Opposing actions of the enantiomers of BAY-K-8644 on calcium currents and ACTH secretion in clonal pituitary corticotrophs

1987 ◽  
Vol 65 (12) ◽  
pp. 2409-2414 ◽  
Author(s):  
J. F. MacDonald ◽  
Z. Miljkovic ◽  
S. Heisler
Keyword(s):  
Bay K 8644 ◽  
Calcium Currents ◽  
Similar Relationship ◽  
Acth Secretion ◽  
Calcium Dependent ◽  
Low Concentrations ◽  
Voltage Dependent ◽  
High Concentrations ◽  
Opposing Effects ◽  
Stimulation Of

BAY-K-8644 in low concentrations is known to stimulate, and in higher concentrations, to depress calcium-dependent ACTH secretion from mouse clonal (tumor) pituitary corticotrophs, AtT-20/D16-16 (AtT-20). In the present study, voltage-dependent inward calcium currents in these cells were potentiated by low concentrations of this compound and depressed by higher concentrations consistent with its actions on ACTH secretion. A similar relationship was demonstrated for a different but related compound, CGP 28 392. Each of BAY-K-8644's enantiomers, BAY-R(−)5417 and BAY-R(+)4407, had opposing effects upon these inward calcium currents and ACTH secretion. The (+)isomer antagonized both inward calcium currents and ACTH secretion. In contrast, the (−)enantiomer was responsible for the stimulatory effects of BAY-K-8644. Nevertheless, some antagonistic properties were noted with high concentrations of this latter enantiomer. The stimulation of ACTH secretion in AtT-20 cells by low concentrations of BAY-K-8644 can be attributed to a potentiation of voltage-activated calcium currents by one of its enantiomers, BAY-R-(−)5417. In contrast, the depression of secretion that occurs at higher concentrations is likely to be the result of the reduction of these currents by the other enantiomer (BAY-R(+)4407).

Effects of endogenous calcium transport inhibitor from heart muscle on the active calcium uptake and passive calcium release properties of sarcoplasmic reticulum

1989 ◽  
Vol 67 (9) ◽  
pp. 999-1006 ◽  
Author(s):  
Njanoor Narayanan ◽  
Philip Bedard ◽  
Trilochan S. Waraich
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Heart Muscle ◽  
Calcium Release ◽  
Membrane Vesicles ◽  
Transport Inhibitor ◽  
Low Concentrations ◽  
Active Calcium ◽  
High Concentrations ◽  
Stimulation Of

In the present study, the effects of the cytosolic Ca2+ transport inhibitor on ATP-dependent Ca2+ uptake by, and unidirectional passive Ca2+ release from, sarcoplassmic reticulum enriched membrane vesicles were examined in parallel experiments to determine whether inhibitor-mediated enhancement in Ca2+ efflux contributes to inhibition of net Ca2+ uptake. When assays were performed at pH 6.8 in the presence of oxalate, low concentrations (<100 μg/mL) of the inhibitor caused substantial inhibition of Ca2+ uptake by SR (28–50%). At this pH, low concentrations of the inhibitor did not cause enhancement of passive Ca2+ release from actively Ca2+-loaded sarcoplasmic reticulum. Under these conditions, high concentrations (>100 μg/mL) of the inhibitor caused stimulation of passive Ca2+ release but to a much lesser extent when compared with the extent of inhibition of active Ca2+ uptake (i.e., twofold greater inhibition of Ca2+ uptake than stimulation of Ca2+ release). When Ca2+ uptake and release assays were carried out at pH 7.4, the Ca2+ release promoting action of the inhibitor became more pronounced, such that the magnitude of enhancement in Ca2+ release at varying concentrations of the inhibitor (20–200 μg/mL) was not markedly different from the magnitude of inhibition of Ca2+ uptake. In the absence of oxalate in the assay medium, inhibition of Ca2+ uptake was observed at alkaline but not acidic pH. These findings imply that the inhibition of Ca2+ uptake observed at pH 6.8 is mainly due to decrease in the rate of active Ca2+ transport into the membrane vesicles rather than stimulation of passive Ca2+ efflux; at alkaline pH (pH 7.4), enhanced Ca2+ efflux contributes substantially, if not exclusively, to the decrease in Ca2+ uptake observed in the presence of the inhibitor. It is suggested that if the cytosolic inhibitor has actions similar to those observed in vitro in intact cardiac muscle, acid–base status of the intracellular fluid would be a major factor influencing the nature of its effects (inhibition of Ca2+ uptake or stimulation of Ca2+ release) on transmembrane Ca2+ fluxes across the sarcoplasmic reticulum.Key words: sarcoplasmic reticulum, Ca2+ uptake, Ca2+ release, endogenous inhibitor, heart muscle.

