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PubMed1999

Superoxide anion-induced formation of inositol phosphates involves tyrosine kinase activation in smooth muscle cells from rat mesenteric artery.

Our previous studies have demonstrated an enhanced production of inositol phosphates (IPs) induced by superoxide in smooth muscle cells (SMCs). The mechanisms for this effect, however, remained largely unknown. In the present study, it was found that superoxide increased IP production in SMCs from rat mesenteric arteries in a time-dependent manner. The effect of superoxide on IP formation was significantly inhibited by the antioxidants n-acetylcysteine or alpha-lipoic acid. Genistein and tyrphostin A25, two tyrosine kinase inhibitors, also inhibited the superoxide-induced IP formation. The application of monoclonal antibody against phospholipase Cgamma (PLCgamma) significantly inhibited the superoxide-induced IP formation. Finally, the expression level of PLCgamma proteins was increased 6 hrs after exposing SMCs to superoxide. The present findings demonstrate that superoxide activates the tyrosine kinase pathway and suggest that the tyrosine kinase-mediated IP formation may represent a novel mechanism underlying the signalling role of superoxide in rat mesenteric artery SMCs.

Acetylcysteine↗
PubMed1990

Cyclic AMP antagonizes mitogen-induced accumulation of inositol phosphates in human peripheral mononuclear leucocytes in vitro.

The effect of intracellular increases of cyclic adenosine monophosphate (cAMP) on the accumulation of inositol phosphates (IPs) in response to various mitogens in vitro in human peripheral mononuclear leucocytes (MNL) was investigated. The beta-adrenoceptor agonists inhibited mitogen-induced IPs-accumulation by about 30-50% with a rank order of potency isoprenaline greater than adrenaline much greater than noradrenaline. This rank order corresponded with the order of potency of the beta-adrenoceptor agonists to generate cAMP. The beta-adrenoceptor agonist-induced inhibition of IPs-accumulation in response to mitogen could be completely prevented by the beta 2-adrenoceptor selective antagonist ICI 118,551, but not by the beta 1-adrenoceptor selective antagonist CGP 20712A. Furthermore, the isoprenaline-induced inhibition of IPs-accumulation in response to mitogen could be enhanced by the phosphodiesterase inhibitor IBMX. We conclude that cAMP antagonizes mitogen-induced IPs-accumulation in human peripheral MNL in vitro.

Adrenergic beta-Agonists↗
PubMed1994

Age-related changes in angiotensin II-stimulated vascular contraction and inositol phosphate accumulation in Fischer 344 rats.

This study examined the influence of age on angiotensin II (AII)-stimulated vascular contractile responses and inositol phosphate (IP) accumulation in Fischer 344 rats. In the aorta, AII-stimulated contraction and IP accumulation were markedly reduced in 6- and 24-month-old rats compared to 1-month-old rats. There was not a significant difference in the contractile response to AII between 6- and 24-month-old rats, although IP hydrolysis showed a further decrease between 6 and 24 months. In tail artery, there were no differences in contraction and phosphoinositol metabolism in response to AII in the different ages. Losartan blocked AII-stimulated vascular contraction and IP hydrolysis in both aorta and tail artery while PD123319 did not inhibit either response. These data indicate that during maturation, there is a decline in AII-stimulated aortic contraction and IP accumulation in aorta but not in tail artery and these changes are due to altered AT1 receptor function.

Aging↗
PubMed1990

Alpha 1-adrenergic receptor subtypes and formation of inositol phosphates in dispersed hepatocytes and renal cells.

