosphate production was also decreased. Experiments with hepatocyte suspensions preloaded with Ca2+ or pH sensitive fluorescent indicators demonstrated that addition of nafenopin caused an increase in intracellular free Ca2+ and transient acidification of the cells. The increase in [Ca2+]i was decreased by only about 25% when extracellular calcium was removed indicating that nafenopin mainly mobilizes Ca2+ from intracellular stores. The recovery to basal pH was amiloride-sensitive indicating the importance of Na+/H+ exchange in pH recovery after intracellular acidification. Amiloride also inhibited DNA synthesis induced by nafenopin and by epidermal growth factor in cultured hepatocytes; but this effect occurred concomitantly with inhibition of basal DNA synthesis. We suggest that hepatic Ca2+ mobilization induced by nafenopin may play an important role in the mechanism by which nafenopin exerts its physiological as well as its tumour promotive activity upon chronic treatment with carcinogenic doses.

Animals↗
PubMed1994

Effects of perphenazine on the metabolism of inositol phospholipids in SK-N-BE(2) human neuroblastoma cells.

Administration of myo-[3H]inositol to SK-N-BE(2) human neuroblastoma cells for 24 hr resulted in equilibrium labelling of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP) and phosphatidylinositol 4,5-bisphosphate (PIP2), as well as in retention of a large intracellular pool of free myo-[3H]inositol. Equilibrium labelling was no longer observed when cells were treated for 2 hr with 20 microM perphenazine (PPZ) in label-free medium; under these conditions, myo-[3H]inositol from the retained intracellular pool was incorporated into PI and PIP but not into PIP2. Analysis of water-soluble myo-[3H]inositol derivatives and inositol 1,4,5-trisphosphate mass determination indicated that PPZ did not stimulate phosphoinositide hydrolysis by phospholipase C. These results indicate that PPZ raises PI and PIP levels, whereas it is ineffective in expanding the PIP2 pool. The latter effect is not due to a concomitant synthesis and hydrolysis of this lipid.

Cell Line↗
PubMed1995

Ethanol inhibits the peak of muscarinic receptor-stimulated formation of inositol 1,4,5-trisphosphate in neuroblastoma SH-SY5Y cells.

The effect of ethanol on muscarinic receptor-stimulated formation of inositol 1,4,5-trisphosphate was studied in human neuroblastoma SH-SY5Y cells. Stimulation with carbachol induced a biphasic increase of inositol 1,4,5-triphosphate with an initial peak after 10 sec declining to a plateau phase of elevation above basal levels, which was sustained for at least 5 min in the presence of agonist. The peak, but not the plateau phase, was concentration-dependently decreased by exposure to ethanol. Maximal inhibition was obtained within 30 sec of exposure to ethanol. Ethanol caused an increase in the EC50 value of carbachol for the initial rate of inositol 1,4,5-trisphosphate formation, measured after 10 sec of stimulation, from 98 microM in the absence to 196 microM in the presence of 100 mM ethanol. The potencies of pirenzepine and hexahydro-sila-difenidol hydrochloride for inhibiting [3H]quinuclidinyl benzilate binding and inositol 1,4,5-trisphosphate formation suggest that both phases are mediated via the muscarinic M1 receptor. Phorbol 12-myristate 13-acetate inhibited both phases of inositol 1,4,5-trisphosphate formation, whereas okadaic acid and modulators of cAMP-dependent protein kinase were without any effect. There was no inhibitory effect of ethanol when protein kinase C was inhibited by H7 and calphostin C, indicating that the ethanol effect is dependent on protein kinase C activity.

Carbachol↗
PubMed1991

Evidence that a proconvulsant action of lithium is mediated by inhibition of myo-inositol phosphatase in mouse brain.

Lithium inhibits myo-inositol mono- and polyphosphatase activity in brain at concentrations similar to those optimal for the treatment of manic depressive psychosis. A consequence of this inhibition is the possibility that the availability of myo-inositol for the regeneration of polyphosphoinositides involved in cellular signalling mechanisms may be reduced. While there are no good models of manic depressive disorders in rodents, lithium is known to alter their behavioural responsiveness to a number of neurotransmitter receptor agonists, but the role of the phosphatidylinositol second messenger system in these effects is unknown. Consistent with the myo-inositol depletion hypothesis, when injected directly into the CNS, myo-inositol, but not its biologically inactive epimer, scyllo-inositol or D-mannitol, has been found to reverse a proconvulsant action of lithium in mice given the muscarinic receptor agonist, pilocarpine.

