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At least 793 records · Page 44Linked to original sources

PubMed1992

Effects of vasopressin on phosphoinositide hydrolysis and myocardial contractility.

The effects of vasopressin on phosphoinositide hydrolysis, ventricular contractility and adrenoceptor-mediated inotropy were studied in the rabbit. Vasopressin caused an accumulation of [3H]inositol monophosphate in ventricular slices prelabelled with myo-[3H]inositol, whereas it elicited a small but definite negative inotropic effect. In addition, vasopressin attenuated the positive inotropic effect elicited via alpha 1- and endothelin receptors without affecting the beta-adrenoceptor-mediated effect. The nonpeptide-selective V1 receptor antagonist OPC 21268 (a quinolinone derivative) inhibited the vasopressin-induced accumulation of [3H]inositol monophosphate. The present results indicate that vasopressin stimulates phosphoinositide hydrolysis via V1 receptors, but inhibits force and the alpha 1-mediated positive inotropic effect in the rabbit ventricular myocardium.

Animals↗

PubMed1994

5-HT1C receptor-mediated phosphoinositide hydrolysis in the rat choroid plexus after chronic treatment with clozapine.

Chronic treatment with clozapine (14 days; 10 and 25 mg/kg/day) decreases 5-HT1C receptor density but not affinity in rat choroid plexus measured with [3H]mesulergine. We now report the effects of the same clozapine treatment regimens on the function of 5-HT1C receptors (measured by maximal stimulation of 5-HT1C receptor-mediated phosphoinositide hydrolysis) in relation to receptor changes in rat choroid plexus. Quantitative 5-HT1C receptor autoradiography indicated that chronic clozapine treatment decreased, in a dose-related manner, 5-HT1C receptor binding sites labeled by antagonist ([3H]mesulergine) and agonist ([125I](+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, [125I]DOI) radioligands. However, only the higher dose of clozapine decreased statistically significantly the maximal 5-HT1C receptor-mediated phosphoinositide hydrolysis response. Chronic administration of haloperidol (0.5 mg/kg/day) did not change any of the 5-HT1C receptor parameters. In conclusion, chronic clozapine treatment is able to modulate the function of 5-HT1C receptors. This further strengthens the possibility that 5-HT1C receptors may contribute to some of the atypical effects of clozapine.

Amphetamines↗

PubMed1987

Phosphoinositide metabolism in resting and thrombin-stimulated human platelets. Evidence against metabolic heterogeneity.

The specific radioactivity of the phosphodiester and phosphomonoester moieties of the phosphoinositides was determined in resting and thrombin-stimulated platelets that were prelabelled with [32P] Pi. In the unstimulated cells, the specific radioactivity of the monoester phosphates of PIP and PIP2 was similar. Both prolonged incubation at 37 degrees C and upon stimulation with 0.5 U/ml of thrombin, the specific radioactivity of the monoester phosphates decreased 10-15% in both polyphosphoinositides. In the unstimulated cells, the specific radioactivity of the diester phosphates was similar in PI, PIP and PIP2 but amounted only to 3% of the activity of the monoester groups. Prolonged incubation of the unstimulated cells as well as stimulation with thrombin induced a similar 5-6 fold increase in specific radioactivity of the diester phosphate of PI, PIP and PIP2. The results indicate that the phosphoinositides in both resting and thrombin-stimulated platelets exist in a metabolically homogeneous pool.

Adenosine Triphosphate↗

PubMed1987

Effect of adrenergic agonists on phosphoinositide breakdown in rat skeletal muscle preparations.

Adrenergic regulation of phosphoinositide breakdown in rat skeletal muscle was investigated in 30-min incubations with 10 mM LiCl. In rat hemidiaphragms, prelabelled with D-myo-[2-3H]inositol, addition of alpha-agonists (epinephrine, norepinephrine, phenylephrine) induced a 5-8-fold increase of [3H]inositol monophosphate accumulation. This could be prevented by inclusion of alpha-antagonists (phentolamine, prazosin). beta-Agonists and/or beta-antagonists had no effect. Similar experiments with isolated flexor digitorum brevis muscle fibers yielded confirmatory results. Functional integrity of beta-receptor mediated processes was suggested by the beta-agonist-induced increase of glucose 6-phosphate in hemidiaphragms and cAMP in fiber preparations. The results indicate that phosphoinositide breakdown in differentiated rat skeletal muscle is, at least in part, under alpha-adrenergic control.