The ability of alpha 1a- and alpha 1b-adrenergic receptor subtypes to stimulate [3H]inositol phosphate [( 3H]InsP) formation was examined in collagenase-dispersed hepatocytes and renal cells. alpha 1-Adrenergic receptor binding sites were labeled with 125I-BE 2254, and the proportion of alpha 1a and alpha 1b subtypes was determined with chloroethylclonidine (CEC) and WB 4101. Hepatocytes contained only alpha 1b-adrenergic receptors, whereas renal cells had approximately equal proportions of both subtypes. Pretreatment of renal cells with CEC selectively inactivated the alpha 1b subtype, leaving a homogeneous population of alpha 1a receptors. Norepinephrine stimulated [3H]InsP accumulation to a similar extent in both hepatocytes and renal cells. Pretreatment with CEC inactivated this response completely in hepatocytes but only partially in renal cells. WB 4101 was 1000-fold more potent in inhibiting the [3H]InsP response in renal cells than hepatocytes; however, some of this difference was due to rapid metabolism of WB 4101 by hepatocytes. After correction for metabolism, WB 4101 was still 11-fold more potent in inhibiting norepinephrine-stimulated [3H]InsP formation in hepatocytes (alpha 1b) than in CEC-pretreated renal cells (alpha 1a). These results demonstrate that both alpha 1a- and alpha 1b-adrenergic receptor subtypes activate formation of [3H]InsP, although the molecular mechanisms by which these responses occur remain to be determined.

Animals↗
PubMed1993

Muscarinic M3 receptors mediate total inositol phosphates accumulation in murine HSDM1C1 fibrosarcoma cells.

Muscarinic receptors in murine fibrosarcoma HSDM1C1 cells were characterized using both radioligand binding and total inositol phosphates accumulation (IPs). Muscarinic agonists elicited a concentration-dependent enhancement of IPs accumulation with a maximum of 14-fold stimulation above basal level. The following potencies (-log EC50) were observed for the full agonists: (+)-cis-dioxolane 5.4, oxotremorine-M 5.3, (+)-muscarine 5.2 and carbachol 5.0. Bethanechol (4.1) and arecoline (5.0) were partial agonists, evoking 43 and 55%, respectively of the maximum level of stimulation to (+)-cis-dioxolane, whereas pilocarpine and McN-A-343 were inactive as agonists (1 mumol/l-1 mmol/1). The apparent affinities for muscarinic antagonists (-log KB) estimated by Schild regression were: 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) 9.2, dicyclomine 7.0, pirenzepine 6.9, (+/-)-p-F-HHSiD (para-fluoro-hexahydro-siladifenidol) 7.0, AF-DX 116 6.2, methoctramine 5.7. In saturation binding studies using [3H]N-methylscopolamine a homogeneous population of sites was identified, with a density of 145 pmol/mg protein. In competition radioligand binding studies, the following apparent affinities (-log Ki) were observed: 4-DAMP 9.7, dicyclomine 8.3, (+/-)-p-F-HHSiD 7.6, AF-DX 116 6.8, methoctramine 6.6 and gallamine 6.8. In binding studies all antagonists studied recognized a single population of sites, as judged by the Hill coefficients from the displacement isotherms. These data are consistent with HSDM1C1 cells expressing an apparent homogeneous muscarinic M3 population that mediates a large level of total IPs accumulation. This clonal line may provide a useful model to further elucidate relationship between endogenous muscarinic M3 receptor stimulation and IPs accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2003

Effects of ginsenosides on carbachol-stimulated formation of inositol phosphates in rat cortical cell cultures.

