Cyclic AMP-specific phosphodiesterase inhibitor rolipram and RO-20-1724 promoted apoptosis in HL60 promyelocytic leukemic cells via cyclic AMP-independent mechanism

The effects of pure [Asp1, Val5]- and [Asn1, Val5]-angiotensin II and also [des-Asp1, Ile5]-angiotensin II (angiotensin III) on cyclic AMP and steroid outputs by dispersed rat capsular cells, comprising 95% zona glomerulosa and 5% zona fasciculata cells, have been studied. The results showed that [Asp1, Val5]- and [Asn1, Val5]-angiotensin II, at doses between 2·5 × 10−1 1 and 2 × 10−4 mol/l, which produced typical increases in steroidogenesis, failed to increase output of cyclic AMP. This lack of effect was observed whether the nucleotide was measured by radioimmunoassay or by adrenal binding protein and under the same conditions in which 8·4 mm-K+ consistently increased the output of cyclic AMP. Instead the results showed a small but significant decrease in cyclic AMP output with angiotensin II. Similar results were obtained with incubations for 60 rather than 120 min and with medium containing a concentration of 5 or 40 g bovine serum albumin/l. Although the levels of cyclic AMP were generally higher in the presence of the phosphodiesterase inhibitor, 3-isobutyl-l-methylxanthine, the same decrease relative to basal outputs was observed with angiotensin II which increased steroidogenesis. Angiotensin III also failed to increase output of cyclic AMP at doses (2·5×10−9 to 2·5×10−6 mol/l) which produced increases in steroid output equivalent to those obtained with angiotensin II. These results indicate that angiotensin II and III can act through a cyclic AMP- independent mechanism.

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Enhancement of Platelet Sensitivity to ADP-Aggregation by Isometric Exercise in Arteriosclerotic Patients and its Prevention

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649233 ◽

1977 ◽

Vol 37 (02) ◽

pp. 329-338 ◽

Cited By ~ 14

Author(s):

Tadahiro Sano ◽

Takeshi Motomiya ◽

Hiroh Yamazaki ◽

Takio Shimamoto

Keyword(s):

Cyclic Amp ◽

Mechanical Stress ◽

Optical Density ◽

Platelet Function ◽

Isometric Exercise ◽

Phosphodiesterase Inhibitor ◽

New Method ◽

Platelet Aggregability ◽

Control Subjects ◽

Healthy Control

SummaryA new method for assessment of platelet sensitivity to ADP-aggregation was devised. Its reproducibility and the correlations between the values obtained by this method, the optical density (O. D.) method, and the screen filtration pressure (SFP) method were assessed. In summary, this method may be said to have three main points:1. It can be performed without centrifugation, avoiding mechanical stress to platelets, using only 0.8 ml. of blood and inexpensive equipment.2. It may reflect different aspects of platelet function from the O. D. method and the SFP method, despite the positive significant correlations between the values obtained by these three methods.3. It was proved to be highly reproducible and is thought to be useful clinically.By using this method, the effect of sustained isometric exercise by handgripping on platelet aggregability was assessed in coronary sclerotic and cerebral arteriosclerotic patients on placebo and EG-626, a newly synthesized cyclic AMP phosphodiesterase inhibitor. On placebo, an enhancement of platelet sensitivity was observed after isometric exercise in coronary and cerebral arteriosclerotic patients but not in healthy control subjects. The enhancement was prevented by pretreatment of EG-626, administered orally 1.5 hours prior to exercise.

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Selective Cytotoxicity of Piperine over Multidrug Resistance Leukemic Cells

Molecules ◽

10.3390/molecules26040934 ◽

2021 ◽

Vol 26 (4) ◽

pp. 934

Author(s):

Julia Quarti ◽

Daianne N. M. Torres ◽

Erika Ferreira ◽

Raphael S. Vidal ◽

Fabiana Casanova ◽

...

Keyword(s):

Multidrug Resistance ◽

Black Pepper ◽

Leukemic Cells ◽

Glycoprotein P ◽

Cytotoxic Effects ◽

Collateral Sensitivity ◽

Main Challenge ◽

Independent Mechanism ◽

High Level ◽

Parp 1

Multidrug resistance (MDR) is the main challenge in the treatment of chronic myeloid leukemia (CML), and P-glycoprotein (P-gp) overexpression is an important mechanism involved in this resistance process. However, some compounds can selectively affect MDR cells, inducing collateral sensitivity (CS), which may be dependent on P-gp. The aim of this study was to investigate the effect of piperine, a phytochemical from black pepper, on CS induction in CML MDR cells, and the mechanisms involved. The results indicate that piperine induced CS, being more cytotoxic to K562-derived MDR cells (Lucena-1 and FEPS) than to K562, the parental CML cell. CS was confirmed by analysis of cell metabolic activity and viability, cell morphology and apoptosis. P-gp was partially required for CS induction. To investigate a P-gp independent mechanism, we analyzed the possibility that poly (ADP-ribose) polymerase-1 (PARP-1) could be involved in piperine cytotoxic effects. It was previously shown that only MDR FEPS cells present a high level of 24 kDa fragment of PARP-1, which could protect these cells against cell death. In the present study, piperine was able to decrease the 24 kDa fragment of PARP-1 in MDR FEPS cells. We conclude that piperine targets selectively MDR cells, inducing CS, through a mechanism that might be dependent or not on P-gp.