Adrenergic alpha-Agonists↗

PubMed1989

Stimulation of phosphoinositide hydrolysis via class I antigen-specific recognition in murine cardiac tissue.

Induction of polyphosphoinositide hydrolysis in cardiac tissue by specific recognition of class I histocompatibility antigens was assayed. C3H (H-2k) mice auricles were labelled with myo-[3H]inositol precursor and inositol phosphate production in the presence or absence of anti-class I k products was measured. Anti-class I, but not anti-class II products specifically increased phosphoinositide turnover. This increment was partially blocked by muscarinic cholinergic and alpha-adrenergic blockers and even more so by the phospholipase C inhibitor NCDC. Alloantibodies specifically directed against class I antigens could then exert stimulation of phospholipase C-mediated phosphoinositide hydrolysis through the interaction with muscarinic cholinergic and/or alpha-adrenergic receptors. The induction of intracellular second messengers by class I antigens and hormone-receptor interactions is discussed.

Animals↗

PubMed1990

Extracellular ATP activates receptor-operated cation channels in mouse lacrimal acinar cells to promote calcium influx in the absence of phosphoinositide metabolism.

In exocrine acinar cells a variety of neurotransmitters (e.g. acetylcholine) stimulate phosphatidylinositol 4,5-bisphosphate hydrolysis elevating intracellular calcium to activate calcium-dependent membrane currents (outward K+ and inward Cl-). This study shows that in lacrimal acinar cells extracellular application of ATP is also associated with outward and inward current responses; these, however, are not the result of phosphoinositide metabolism. ATP directly activates receptor-operated cation channels which permit influx of Na+ and Ca+ (the inward current). The elevation in [Ca2+]i which results is sufficient to activate the outward K+ current. ATP thus promotes Ca+ influx in the absence of phosphoinositide metabolism.

Acetylcholine↗

PubMed1991

Characterization of the interaction of doxorubicin with (poly)phosphoinositides in model systems. Evidence for specific interaction with phosphatidylinositol-monophosphate and -diphosphate.

The anticancer drug doxorubicin penetrates into Langmuir monolayers containing phosphoinositides. Upon binding of doxorubicin to phosphoinositide-containing SUV, its fluorescence is self-quenched due to self-association. As compared to other anionic phospholipids, as much as 2- to 3-fold larger effects were obtained with PIP and PIP2, in mixtures of these lipids with DOPC. Doxorubicin competes efficiently with the non-penetrating antibiotic neomycin for binding to PIP2. According to its penetration, specific binding of doxorubicin was half-maximal at 5-15 microM. It is likely that also in biological membranes doxorubicin binds specifically to PIP and PIP2.

Doxorubicin↗

PubMed1994

Erythrocyte band 3 protein strongly interacts with phosphoinositides.

85% of the phosphorus coisolated with band 3 protein during separation of the intrinsic proteins of the human erythrocyte membrane by zonal electrophoresis in high concentrations of acetic acid was found to be derived from phosphoinositides, mainly phosphatidylinositol 4,5-bisphosphate. When native band 3 protein and pyrene-labelled phospholipids were present in micelles of the nonionic detergent nonaethyleneglycol lauryl ether, strong resonance energy transfer was observed between the tryptophan residues and phosphatidylinositol 4,5-bisphosphate and, to a smaller degree, phosphatidylinositol 4-phosphate. We conclude that band 3 protein strongly interacts with phosphoinositides, in particular with phosphatidylinositol 4,5-bisphosphate.

Anion Exchange Protein 1, Erythrocyte↗

PubMed1990

Serotonin plays a major role in serum-induced phospholipase C-mediated hydrolysis of phosphoinositides and DNA synthesis in vascular smooth muscle cells.

Whole blood serum (WBS) rapidly induced the phospholipase C-mediated hydrolysis of phosphoinositides and subsequently stimulated DNA synthesis in cultured rabbit vascular smooth muscle cells (VSMCs). Ketanserin, a serotonin (S2) receptor antagonist, markedly inhibited the WBS-induced phospholipase C reaction and DNA synthesis. Serotonin by itself had a weak mitogenic activity for VSMCs, but this vasoconstrictor markedly stimulated the platelet-derived growth factor- and epidermal growth factor-induced DNA synthesis. The stimulatory effect of serotonin on the growth factor-induced DNA synthesis was inhibited by ketanserin. The amount of serotonin contained in WBS was sufficient to induce the phospholipase C reaction and stimulate the growth factor-induced DNA synthesis. These results indicate that serotonin plays a major role in the WBS-induced phospholipase C-mediated hydrolysis of phosphoinositides and DNA synthesis in rabbit VSMCs and suggest that serotonin may act as an important growth regulator for VSMCs in addition to acting as a vasoconstrictor.