We examined the effect of ginseng total saponins (GTS) on phosphoinositide metabolism stimulated by activation of muscarinic receptor using rat cortical cultures. Carbachol stimulated formation of [3H]inositol phosphates ([3H]InsPs) by 3.3-fold over basal level in [3H]inositol-prelabeled cells. Pretreatment of GTS inhibited formation of [3H]InsPs evoked by carbachol by 70%-90%. Addition of GTS alone had no effect on the basal formation of [3H]InsPs. The inhibitory effect of the GTS on carbachol-stimulated formation of [3H]InsPs was dose- and time-dependent. IC50 was 6.0 +/- 2.8 microg/ml. We also examined the effect of GTS on [3H]InsP1, [3H]InsP2, or [3H]InsP3 formation evoked by carbachol. Although GTS had no effect on the basal [3H]InsP1, [3H]InsP2, or [3H]InsP3 formation, pretreatment of GTS inhibited [3H]InsP1, [3H]InsP2, or [3H]InsP3 formation evoked by carbachol, respectively. Addition of individual ginsenosides such as ginsenoside Rb1, Rc, Rd, Re, or Rg2 had no effect on the basal formation of [3H]InsPs, whereas pretreatment of ginsenoside Rb2, Rc, Rd, Re, Rf, Rg1 or Rg2 inhibited formation of [3H]InsPs evoked by carbachol by 79%-89%. The results suggest that the inhibitory effect of GTS and its individual ginsenosides on carbachol-stimulated formation of [3H]InsPs in cortical neurons could be one pharmacological action of Panax ginseng.

Animals↗
PubMed1989

Angiotensin II receptor-mediated stimulation of cytosolic-free calcium and inositol phosphates in chick myocytes.

We have described previously positive inotropy and increased levels of inositol-l-phosphate as in vitro responses to angiotensin II in cardiac tissue. In this study, changes in cardiac myocyte-free cytosolic calcium stimulated by angiotensin II were monitored with the fluorescent calcium indicator dye Fura-2. There was an initial peak transient increase followed by a sustained increase in cytosolic-free calcium in response to angiotensin II (10(-9)-10(-6) M). The peak transient response in cytosolic-free calcium after addition of angiotensin II (10(-7) M) occurred at 23 +/- 4 sec and was stimulated 2.16-fold (332 +/- 56 nM) above basal levels (154 +/- 14.7 nM). The calcium response was blocked or reversed by addition of verapamil (10(-8) M), lanthanum (0.2 mM) and zero calcium buffer. Angiotensin II receptor-mediated stimulation of inositol phosphates was quantified after separation by high-performance liquid chromatography in cultured chick heart cells prelabeled with L-myo-[1,2-3H(N)]inositol. A time course indicated that the peak response of the angiotensin II (10(-8) M)-stimulated increase in inositol-1,4,5-trisphosphate was at 30 sec. Angiotensin II (10(-8) M) significantly stimulated inositol-1,4-diphosphate (45%) and inositol-1,4,5-trisphosphate (78%) above basal levels. Bordetella pertussis toxin treatment of myocyte cultures in doses (500 ng/ml, 24 hr) shown to fully ADP-ribosylate a toxin-sensitive 41 KD alpha-subunit, blocked completely the angiotensin II-stimulated increases in inositol 1,4-diphosphate, inositol-1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. The rise in cytosolic-free calcium in response to angiotensin II was not blocked or inhibited by toxin pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed2002

Stimulatory effects of pituitary adenylate cyclase-activating polypeptide on inositol phosphates accumulation in avian cerebral cortex and hypothalamus.

This study has demonstrated that the short and long form of the pituitary adenylate cyclase-activating polypeptide (PACAP), i.e. PACAP(27) and PACAP(38), moderately but significantly, and in a concentration (0.5-5 microM)-dependent manner, stimulated inositol phosphates (IPs) accumulation in myo-[(3)H]inositol-prelabeled cerebral cortical and hypothalamal slices of chick and duck, and in slices of rat cerebral cortex; both peptides had no effect on IPs formation in rat hypothalamus. Vasoactive intestinal peptide (VIP; 0.5-5 microM) weakly enhanced IPs accumulation in chick hypothalamus, had no significant action in chick cerebral cortex (in fact there was a tendency to attenuate the IPs response in this tissue), and slightly, but significantly, inhibited the IPs accumulation in rat cerebral cortex. VIP showed no activity in rat hypothalamus. It is concluded that the stimulatory action of PACAP on phosphoinositide metabolism in avian cerebral cortex, similar to rat cerebral cortex, is mediated via phospholipase C-linked PAC(1) type receptors. In chick hypothalamus, however, there may be a component of VPAC type receptors stimulating IPs formation.