Animals↗
PubMed1991

Estrogen modulates stimulation of inositol phospholipid hydrolysis by norepinephrine in rat brain slices.

The influence of estrogen on stimulation of inositol phospholipid hydrolysis by norepinephrine and carbamylcholine has been studied by measuring the accumulation of [3H]inositol-monophosphate ([3H]InsP) in cortical, hippocampal and striatal slices from ovariectomized rats. Repeated (but not a single) subcutaneous injections of estradiol benzoate (EB) (2 micrograms/animal once every 2 days for 10 days) markedly reduced stimulation of inositol phospholipid hydrolysis by norepinephrine in hippocampus and corpus striatum. Conversely, the efficacy of norepinephrine was increased in cortical slices. Estrogen treatment did not affect basal or carbamylcholine-stimulated [3H]InsP formation. In vitro addition of 17 beta-estradiol (1-100 nM) failed to modify norepinephrine- or carbamylcholine-induced [3H]InsP production in all regions examined. An increased density of alpha 1-adrenergic binding sites in cortical membranes paralleled the enhanced responsiveness of inositol phospholipid hydrolysis to norepinephrine induced by EB treatment in this area, whereas no significant changes in [3H]prazosin binding were found in membranes from hippocampus and corpus striatum. These results indicate that estrogen may affect inositol phospholipid hydrolysis in discrete brain areas, suggesting a complex role for estradiol in modulating noradrenergic receptor activity in the central nervous system.

Animals↗
PubMed1991

Ca2+ channel agonists enhance thyrotropin-releasing hormone-induced inositol phosphates and prolactin secretion.

The dihydropyridine Ca2+ channel activator BAY K 8644 (1 microM) stimulated basal prolactin secretion from perifused primary cultures of anterior pituitary cells and potentiated the stimulation of prolactin secretion by 1 microM thyrotropin-releasing hormone (TRH) 5-fold over 30 min. This potentiation was mimicked by other dihydropyridine agonists CGP 28392 and (+)-SDZ 202-791 and by (-)-BAY K 8644 (1 microM), but not by (+)-BAY K 8644. The Ca2+ channel antagonist nimodipine, at a concentration sufficient to block BAY K 8644-stimulated 45Ca2+ uptake in GH4C1 anterior pituitary tumor cells, decreased basal prolactin secretion and blocked the enhancement of basal and TRH-stimulated secretion by BAY K 8644. These results suggest that dihydropyridine agonists potentiate TRH-induced secretion through interaction with known stereospecific sites on Ca2+ channels. In GH4C1 cells, BAY K 8644 alone did not affect inositol polyphosphate accumulation, but potentiated TRH-stimulated accumulation of inositol 1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Accumulation of the Ca(2+)-mobilizing isomer inositol 1,4,5-trisphosphate was not potentiated, suggesting that potentiation of TRH-stimulated hormone secretion by BAY K 8644 does not result from synergistic stimulation of phospholipase C, but may correlate with enhanced inositol trisphosphate-3-kinase activity.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1985

Reversal of deficits in axonal transport and nerve conduction velocity by treatment of streptozotocin-diabetic rats with myo-inositol.

This study examined the effects of myo-inositol treatment on the deficits of motor nerve conduction velocity and of axonal transport of choline acetyltransferase in rats with streptozotocin-induced diabetes. Motor nerve conduction velocity was measured in seven groups of male rats. Two groups formed nondiabetic controls; one survived for 3 and the other for 6 weeks, then motor nerve conduction velocity was again measured and the accumulation of choline acetyltransferase activity proximal to a 24-h sciatic nerve constriction was estimated. The other five groups were rendered diabetic and subjected to similar measurements. Two diabetic groups were untreated and survived 3 or 6 weeks. The other three groups received myo-inositol for 1, 2, and 3 weeks, respectively, commencing 21 days after induction of diabetes. These groups survived for 4, 5, or 6 weeks, respectively. In all groups surviving for longer than 3 weeks an interim measurement of motor nerve conduction velocity was made 21 days after the start of the experiment (immediately before onset of treatment in the treated groups). In these groups a third measurement was made on the day before death. At death, choline acetyltransferase accumulation was measured and the remainder of the sciatic nerves was assayed for sorbitol and myo-inositol. In the two untreated diabetic groups we found reduced motor nerve conduction velocity, a deficit in the accumulation of choline acetyltransferase proximal to the sciatic nerve constriction, and a marked build-up of nerve sorbitol and a depletion of nerve myo-inositol. All three treated groups showed a reversal of this myo-inositol depletion without a reduction in the nerve sorbitol content.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Changes in the kinetics of inositol transport during TPA-induced differentiation of HL60 cells towards monocytes.