Animals↗

PubMed1992

The effects of low density lipoprotein and high density lipoprotein on phosphoinositide hydrolysis in bovine aortic endothelial cells.

Low density lipoprotein (LDL) and high density lipoprotein (HDL3) were tested for their ability to induce inositol phospholipid turnover and inositol phosphate production in bovine aortic endothelial cells (BAEC). The production of inositol phosphates following hydrolysis of the phosphoinositides was demonstrated by two methods; release of [3H]inositol phosphates after labelling with [3H]myo-inositol and by a direct binding assay for inositol 1,4,5-trisphosphate (InsP3). Acute exposure to LDL induced InsP3 release at low concentrations of the lipoprotein within the physiological range of LDL in tissues. HDL3 did not cause any release of the inositol phosphates. Pre-incubation of BAEC with HDL3 suppressed bradykinin- and LDL-induced inositol phosphate production in BAEC in a concentration-dependent manner. It is concluded that LDL acutely stimulates phosphoinositide breakdown and that pre-incubation of cells with HDL3 inhibits this effect. The mechanism responsible for these effects remains to be elucidated.

Animals↗

PubMed1989

Phorbolester inhibits alpha 1-adrenoceptor mediated phosphoinositide breakdown in cardiomyocytes.

The regulation of and the intracellular events following alpha 1-adrenergic receptor stimulation of myocardium are not completely understood. The alpha 1-adrenergic stimulation of phosphoinositide breakdown was examined in a culture of neonatal rat ventricular myocytes and the influence of a protein kinase C activator, phorbol 12-myristate 13-acetate, on this process was studied. Inositolphosphate accumulation was stimulated by phenylephrine (EC50 5 microM) in the presence of 10 mM LiCl. The increase was antagonized by prazosin (10(-6) M) but not by propranolol (10(-6) M). The rate of inositolphosphate accumulation after prolonged alpha 1-adrenoceptor stimulation decreased without clear evidence of depletion of the membrane phosphatidylinositolbisphosphate pool. Phorbol ester treatment (IC50 10(-8) M) led to a dose-dependent inactivation of alpha 1-adrenoceptor stimulated phosphoinositide breakdown. These findings provide evidence that protein kinase C plays a role in the regulation of alpha 1-adrenoceptor sensitivity.

Animals↗

PubMed1989

Proopiomelanocortin-derived peptides, phosphoinositides, cAMP, and aldosterone secretion.

Since the intracellular messengers of various proopiomelanocortin-derived peptides remain ambiguous at best, we have investigated the possible involvement of phosphoinositide metabolism in aldosterone secretion evoked by alpha-MSH, beta-LPH, as well as ACTH in rat and calf adrenal glomerulosa cells. We have also examined the cAMP responses in the adrenal glomerulosa cells to alpha-MSH comparing it with those of ACTH. Our results showed that neither alpha-MSH, beta-LPH, nor ACTH increased inositol triphosphate (IP3) or other inositol phosphates in adrenal glomerulosa cells while increasing aldosterone secretion from the same cells. Angiotensin II, known to cause hydrolysis of the phosphoinositides, increased IP3 in these adrenal cells in a dose-dependent manner. Both ACTH and alpha-MSH raised the cAMP levels in the calf adrenal glomerulosa cells, although the magnitude of the increase of cAMP in response to ACTH was greater. These findings suggest that IP3 as a mediator of alpha-MSH- and beta-LPH-induced aldosterone secretion is not likely and other mediator(s) may be involved.

Adrenocorticotropic Hormone↗

PubMed1991

Melittin stimulates phosphoinositide hydrolysis and placental lactogen release: arachidonic acid as a link between phospholipase A2 and phospholipase C signal-transduction pathways.

Previous investigations from this laboratory have implicated both phospholipase A2 and phospholipase C in the regulation of human placental lactogen release from human trophoblast. To study further the role of endogenous phospholipase A2 and the relationship between phospholipase A2 activation and phosphoinositide metabolism, we examined hPL and [3H]-inositol release from trophoblast cells in response to agents that stimulate or inhibit the endogenous enzyme. Melittin (0.5-2.0 micrograms/ml) stimulated rapid, dose-dependent, and reversible increases in the release of hPL, prostaglandin E, and [3H]-inositol. Mepacrine (0.1-0.25 mM) inhibited this stimulation. However, mepacrine had no effect on the stimulation of hPL and [3H]-inositol release by exogenous arachidonic acid (AA). These results indicate that the stimulation by melittin of phosphoinositide metabolism and hPL release is mediated by initial activation of phospholipase A2. Furthermore, the results support the possibility that AA, released as a consequence of phospholipase A2 activation, can act as a second messenger linking the two phospholipase pathways.