Animals↗
PubMed1986

The labelling of polyphosphoinositides with [32P]Pi and the accumulation of inositol phosphates in vasopressin-stimulated hepatocytes.

When hepatocytes were incubated with [32P]Pi, the kinetics for the labelling of the monoester phosphate groups of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate were similar to each other and slightly slower than that for the labelling of the gamma-phosphate of ATP. Analysis of the water-soluble 3H-labelled materials derived from [3H]inositol-labelled hepatocytes revealed that, in addition to inositol and its mono-, bis- and tris-phosphates (Ins, InsP, InsP2 and InsP3), these cells contained two unidentified radioactive compounds which co-eluted with InsP on anion-exchange chromatography. When [3H]inositol-labelled hepatocytes were stimulated with 0.23 microM-vasopressin in the presence of 10 mM-Li+, there was an accumulation of radioactivity in InsP, InsP2 and InsP3 but not in Ins or the two unidentified compounds. Further analysis of these inositol phosphates by h.p.l.c. revealed that vasopressin also stimulates the accumulation of inositol tetrakisphosphate (InsP4) in these cells. Vasopressin-stimulated InsP and InsP2 accumulations were maximal in the presence of 1-10 mM-Li+ but InsP3 accumulation continued to increase up to 50 mM-Li+. Accumulated inositol phosphates were retained within the cell. Li+ from 1 to 50 mM did not influence the extent of vasopressin-stimulated inositol lipid degradation in hepatocytes. In the absence of Li+, radioactivity in vasopressin-stimulated hepatocytes accumulated almost entirely in free inositol. The vasopressin-stimulated accumulation of inositol phosphates in the presence of 10 mM-Li+ was abolished by a V1-vasopressin antagonist. Inositol phosphate accumulation was not influenced by ionophore A23187, dimethyl sulphoxide or indomethacin.

Adenosine Triphosphate↗
PubMed1992

Noradrenaline-stimulated inositol phosphate accumulation in arteries from spontaneously-hypertensive rats.

1. The effects of noradrenaline upon polyphosphoinositide (PPI) breakdown was investigated by measuring the accumulation of inositol phosphates (IPs) in tail arteries from normo- (WKY) and spontaneously-hypertensive (SHR) rats. 2. Noradrenaline (10(-7)-10(-3) M) evoked a concentration-dependent increase in total IP accumulation in both WKY and SHR rats but no significant differences between the populations were detected. 3. In contrast, significant differences in the accumulation of the individual IPs, which contributed to the total IP, occurred. A significantly greater noradrenaline-stimulated accumulation of inositol trisphosphate (IP3) was observed in tissues from SHR compared with those from WKY rats at each effective concentration of noradrenaline. This was paralleled by an equivalent reduction in inositol monophosphate (IP1) accumulation, consistent with the lack of a significant difference in noradrenaline-stimulated total IP accumulation between the two populations. 4. In time course studies, an enhanced noradrenaline-induced accumulation of IP3, in SHR compared to WKY rats, occurred from the earliest time point studied after the addition of the catecholamine both in the presence and absence of LiCL (10 mM). In the presence of LiCl (10 mM) no significant difference in noradrenaline-evoked total IP accumulation between SHR and WKY rats was observed; in the absence of LiCl noradrenaline-evoked a greater total IP accumulation in SHR than in WKY rats at all time points investigated. 5. These studies suggest that the main reason for the enhanced noradrenaline-induced accumulation of IP3 in arteries from SHR rats is a reduced rate of dephosphorylation of both IP3 and inositol bisphosphate (IP2) rather than a greater formation of IP3 from PPIs.6. This enhanced accumulation of IP3 may result in an increased calcium mobilisation accounting for the increased contractility to noradrenaline of tail arteries from SHR as compared with those from WKY rats.

Animals↗
PubMed1993

Alteration of membrane fatty acid composition and inositol phosphate metabolism in HT-29 human colon cancer cells.