Effects of cholera toxin and isobutylmethylxanthine on growth of human fibroblasts

1986 ◽  
Vol 251 (2) ◽  
pp. C238-C246 ◽  
Author(s):  
B. Espinoza ◽  
W. Wharton
Keyword(s):  
Cholera Toxin ◽  
Human Fibroblasts ◽  
Phosphodiesterase Inhibitor ◽  
Serum Starvation ◽  
Final Density ◽  
Low Concentrations ◽  
High Concentrations ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Stimulation Of

Cholera toxin produced a dose-dependent decrease in the restimulation of G0/G1 traverse in density-arrested human fibroblasts but did not inhibit the stimulation of cells arrested in G0 after serum starvation at low density. In addition, cholera toxin did not inhibit the proliferation of sparse logarithmically growing human fibroblasts, even when low concentrations of the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) were also present. However, the final density to which sparse cells grew was limited by cholera toxin, when added either alone or together with low concentrations of IBMX. In contrast, high concentrations of the phosphodiesterase inhibitor alone produced a profound inhibition in the growth of sparse human fibroblasts. IBMX produced an inhibition both in the G1 and in the G2 phases of the cell cycle by a mechanism(s) that was not related to the magnitude of the increases in adenosine 3',5'-cyclic monophosphate concentrations.

The development of voltege-dependent ionic conductances In murine spinal cord neurones in culture

1988 ◽  
Vol 66 (10) ◽  
pp. 1328-1336 ◽  
Author(s):  
C. Krieger ◽  
T. A. Sears
Keyword(s):  
Spinal Cord ◽  
Sodium Current ◽  
Potassium Conductance ◽  
Calcium Currents ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Calcium Dependent ◽  
Ionic Conductances ◽  
Voltage Dependent

The development of voltage-dependent ionic conductances of foetal mouse spinal cord neurones was examined using the whole-cell patch-clamp technique on neurones cultured from embryos aged 10–12 days (E10–E12) which were studied between the first day in vitro (V1) to V10. A delayed rectifier potassium conductance (IK) and a leak conductance were observed in neurones of E10.V1, E11, V1, and E12, V1 as well as in neurones cultured for longer periods. A rapidly activating and inactivating potassium conductance (IA) was seen in neurones from E11, V2 and E12, V1 and at longer times in vitro. A tetrodotoxin (TTX) sensitive sodium-dependent inward current was observed in neurones of E11 and E12 from V1 onwards. Calcium-dependent conductances were not detectable in these neurones unless the external calcium concentration was raised 10- to 20-foid and potassium conductances were blocked. Under these conditions calcium currents could be observed as early as E11, V3 and E12, V2 and at subsequent times in vitro. The pattern of development of voltage-dependent ionic conductances in murine spinal neurones is such that initially leak and potassium currents are present followed by sodium current and subsequently calcium current.

scholarly journals Adenosine 3':5'-monophosphate content and actions in the division cycle of synchronized HeLa cells.