Arachidonic Acid↗

PubMed1991

Leukotriene C4-induced phosphoinositide hydrolysis in rat basophilic leukemia cell.

Leukotriene C4 (LTC4), one of the major constituents of the slow reacting substance of anaphylaxis, induced a dose-dependent hydrolysis of phosphoinositides in [3H]inositol-prelabeled rat basophilic leukemia (RBL-1) cells. The EC50 for LTC4 to elicit the half maximum accumulation of [3H]inositol phosphates (IPs) was around 20 nM. The increase in the formation of [3H]inositol bisphosphate (IP2) and [3H]inositol trisphosphate (IP3) was detectable at 2 min after the stimulation and progressed up to 30 min. Accumulation of [3H]inositol monophosphate (IP1) was observed only during the late phase of 5-30 min in the presence of LiCl. When cells were stimulated with LTC4 and LTD4 together, there was no additive accumulation in [3H]IPs. Pretreatment of cells with either LTC4 or LTD4 resulted in a decrease in production of [3H]IPs on further stimulation with the same agonist. The desensitization appeared to be heterologous since pretreatment of cells with LTC4 attenuated the responsiveness to LTD4. Conversely, pretreatment with LTD4 also diminished the responsiveness to LTC4 markedly. These results suggest that both LTC4- and LTD4-induced hydrolysis of phosphoinositides are mediated through the same effector in RBL-1 cells.

Animals↗

PubMed1992

Chronic cocaine administration decreases norepinephrine-induced phosphoinositide hydrolysis in rat aorta.

The effect of chronic cocaine administration on norepinephrine stimulated hydrolysis of inositol 1,4,5-trisphosphate from the membrane phosphatidylinositol phosphate pool in isolated rat aorta was investigated. Rats received saline (controls), or 10 or 20 mg/kg cocaine once a day for 15 days. This treatment resulted in a dose-dependent reduction in norepinephrine (0.36 microM) stimulated phosphoinositide hydrolysis. The effect of acute cocaine was determined by adding 30 microM cocaine to the in vitro incubation solution. When aortas were exposed to cocaine and norepinephrine simultaneously, in vitro, inositol phosphate formation doubled. By itself, cocaine did not affect phosphoinositide hydrolysis. Contraction of aortic helical strips by norepinephrine decreased in tissues from rats chronically treated with 20 mg/kg cocaine. In vitro cocaine shifted the norepinephrine concentration/response curve to the left and increased the maximum response. Neither acute nor chronic cocaine treatment affected prazosin's apparent dissociation constant, suggesting that cocaine did not affect receptor affinity. These data suggest that chronic, but not acute cocaine administration may interfere with pharmacomechanical coupling in rat aorta.

Animals↗

PubMed1994

Stimulation of phosphoinositide hydrolysis by glyceraldehyde-3-phosphate in electroporated HIT-T15 cells.

HIT-T15 cells labeled with myo-[3H] inositol were permeabilized by electroporation and subsequently stimulated with various glycolytic intermediates in the presence of 20 mM LiCl in a buffer mimicking cytosolic ionic composition. Of the various glycolytic intermediates tested, only D-glyceraldehyde-3-phosphate (G3-P) stimulated the formation of labeled inositol phosphates. The half-maximal response to G3-P occurred at a concentration of 0.75 mM. Formation of inositol phosphates in electroporated cells was also observed in response to GTP. G3-P further potentiated the formation of inositol phosphates in response to GTP, however, the interaction between G3-P and GTP was additive rather than synergistic, indicating that G3-P stimulates phosphoinositide hydrolysis in a manner different than the receptor mediated GTP-dependent activation of phospholipase C. The potentiation of the GTP response by G3-P did not appear to involve inhibition of the GTPase activity of a phosphoinositide-specific G protein, since G3-P also potentiated the formation of inositol phosphates in response to GTP-gamma-S or NaF in a nearly additive manner.

Analysis of Variance↗

PubMed1993

Serotonergic, 5-HT2, receptor-mediated phosphoinositide turnover and mobilization of calcium in cultured rat retinal pigment epithelium cells.