When exposed to the phorbol ester TPA, HL60 cells undergo growth arrest and differentiate towards monocytes. During TPA-induced differentiation there was a 2.6-fold increase in the rate of inositol transport (Vmax), a 2.1-fold increase in intracellular inositol and a 1.5-fold increase in inositol lipid. An increase in the Vmax of inositol transport did not occur when the variant cell line HL60Ast3 was exposed to TPA, which has been shown in this cell line to induce growth arrest but not differentiation. This observation suggests that the change in inositol transport during HL60 monocyte differentiation is specifically associated with the process of cell differentiation as opposed to growth arrest.

Biological Transport↗
PubMed1987

Differential effect of progesterone on the labeling of phosphatidylinositol with [3H]inositol and [32P]phosphate in the uterus of the estrogen-treated ovariectomized rat.

In rat uterine mince incubated in vitro [3H]inositol was found to be incorporated into phosphatidylinositol (PI) predominantly via a pathway which could be markedly and dose dependently activated with Mn2+ (0.1-10 mM) and inhibited by Ca2+ (1-10 mM). These ions had no effect on the incorporation of [32P]phosphate (32P) into PI indicating a distinct inositol-exchange mechanism for the labeling of PI with [3H]inositol. Treatment of ovariectomized rats for 5 days with 2 micrograms estradiol dipropionate (EDP) increased about 3-fold (when measured in the presence of 1 mM Mn2+) and 4-5-fold (when measured in the presence of 1 mM Ca2+) the inositol-exchange activity in the rat uterus, and these effects were suppressed by 40 and 30% respectively by the concomitant administration of 2 mg progesterone (P). EDP alone or in combination with P increased to the same extent (by a factor of 2-3) the rate of labeling with 32P of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and plasmenylethanolamine (PmE). The labeling rate of PI was increased 1.5-1.7-fold by treatment with EDP and this increase was selectively augmented further to about 2.5-fold by the simultaneous administration of P. Treatment with P alone had no significant effect on the incorporation of either labeled precursor. Steroid hormone treatments had no effect on the amount of these phospholipids in 100 mg uterine tissue, but they increased about 1.7-fold the rate of labeling of ATP with 32P. We conclude that P, when administered together with estradiol, regulates differentially the turnover of the inositol and phosphate moieties of PI with possible physiological consequences.

Adenosine Triphosphate↗
PubMed1985

Serotonergic agonists stimulate inositol lipid metabolism in rabbit platelets.

The metabolism of inositol phospholipids in response to serotonergic agonists was investigated in rabbit platelets. In platelets prelabelled with [3H]-inositol, in a medium containing 10 mM LiCl which blocks the enzyme inositol-1-phosphatase, 5-hydroxytryptamine (5-HT) caused a dose-dependent accumulation of inositol phosphates (IP). This suggests a phospholipase-C-mediated breakdown of phosphoinositides. Ketanserin, a selective 5-HT2 antagonist, was a potent inhibitor of the 5-HT response, with a Ki of 28 nM, indicating that 5-HT is activating receptors of the 5-HT2 type in the platelet. Lysergic acid diethylamide (LSD) and quipazine also caused dose-related increases in inositol phosphate levels, though these were considerably less than those produced by 5-HT. These results show that relatively small changes in phosphoinositide metabolism induced by serotonergic agonists can be investigated in the rabbit platelet, and this cell may therefore be a useful model for the study of some 5-HT receptors.

Animals↗
PubMed1996

Inhibition by NMDA of carbachol-stimulated inositol tetrakisphosphate accumulation in rat brain cortical slices.