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Forskolin and phosphodiesterase inhibitors release adenosine but inhibit morphine-evoked release of adenosine from spinal cord synaptosomes

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-133 ◽

1991 ◽

Vol 69 (6) ◽

pp. 877-885 ◽

Cited By ~ 4

Author(s):

D. Nicholson ◽

T. D. White ◽

J. Sawynok

Keyword(s):

Spinal Cord ◽

Cyclic Amp ◽

Phosphodiesterase Inhibitor ◽

Phosphodiesterase Inhibitors ◽

Dorsal Spinal Cord ◽

Adenosine Release ◽

Basal Release ◽

Phosphodiesterase Isoenzymes ◽

Dorsal Spinal ◽

Ventral Spinal Cord

The effects of forskolin, Ro 20-1724, rolipram, and 3-isobutyl-1-methylxanthine (IBMX) on morphine-evoked release of adenosine from dorsal spinal cord synaptosomes were evaluated to examine the potential involvement of cyclic AMP in this action of morphine. Ro 20-1724 (1–100 μM), rolipram (1–100 μM), and forskolin (1–10 μM) increased basal release of adenosine, and at 1 μM inhibited morphine-evoked release of adenosine. Release of adenosine by Ro 20-1724, rolipram, and forskolin was reduced 42–77% in the presence of α, β-methylene ADP and GMP, which inhibits ecto-5′-nucleotidase activity by 81%, indicating that this adenosine originated predominantly as nucleotide(s). Significant amounts of adenosine also were released from the ventral spinal cord by these agents. Ro 20-1724 and rolipram did not significantly alter the uptake of adenosine into synaptosomes. Although Ro 20-1724 and rolipram had only limited effects on the extrasynaptosomal conversion of added cyclic AMP to adenosine, IBMX, a phosphodiesterase inhibitor with a broader spectrum of inhibitory activity for phosphodiesterase isoenzymes, significantly inhibited the conversion of cyclic AMP to adenosine and resulted in recovery of a substantial amount of cyclic AMP. As with the non-xanthine phosphodiesterase inhibitors, IBMX increased basal release of adenosine and reduced morphine-evoked release of adenosine. Adenosine released by IBMX was reduced 70% in the presence of α, β-methylene ADP and GMP, and release from the ventral spinal cord was 61% of that from the dorsal spinal cord. Collectively, these results indicate that forskolin and phosphodiesterase inhibitors release nucleotide(s) which is (are) converted extrasynaptosomally to adenosine. For forskolin, Ro 20-1724, and rolipram, the nucleotide released could be cyclic AMP. Morphine releases adenosine per se, and forskolin and phosphodiesterase inhibitors reduce this release. The lack of increase in the action of morphine with phosphodiesterase inhibitors in particular does not support a role for stimulation of cyclic AMP production by morphine in the release of adenosine. The reduction in morphine-evoked release of adenosine by forskolin and phosphodiesterase inhibitors suggests either (a) that a reduction in cyclic levels by morphine promotes adenosine release, or (b) that cyclic AMP interferes with the release process.Key words: forskolin, Ro 20-1724, 3-isobutyl-1-methylxanthine, cyclic AMP, morphine, adenosine release, spinal cord.

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Effects of epinephrine and the cyclic AMP phosphodiesterase inhibitor SQ 20009 on glucose and glycogen metabolism in skeletal muscle

Biochemical Pharmacology ◽

10.1016/0006-2952(79)90362-9 ◽

1979 ◽

Vol 28 (6) ◽

pp. 807-813 ◽

Cited By ~ 5

Author(s):

Sandra Davidheiser ◽

Ella S. Haugaard ◽

Niels Haugaard

Keyword(s):

Skeletal Muscle ◽

Cyclic Amp ◽

Phosphodiesterase Inhibitor ◽

Glycogen Metabolism ◽

Cyclic Amp Phosphodiesterase

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Prevention of methamphetamine-induced behavioral sensitization in rats by a cyclic AMP phosphodiesterase inhibitor, rolipram

European Journal of Pharmacology ◽

10.1016/0014-2999(96)00479-7 ◽

1996 ◽

Vol 312 (2) ◽

pp. 163-170 ◽

Cited By ~ 26

Author(s):

Masaomi Iyo ◽

Ying Bi ◽

Kenji Hashimoto ◽

Toshiya Inada ◽

Susumu Fukui

Keyword(s):

Cyclic Amp ◽

Behavioral Sensitization ◽

Phosphodiesterase Inhibitor ◽

Cyclic Amp Phosphodiesterase

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Serotonergic modulation of locust motor neurons