1976 ◽  
Vol 71 (2) ◽  
pp. 515-534 ◽  
Author(s):  
C E Zeilig ◽  
R A Johnson ◽  
E W Sutherland ◽  
D L Friedman
Keyword(s):  
Cell Cycle ◽  
Cyclic Amp ◽  
Hela Cells ◽  
S Phase ◽  
Intracellular Camp ◽  
Specific Effects ◽  
Low Concentrations ◽  
High Concentrations ◽  
Camp Levels ◽  
Stimulation Of

The involvement of adenosine 3':5'-monophosphate (cAMP) in the regulation of the cell cycle was studied by determining intracellular fluctuations in cAMP levels in synchronized HeLa cells and by testing the effects of experimentally altered levels on cell cycle traverse. Cyclic AMP levels were lowest during mitosis and were highest during late G-1 or early S phase. These findings were supported by results obtained when cells were accumulated at these points with Colcemid or high levels of thymidine. Additional fluctuations in cAMP levels were observed during S phase. Two specific effects of cAMP on cell cycle traverse were found. Elevation of cAMP levels in S phase or G-2 caused arrest of cells in G-2 for as long as 10 h and lengthened M. However, once cells reached metaphase, elevation of cAMP accelerated the completion of mitosis. Stimulation of mitosis was also observed after addition of CaCl2. The specificity of the effects of cAMP was verified by demonstrating that: (a) intracellular cAMP was increased after exposure to methylisobutylxanthine (MIX) before any observed effects on cycle traverse; (b) submaximal concentrations of MIX potentiated the effects of isoproterenol; and (c) effects of MIX and isoproterenol were mimicked by 8-Br-cAMP. MIX at high concentrations inhibited G-1 traverse, but this effect did not appear to be mediated by cAMP. Isoproterenol slightly stimulated G-1 traverse and partially prevented the MIX-induced delay. Moreover, low concentrations of 8-Br-cAMP (0.10-100 muM) stimulated G-1 traverse, whereas high concentrations (1 mM) inhibited. Both of these effects were also observed with the control, Br-5'-AMP, at 10-fold lower concentrations.

scholarly journals Stimulation of hepatic biogenesis of sterols on administration of adenosine compounds

1976 ◽  
Vol 154 (3) ◽  
pp. 639-645 ◽  
Author(s):  
G. S Rao ◽  
R George ◽  
T. Ramasarma
Keyword(s):  
Fatty Acids ◽  
Food Intake ◽  
Regulatory Role ◽  
Liver Slices ◽  
Low Concentrations ◽  
High Concentrations ◽  
Partial Deficiency ◽  
Coa Reductase ◽  
Stimulation Of

1. Re-feeding starved rats increased the biogenesis of sterols in livers, with highest activity at 6h after the start of food intake. 2. Complete deficiency of protein or fat and partial deficiency of carbohydrate in the diet had no effect on sterol biogenesis. 3. Glucose, citrate or pyruvate, when administered intraperitoneally to starved rats, stimulated the biogenesis of sterols only at high concentrations. 4. ATP given intraperitoneally at low concentrations (10mg/rat) stimulated biogenesis of sterols, but not of fatty acids, from [1-14C]acetate. This effect was also obtained with other adenosine compounds, but not with adenine or guanosine. 5. Administration of adenosine compounds to starved rats also increased the incorporation of [1-14C]acetate into sterols in liver slices and also the activity of microsomal 3-hydroxy-3-methylglutaryl-CoA reductase. The results suggest a regulatory role for adenosine compounds in the hepatic biogenesis of isoprenoid compounds.

Potentiation of Adrenaline-Induced Platelet Aggregation by Angiotensin II

1985 ◽  
Vol 54 (03) ◽  
pp. 717-720 ◽  
Author(s):  
Yu-An Ding ◽  
D Euan MacIntyre ◽  
Christopher J Kenyon ◽  
Peter F Semple
Keyword(s):  
Platelet Aggregation ◽  
Angiotensin Ii ◽  
Human Platelet ◽  
Inhibitory Effect ◽  
Facilitatory Effect ◽  
Ang Ii ◽  
Human Platelet Aggregation ◽  
Low Concentrations ◽  
High Concentrations ◽  
Stimulation Of