The present studies examined the effect of NMDA on carbachol-stimulated accumulation of inositol polyphosphates, with emphasis on the accumulation of inositol 1,3,4,5-tetrakisphosphate (Ins 1,3,4,5-P4), at short time periods in rat brain cortical slices. There was a stimulatory effect of NMDA on accumulation of labeled inositol mono-, bis- and trisphosphates but not on labeled inositol tetrakisphosphates. In the presence of carbachol Ins 1,3,4,5-P4 accumulation was preferentially inhibited by NMDA at early time periods (within 30 seconds after NMDA addition). Subsequently, total phosphoinositide breakdown was inhibited by NMDA. NMDA did not stimulate accumulation of total Ins 1,3,4,5-P4 but immediately inhibited carbachol stimulated accumulation of Ins 1,3,4,5-P4. The inhibitory effect of NMDA (1 mM) was not mimicked by increasing K+ in the medium from 10 to 30 mM. However 30 mM K+ reversed the inhibitory effect of 1 mM NMDA on carbachol-stimulated Ins 1,3,4,5-P4. Parallel experiments with veratridine (a sodium channel activator) suggest that the early inhibitory effects of NMDA on Ins 1,3,4,5-P4 accumulation are not due to decreases in ATP availability or elevations in intracellular Na+. These data indicate that NMDA increases inositol mono-, bis- and trisphosphate accumulation while blocking muscarinic cholinergic stimulated accumulation of Ins 1,3,4,5-P4.

Adenosine Triphosphate↗
PubMed1985

Inositol affects the intracellular turnover of pulmonary surfactant phospholipids in the rat.

Rats, given a diet supplemented with 20% inositol, had threefold increased plasma inositol concentrations. The pool size of their alveolar surfactant fraction and their lamellar body fraction were the same as in the control rats and differences in phospholipid composition of the surfactant fractions were mainly restricted to changes in the percentages phosphatidylinositol (PI) and phosphatidylglycerol (PG). The change in phospholipid composition did not affect the pressure-volume relationship of the lungs. The labeling of phosphatidylcholine (PC), saturated phosphatidylcholine (SPC) or PI in the alveolar lavage fraction was the same for both groups, whereas labeling of alveolar PG was delayed in the inositol-fed rats. The specific activity-time relationships of the lamellar body phospholipids differed significantly between the control and inositol-fed rats and the differences in disappearance rate of the label from these fractions suggest that approximately 25-30% of the lamellar body material in inositol-fed rats is directed to a third, intracellular pool. We conclude that an increase in PI and a concomitant decrease in PG content of surfactant do not affect the clearance of alveolar surfactant, but enlarge the turnover of the lamellar body fraction because of intracellular degradation.

Animals↗
PubMed1988

Muscarinic stimulation of inositol phosphate formation in rat retina: developmental changes.

The stimulation of inositol phosphates by various cholinergic agonists and the effect of antagonists was studied in rat retinal slices of different ages. The potency order of muscarinic agonists and antagonists for receptors linked to inositol phosphate production was the same for retinas of all ages. The maximum stimulation of inositol phosphate production varied between retinas of different ages, being greatest in the younger animals and lowest in the adult. However, no difference was found in the EC50 values. This contrasts with the neurotransmitters, noradrenaline and serotonin, both known to stimulate phosphoinositide metabolism; neither was found to have the same developmental profile of carbachol-induced stimulation of inositol phosphates. In contrast to the muscarinic receptors linked to phosphoinositide hydrolysis, the density of muscarinic binding sites measured by [3H]QNB binding increased in retinas during development. The affinity constants (KD) remained constant, however. The results are interpreted as suggesting that muscarinic receptors linked to inositol phosphate production are more efficiently coupled (to a guanine regulator protein) in retinas of young animals than in the adult.

Animals↗
PubMed1986

Protein kinase C phosphorylates human platelet inositol trisphosphate 5'-phosphomonoesterase, increasing the phosphatase activity.

Phosphoinositide breakdown in response to thrombin stimulation of human platelets results in the formation of the calcium-mobilizing messenger molecules inositol 1,4,5-trisphosphate and inositol 1,2-cyclic-4,5-trisphosphate and of diglyceride, which activates protein kinase C. We find that protein kinase C phosphorylates and thereby increases the activity of inositol 1,4,5-trisphosphate 5'-phosphomonoesterase, a phosphatase that hydrolyzes these molecules to inert compounds. The 5'-phosphomonoesterase phosphorylated using [gamma-32P]ATP comigrates on SDS-polyacrylamide gels with a protein (40 kd) phosphorylated rapidly in response to thrombin stimulation of 32PO4-labeled platelets. Peptide maps of proteolytic digests of these two phosphorylated proteins indicate that they are the same. We propose that platelet Ca2+ mobilization is regulated by protein kinase C phosphorylation of the inositol 1,4,5-trisphosphate 5'-phosphomonoesterase. These results explain the observation that phorbol ester treatment of intact human platelets results in decreased levels of inositol trisphosphate and decreased Ca2+ mobilization upon subsequent thrombin addition.

Blood Platelets↗