Journal of Neurophysiology ◽

10.1152/jn.1995.73.3.923 ◽

1995 ◽

Vol 73 (3) ◽

pp. 923-932 ◽

Cited By ~ 21

Author(s):

D. Parker

Keyword(s):

Cyclic Amp ◽

Motor Neurons ◽

Schistocerca Gregaria ◽

Phosphodiesterase Inhibitor ◽

Membrane Resistance ◽

Excitatory Postsynaptic Potential ◽

Metathoracic Ganglion ◽

Bath Application ◽

Potassium Conductances ◽

5 Ht Uptake

1. The effects of the putative endogenous neuromodulator serotonin (5-HT) on the fast extensor and flexor tibiae motor neurons in the locust (Schistocerca gregaria) metathoracic ganglion, were analyzed. 2. 5-HT consistently increased the duration of the fast extensor spike and usually reduced the afterhyperpolarization, although this effect was less consistent. The spike broadening in the fast extensor was associated with an increase in the amplitude of the excitatory postsynaptic potential (EPSP) evoked monosynaptically in the flexor motor neurons by fast extensor stimulation. 5-HT also increased the membrane resistance of the fast extensor and flexor tibiae motor neurons. 3. The effects of 5-HT were mimicked by bath application of the 5-HT uptake inhibitor imipramine, and blocked by the 5-HT receptor antagonist ketanserin. The effects were also mimicked by dibutryl cyclic AMP, a membrane permeant analogue of cyclic AMP, and by the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine, but not by dibutryl cyclic GMP. The 5-HT-dependent modulation was blocked by the protein kinase A inhibitor H8. In addition, injection of cyclic AMP into the fast extensor or a flexor motor neuron could mimic the effects of 5-HT on these neurons. 4. 5-HT probably broadened the FETi action potential by modulating potassium conductances responsible for spike repolarization. 5. These results show that 5-HT modulates both the fast extensor and flexor tibiae motor neurons, resulting in potentiation of synaptic transmission between these neurons. In addition, the increase in flexor membrane resistance will potentiate other inputs onto these cells, which will affect the output of the motor neurons during locomotion.

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Inhibition of expression of major histocompatibility complex class II molecules in macrophages infected with Leishmania donovani occurs at the level of gene transcription via a cyclic AMP-independent mechanism.

Infection and Immunity ◽

10.1128/iai.60.5.2115-2120.1992 ◽

1992 ◽

Vol 60 (5) ◽

pp. 2115-2120 ◽

Cited By ~ 27

Author(s):

W C Kwan ◽

W R McMaster ◽

N Wong ◽

N E Reiner

Keyword(s):

Major Histocompatibility Complex ◽

Cyclic Amp ◽

Major Histocompatibility Complex Class ◽

Gene Transcription ◽

Leishmania Donovani ◽

Class Ii ◽

Complex Class ◽

Major Histocompatibility ◽

Histocompatibility Complex ◽

Independent Mechanism

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Increase in pituitary adenosine 3′:5′-cyclic monophosphate content and potentiation of growth-hormone release from heifer anterior pituitary slices incubated in the presence of 3-isobutyl-1-methylxanthine

Biochemical Journal ◽

10.1042/bj1420295 ◽

1974 ◽

Vol 142 (2) ◽

pp. 295-300 ◽

Cited By ~ 10

Author(s):

J. George Schofield ◽

Margaret McPherson

Keyword(s):

Growth Hormone ◽

Cyclic Amp ◽

Prostaglandin E2 ◽

Anterior Pituitary ◽

Phosphodiesterase Inhibitor ◽

Secretory Process ◽

Hormone Release ◽

Growth Hormone Release ◽

Inhibitor Concentration ◽

Stimulation Of

The release of growth hormone from heifer anterior pituitary slices and the cyclic AMP content of the slices were increased by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, both increases being related to inhibitor concentration over the range 0.1–1.0mm. Neither Ba2+(6.9 or 2.3mm), K+(72mm), nor p-chloromercuribenzoate (20μm) had any effect on pituitary cyclic AMP content over a 20min period. 3-Isobutyl-1-methylxanthine potentiated the release of growth hormone in response to Ba2+(2.3mm) and K+(24mm), but the degree of potentiation did not depend on inhibitor concentration in the same way as did tissue cyclic AMP content. 3-Isobutyl-1-methylxanthine decreased the concentration of K+required to give maximum stimulation of growth-hormone release, but did not significantly increase the maximum response to Ba2+. Growth-hormone release in the presence of prostaglandin E2 (1μm) was increased by 3-isobutyl-1-methylxanthine and was inhibited by the prostaglandin antagonist, 7-oxa-13-prostynoic acid, although this antagonist increased the pituitary cyclic AMP concentration and potentiated the prostaglandin E2-induced rise in cyclic AMP content. The stimulation of growth-hormone release by p-chloromercuribenzoate was not potentiated by 3-isobutyl-1-methylxanthine. The data suggest that Ba+and K+act at the same point in the secretory process as 3-isobutyl-1-methylxanthine, although by a different mechanism, and that p-chloromercuribenzoate has a different point of action.

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