SummaryThe effects of angiotensin II (ANG II) alone and in combination with other agonists on human platelet aggregation, thromboxane B2 (TxB2) and cytosolic [Ca2+]i were investigated. ANG II (10™11 - 10™7 M) alone had no direct effect on aggregation, TxB2 production or [Ca2+]i after short- (<2 min) or longterm (30 min) incubation. In contrast, low concentrations of ANG II (10™11 M) enhanced adrenaline-induced platelet aggregation but high concentrations (10™7 M) had an inhibitory effect. Moreover, ANG II (10™11 - 10™7 M) augmented platelet responses to the TxA2 mimetic, U44069. Pretreatment of platelets with flurbiprofen abolished this facilitatory effect of ANG II on adrenaline- but not on U44069-induced platelet aggregation. These results suggest that ANG II stimulation of agonist-induced platelet activation may be due to potentiation of the effects rather than the synthesis of TxA2

Coupling of methyl coenzyme M reduction with carbon dioxide activation in extracts of Methanobacterium thermoautotrophicum

1982 ◽  
Vol 152 (2) ◽  
pp. 840-847
Author(s):  
J A Romesser ◽  
R S Wolfe
Keyword(s):  
Carbon Dioxide ◽  
Co2 Reduction ◽  
Methanobacterium Thermoautotrophicum ◽  
Coenzyme M ◽  
Cell Extracts ◽  
Low Concentrations ◽  
Efficient Reduction ◽  
High Concentrations ◽  
Reduction Of Co2 ◽  
Stimulation Of

The stimulation of carbon dioxide reduction to methane by addition of 2-(methylthio)ethanesulfonate (CH3-S-CoM) to cell extracts of Methanobacterium thermoautotrophicum was investigated. Similar stimulation of CO2 reduction by CH3-S-CoM was found for cell extracts of Methanobacterium bryantii and Methanospirillum hungatei. The CH3-S-CoM requirement could be met by the methanogenic precursors formaldehyde, serine, or pyruvate, or by 2-(ethylthio)ethanesulfonate (CH3CH2-S-CoM), but not by other coenzyme M derivatives. Efficient reduction of CO2 to CH4 was favored by low concentrations of CH3-S-CoM and high concentrations of CO2. Sulfhydryl compounds were identified as effective inhibitors of CO2 reduction. Both an allosteric model and a free-radical model for the mechanism of CO2 activation and reduction are discussed.

Action of theophylline on secretagogue-stimulated amylase release from dispersed pancreatic acini

1980 ◽  
Vol 239 (4) ◽  
pp. G324-G333
Author(s):  
L. Y. Korman ◽  
M. D. Walker ◽  
J. D. Gardner
Keyword(s):  
Guinea Pig ◽  
Vasoactive Intestinal Peptide ◽  
Enzyme Secretion ◽  
Amylase Release ◽  
Pancreatic Acini ◽  
Modes Of Action ◽  
Low Concentrations ◽  
High Concentrations ◽  
Stimulation Of

In dispersed acini from guinea pig pancreas, theophylline did not alter basal amylase release, but had three functionally distinct modes of action on the stimulation of amylase release caused by various secretagogues. 1) At relatively low concentrations (0.1-1.0 mM), theophylline augmented the increase in enzyme secretion caused by vasoactive intestinal peptide, secretin, or 8-bromoadenosine 3',5'-monophosphate, but did not alter the increase in amylase release caused by other secretagogues. 2) At intermediate concentrations (1-10 mM), theophylline selectively altered the increase in enzyme secretion caused by carbamylcholine, but did not alter the effects of cholecystokinin or bombesin, secretagogues whose modes of action are similar to that of cabamylcholine. 3) At high concentrations (greater than 10 mM), theophylline inhibited the increase in enzyme secretion caused by all secretagogues tested.