The present study was designed to investigate the role of membrane fatty acid (FA) composition on inositol phosphate (InsP) release by a human colon tumor cell line. Cells were supplemented for five days in culture with 0, 10, 30, or 100 microM sodium stearate (18:0), linoleate [18:2(omega-6)], or linolineate [18:3(omega-3)]. These FAs were supplied as a complex with FA-free bovine serum albumin. InsP release was examined in these cells with or without stimulation with deoxycholic acid (DCA) after they were labeled with [3H]myoinositol. FA enrichment was found to influence inositol incorporation into membrane lipids. Although 18:0 had no effect, 18:2(omega-6) decreased the incorporation. On the other hand, 18:3(omega-3) increased the incorporation of inositol compared with the cells supplemented with the other FAs, but they were not different from control. Basal release of total InsP was elevated only with supplementation of 10 and 30 microM 18:3(omega-3). FA supplementation with 18:0 at 30 microM and 18:2 at 30 and 100 microM resulted in downregulation of bsal release of InsP. Enrichment of HT-29 cell membranes with polyunsaturated FAs resulted in a significant increase in stimulated release of InsP, but this was not seen with saturated FA supplementation. At 10 microM supplementation, 18:2 had the greatest effect on stimulated InsP release. This effect of 18:2 disappeared at 30 microM. However, the increase in the stimulated InsP release caused by 18:3 occurred at 10 and 30 microM. DCA-stimulated release of InsP was not downregulated by any FA supplementation. This study showed that enrichment of the membranes with polyunsaturated FAs increases the response of the phosphatidylinositol cycle to DCA stimulation. In addition, enrichment with 18:3(omega-3) increases the basal turnover of InsP. It is concluded that alteration of membrane FAs has a profound effect on the phosphatidylinositol cycle.

Colonic Neoplasms↗
PubMedDate not supplied

Angiotensin II stimulates inositol phosphate formation in rat anterior pituitary glands.

The effect of angiotensin II (AII) on polyphosphoinositide (PPI) turnover at the pituitary was studied. When [3H]inositol-prelabelled rat anterior hemipituitaries were incubated with AII (10 microM) for 30 min in the presence of Li+ (10 mM), the production of IP, IP2 and IP3 were increased to 182, 199 and 158% of paired control values. Time course studies showed that the stimulation of IP3 formation by AII was significant after 2 min incubation and preceded the accumulation of the other inositol phosphates. The specificity of the AII effect was confirmed by inhibition with the specific AII antagonist, saralasin. These findings suggest that AII action at the anterior pituitary can be mediated via the early hydrolysis of PPI.

Angiotensin II↗
PubMed1986

Stimulation, by vasopressin and other agonists, of inositol-lipid breakdown and inositol phosphate accumulation in WRK 1 cells.

WRK 1 cells were labelled to equilibrium with 2-myo-[3H]inositol and stimulated with vasopressin. Within 3 s of hormone stimulation there was a marked accumulation of 3H-labelled InsP2 and InsP3 (inositol bis- and tris-phosphate), but not of InsP (inositol monophosphate). There was an associated, and rapid, depletion of 3H-labelled PtdInsP and PtdInsP2 (phosphatidylinositol mono- and bis-phosphates), but not of PtdIns (phosphatidylinositol), in these cells. Some 4% of the radioactivity in the total inositol lipid pool of WRK 1 cells was recovered in InsP2 and InsP3 after 10 s stimulation with the hormone. The selectivity of the vasopressin receptors of WRK 1 cells for a variety of vasopressin agonists and antagonists revealed these to be of the V1a subtype. There was no receptor reserve for vasopressin-stimulated inositol phosphate accumulation in WRK 1 cells. The accumulation of inositol phosphates was enhanced in the presence of Li+ions. Half-maximal accumulation of InsP, InsP2 and InsP3 in vasopressin-stimulated cells was observed with 0.9, 3.0 and 3.6 mM-Li+ respectively. Bradykinin and 5-hydroxytryptamine also provoked inositol phosphate accumulation in WRK 1 cells. The effects of sub-optimal concentrations of bradykinin and vasopressin upon inositol phosphate accumulation were additive, but those of optimal concentrations of the hormones were not.