Cultured rat retinal pigment epithelium cells are shown to contain serotonergic, 5-HT2, receptors associated with phosphoinositide turnover and mobilization of intracellular calcium. Serotonin at a concentration of 10 microM induced a 2.5-fold increase in [3H]-inositol phosphates (more than 75% is in the form of [3H]-inositol-1-phosphate) accumulation within 30 min in cells preincubated in [3H]-myo-inositol and exposed to 5 mM lithium chloride. The EC50 value of serotonin was approx. 0.9 microM and the saturation concentration was 100 microM. Serotonin analogues like tryptamine, 5-methoxytryptamine, alpha-methyl-serotonin and the 5-HT2 agonists quipazine and DOI (1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane) all stimulated InsPs accumulation to some degree. Carbachol, noradrenaline, isoproterenol, dopamine, tryptophan, 5-hydroxytryptophan, 8-hydroxy-2(di-n-propyl-amino) tetralin, 2-methyl-serotonin and NECA (5'-[N-ethyl]-carboxamidoadenosine) were inactive. The serotonin-induced response was blocked most effectively by ketanserin and methysergide but not by 5-HT3 or 5-HT1 antagonists. The serotonin response was attenuated by the active phorbol ester, 4 beta-phorbol 12-myristate 13-acetate and this was attenuated by the non-selective protein kinase C inhibitor, staurosporine. Pertussis toxin failed to influence the serotonin-mediated phosphoinositide turnover. Addition of serotonin to cultures loaded with Fura-2 showed a transient increase in calcium concentrations in most of the cells. This change in calcium was independent of external calcium and the serotonin response was attenuated by ketanserin but not by the 5-HT3 antagonist granisetron.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Thrombin-induced abnormal platelet activation in spontaneously hypertensive rats is linked with phosphoinositides turnover and phosphorylation of 47,000 and 20,000 dalton proteins.

We have shown earlier that abnormal platelet aggregation in spontaneously hypertensive rats (SHR) is not caused by prostaglandins. In this study platelets from SHR and normotensive (Wistar Kyoto, WKY) rats were used to examine the role of phosphoinositides and phosphorylation of 47,000 and 20,000 Dalton proteins in abnormal platelet activation in hypertension. Thrombin (0.05 U/ml) induced a rapid decrease in (32P)-P04 labelled phosphatidylinositol-4, 5-bisphosphate (PIP2), phosphatidylinositol-4-phosphate (PIP) and phosphatidylinositol (PI) in washed rat platelets. However, significantly greater loss of PIP2 and PI was seen in SHR platelets than in WKY platelets. For example the level of PIP2 declined by 32% in SHR platelets and only by 13% in WKY platelets at five seconds of incubation with thrombin. The loss of PI was similar in SHR and WKY platelets for the first five seconds of incubation with thrombin. However, by 15 seconds SHR platelets showed a significantly greater loss (24%) in PI than in WKY platelets (8%). Thrombin induced a 14% and 18% decrease in PIP at three seconds in WKY and SHR platelets respectively. In SHR platelets PIP level returned to the baseline in five seconds and then rose to 20% above the baseline by 30 seconds. In contrast PIP level in WKY platelets slowly reached the basal value by 30 seconds. Thrombin also produced a two- to three-fold greater accumulation of (32P)-phosphatidic acid (PA) in SHR platelets than in WKY platelets. Thrombin (0.05 U/ml) induced rapid phosphorylation of 47,000 Dalton (P47) and 20,000 Dalton (P20) proteins in both WKY and SHR platelets. Thrombin induced a four-fold greater increase in phosphorylation of P47 in SHR platelets than in WKY platelets in the first five seconds. Thrombin produced significantly greater increase in phosphorylation of P20 in SHR platelets (34% and 41%) than in WKY platelets (18% and 28%) at 5 and 15 seconds. Phosphorylation of P20 was followed by dephosphorylation in both WKY and SHR platelets. Aspirin (500 microM) did not affect phosphorylation of either P47 or P20 in SHR or WKY platelets. In other experiments prostaglandin E1 (0.5 microM), which stimulates adenylate cyclase via a guanine nucleotide regulatory protein termed Gs, caused an eighteen-fold increase in cyclic AMP level in SHR platelets as compared to a six-fold increase in WKY platelets. These data lead us to suggest that increased turnover of phosphoinositides and increased phosphorylation of P47 and P20 are involved in abnormal platelet activation in SHR platelets.

Alprostadil↗