Physiological and Pharmacological Observations on Muscle Receptor Organs of the Crayfish, Cambarus Clarkii Girard

1953 ◽  
Vol 30 (1) ◽  
pp. 136-150 ◽  
Author(s):  
C. A. G. WIERSMA ◽  
E. FURSHPAN ◽  
E. FLOREY
Keyword(s):  
High Frequency ◽  
Sensory Function ◽  
Panulirus Interruptus ◽  
Sensory Axons ◽  
Low Concentrations ◽  
Low Threshold ◽  
High Concentrations ◽  
Almost All ◽  
Stimulation Of ◽  
Sensory Mechanism

1. The muscle organs recently described by Alexandrowicz in the tails of Homarus vulgaris and Palinurus vulgaris, have also been found to be present in the crayfish (Cambarus clarkii) and the rock lobster (Panulirus interruptus), and a study of them in the latter animals has been undertaken. 2. The position of these units within the abdomen of the crayfish differs from their position in the lobsters. In almost all other respects, however, there is substantial correspondence in their morphological features. 3. The organs are easily isolated and it is found that stretching them is accompanied by a discharge in one of the axons supplying each unit. There are two receptors in each half-segment of the abdomen and their responses show considerable differences. One has a very low threshold and can be sustained in continuous discharge for several hours. The threshold of the other is high and this receptor usually adapts completely to the most extreme stretch in less than 1 min. 4. A phenomenon which is designated ‘over-stretch’ has been observed. All-but-maximal stretch causes a reversible cessation of the previous high-frequency discharge. The discharge can be restored by slight release of tension, but even if the tension producing ‘over-stretch’ is maintained for a sufficient length of time, discharge will resume spontaneously. The possibility that this spontaneous return is due to a slow rupture of the receptor tissues is not excluded. 5. The muscular regions of the organs are not necessary for their sensory function. 6. It has been possible to show that stimulation of the nerve trunk can induce contraction in these muscular regions and that such contraction results in discharge in the sensory axons. 7. The unit with the low stretch-threshold responds to low concentrations of ACh and this effect is potentiated by eserine. In concentrations above 10-6 before eserinization and above 10-8 after eserinization, ACh consistently initiates rhythmic responses in relaxed units and augments the discharge from those under tension. 8. ACh affects the sensory mechanism directly; the muscular regions of the organs are not necessary for its action. 9. Atropine inhibits the ACh excitation, but only increases the response of the receptors to stretch. Eserine, except in high concentrations, has no consistent effect on the normal stretch discharge. 10. The possibility that ACh has a role in the normal receptor mechanism is discussed, but the question is left open.

Mobilization of 45Ca from insulin-producing RINm5F cells attached to microcarriers

1984 ◽  
Vol 247 (6) ◽  
pp. E719-E725
Author(s):  
H. Abrahamsson ◽  
P. O. Berggren ◽  
B. Hellman
Keyword(s):  
Plasma Membrane ◽  
Pancreatic Islets ◽  
Cell Line ◽  
Rinm5f Cells ◽  
Clonal Cell Line ◽  
Low Concentrations ◽  
Voltage Dependent ◽  
K Concentration ◽  
45Ca Efflux ◽  
Stimulation Of

A technique was designed allowing studies of 45Ca efflux from insulin-releasing cells of a clonal cell line (RINm5F) attached to fibronectin-coated plastic beads. Supporting the existence of Ca2+-Ca2+ and Na+-Ca2+ exchange mechanisms, the efflux of 45Ca in a Ca2+-deficient perifusion medium was increased after introduction of Ca2+ and decreased after removal of Na+. The washout of radioactivity was similar to that from pancreatic islets in also being inhibited by glucose in the presence of low concentrations of extracellular Ca2+. During perifusion with a medium containing 2.56 mM Ca2+, increasing the K+ concentration resulted in an increased 45Ca efflux, a process counteracted by D-600. Also, exposure to tolbutamide resulted in a distinct stimulatory peak. Glucose was a poor stimulator of 45Ca efflux, suggesting that this sugar lacks the ability to depolarize the RINm5F cells sufficiently to induce normal opening of the voltage-dependent channels in the plasma membrane. Such a defect might well explain why the RINm5F cells do not respond to glucose with stimulation of insulin release.

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