Animals↗
PubMed2006

myo-Inositol phosphate isomers generated by the action of a phytate-degrading enzyme from Klebsiella terrigena on phytate.

For the first time a dual pathway for dephosphorylation of myo-inositol hexakisphosphate by a histidine acid phytase was established. The phytate-degrading enzyme of Klebsiella terrigena degrades myo-inositol hexakisphosphate by stepwise dephosphorylation, preferably via D-Ins(1,2,4,5,6)P5, D-Ins(1,2,5,6)P4, D-Ins(1,2,6)P3, D-Ins(1,2)P2 and alternatively via D-Ins(1,2,4,5,6)P5, Ins(2,4,5,6)P4, D-Ins(2,4,5)P3, D-Ins(2,4)P2 to finally Ins(2)P. It was estimated that more than 98% of phytate hydrolysis occurs via D-Ins(1,2,4,5,6)P5. Therefore, the phytate-degrading enzyme from K. terrigena has to be considered a 3-phytase (EC 3.1.3.8). A second dual pathway of minor importance could be proposed that is in accordance with the results obtained by analysis of the dephosphorylation products formed by the action of the phytate-degrading enzyme of K. terrigena on myo-inositol hexakisphosphate. It proceeds preferably via D-Ins(1,2,3,5,6)P5, D-Ins(1,2,3,6)P4, Ins(1,2,3)P3, D-Ins(2,3)P2 and alternatively via D-Ins(1,2,3,5,6)P5, D-Ins(2,3,5,6)P4, D-Ins(2,3,5)P3, D-Ins(2,3)P2 to finally Ins(2)P. D-Ins(2,3,5,6)P4, D-Ins(2,3,5)P3, and D-Ins(2,4)P2 were reported for the first time as intermediates of enzymatic phytate dephosphorylation. A role of the phytate-degrading enzyme from K. terrigena in phytate breakdown could not be ruled out. Because of its cytoplasmatic localization and the suggestions for substrate recognition, D-Ins(1,3,4,5,6)P5 might be the natural substrate of this enzyme and, therefore, may play a role in microbial pathogenesis or cellular myo-inositol phosphate metabolism.

6-Phytase↗
PubMed1994

Growth factor induced mitogenic effects and inositol phosphate responses in primary hepatocyte cultures from normal rat liver and rat liver nodules.

In our studies of normal and neoplastic growth regulation, we have compared growth factor induced second messenger response and mitogenic activity in a rat hepatocarcinogenesis model. Inositol phosphate (IP) turnover was measured by incubating the cells with [3H]inositol and stimulating them with either epidermal growth factor, diferric transferrin, ferricyanide, vasopressin, norepinephrine, angiotensin II or bombesin for 2 min. The IPs formed were separated on HPLC. Mitogenic responses were monitored by bromodeoxyuridine uptake and labeling index. IP turnover was stimulated by vasopressin, norepinephrine and angiotensin II in both normal and nodular cells, but not by the other four agonists tested. The IP response was somewhat lower in cells from liver nodules. All compounds except bombesin were mitogenic to both nodular cells and cells from normal rats of different ages, with epidermal growth factor inducing the largest mitogenic response. Bombesin, on the other hand, had only a minor effect on normal cells, but induced a pronounced mitogenic response in nodular cells. In normal rats, the cells' ability to respond to growth stimulation decreased with increasing rat age. In this respect, nodular cells behaved in a way more like young normal cells than their age-matched controls. Taken together, these data support the view of liver nodules being a more autonomous cell population, with increased sensitivity to growth factors and possibilities for autocrine growth stimulation.

Animals↗
PubMed1989

K+ differentially affects the excitatory amino acids- and carbachol-elicited inositol phosphate formation in rat brain synaptoneurosomes.

K+, excitatory amino acids (EAAs) and carbachol (Carb) were tested separately or in pairs for their ability to stimulate inositol phosphate (IPs) formation in rat forebrain synaptoneurosomes. K+ ions per se, stimulate IPs synthesis (158% of the control value) as well as EAAs and Carb. The glutamate (Glu)- and quisqualate (QA)-elicited IPs formation is not additive with that evoked by K+. Inversely, K+ ions (up to 30 mM) potentiate the Carb-induced IPs accumulation. These results indicate that QA (or Glu) and Carb enhance IPs formation independently and that QA- and K+ -induced IPs responses are interdependent. This suggests that they share a 'common intermediate' step in the multistep mechanism which leads from receptor activation to the IPs synthesis. This 'common intermediate' step may be depolarization and/or Na+ influx.

Amino Acids↗
PubMedDate not supplied

Acute stress stimulates 3H-inositol phosphates accumulation in rat cerebral cortex. An in vivo determination.

Using an in vivo method, we examined the effects of acute stress on rat brain inositol phosphates (IPs) levels. Cerebral phosphoinositides were prelabeled with 3H-myoinositol injected i.c.v. 24 h prior to a 15 min forced swimming stress. The stressful condition resulted in a 35% increase in whole brain 3H-IPs content, mainly due to an enhancement in cerebral cortical 3H-IPs accumulation. Cerebellar and brain minus cortex levels of 3H-IPs showed no alteration in stressed animals. Among the IPs, stress induced a 102% and 92% increase in the cerebral cortical content of 3H-IP and 3H-IP2 respectively. Pretreatment of animals with diazepam (2 mg/kg, i.p.) prevented the stress-induced 3H-IPs increase, in both the whole brain and the cerebral cortex. Diazepam administration alone did not produce changes in 3H-IPs. These results suggest that an acute stress condition stimulates in vivo the brain IPs turnover, probably because of an enhanced receptor-linked hydrolysis of phosphoinositides.

Animals↗
PubMed1987

Stimulation of inositol phosphate formation in FRTL-5 rat thyroid cells by catecholamines and its relationship to changes in 45Ca2+ efflux and cyclic AMP accumulation.

Catecholamines specifically stimulated the rapid formation of inositol phosphates, bisphosphates and trisphosphates in a concentration-dependent manner in FRTL-5 thyroid cells. Further analysis by high performance liquid chromatography revealed the presence of two isomers of inositol trisphosphate, 1,4,5- and 1,3,4-trisphosphate, suggesting that the 1,4,5-trisphosphate of inositol is further metabolized to the 1,3,4-trisphosphate isomer. The alpha 1-adrenoreceptor antagonist, prazosin, inhibited the effects of epinephrine, while the alpha 2-adrenoreceptor antagonist, yohimbine, was without effect. Treatment of FRTL-5 cells with pertussis toxin (to inhibit Ni) did not abolish the epinephrine effect on inositol trisphosphate formation. Carbachol, N6-[L-2-phenylisopropyl]-adenosine and forskolin were without effect on phosphoinositide metabolism. Both epinephrine and the calcium ionophore A23187 stimulated 45Ca2+ efflux from 45Ca2+-loaded FRTL-5 cells. The time-course of the epinephrine effect indicates that inositol 1,4,5-trisphosphate formation (t1/2 approximately 1 s) precedes both the efflux of 45Ca2+ (t1/2 approximately 30 s) as well as the reduction of cyclic AMP levels (t1/2 approximately 90 s) in response to epinephrine. These results strongly suggest that inositol 1,4,5-trisphosphate has the appropriate properties to act as a second messenger by which alpha 1-adrenergic hormones, through mobilization of intracellular Ca2+ and activation of cyclic AMP phosphodiesterase, reduce cyclic AMP levels in FRTL-5 cells.

Animals↗