Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intact yellow perch (Perca flavescens) follicles stimulated by 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17 alpha, 20 beta-PG) to undergo germinal vesicle breakdown (GVBD) in vitro were incubated with several agents which have been shown to increase cellular cAMP levels. Two phosphodiesterase inhibitors, SQ20,006 and isobutyl-methyl-xanthine, blocked GVBD at 1.0 mM. At lower levels (0.5, 0.1 mM) there was a dose-response effect and SQ20,006 was more inhibitory. Forskolin at 1.0-20.0 microM blocked steroid-induced GVBD, but levels of 0.1 microM or less were noninhibitory. In time-course experiments, significant inhibition of GVBD was observed when SQ20,006 (1.0 mM) was added within 6 hr after steroid stimulation or forskolin (10.0 microM) was added within 12 hr. When SQ20,006 was administered in 6-hr pulses and then removed, inhibition was observed only when the steroid was given as a 1-hr prepulse which was removed at the start of the incubation period. In this case, GVBD was blocked if the SQ20,006 pulse was given before 18 hr. At 10.0 mM, cAMP completely inhibited GVBD but was noninhibitory at lower levels. However, lower levels of cAMP (1.0, 0.5 mM) and forskolin (0.1 microM) were inhibitory if the follicles were also incubated with 1.0 microgram/ml of cyanoketone, an inhibitor of steroidogenesis. These results indicate that in vitro, increases in cAMP are inhibitory to steroid-induced meiotic maturation but may stimulate steroidogenesis in the follicle wall as well. Furthermore, in vitro steroid-stimulated maturation can be inhibited by increased cAMP for a relatively long time, following steroid treatment.
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PMID:The effects of forskolin, cAMP, and cyanoketone on steroid-induced meiotic maturation of yellow perch (Perca flavescens) oocytes in vitro. 303 15

The effects of systemically administered forskolin, a direct activator of the catalytic subunit of adenylate cyclase, on locomotor activity, rectal temperature and the incidence of grooming and head twitches were studied in rats. Forskolin, 0.1-25 mg/kg, decreased locomotor activity and lowered rectal temperature. The incidence of grooming and head twitches increased dose-dependently after forskolin, 6.25 25 mg/kg. The combination of a threshold dose of forskolin with a threshold dose of the cAMP-selective phosphodiesterase (PDE) inhibitor rolipram resulted in a marked, statistically significant enhancement of the behavioral, hypothermic and brain cAMP elevating effect. The present findings support the assumption that enhanced brain cAMP availability is associated with a characteristic behavioral syndrome in rats as was previously shown with dibutyryl cAMP or neurotropic cAMP-selective PDE inhibitors like rolipram. Ro 20-1724 or ICI 63 147.
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PMID:Effects of forskolin on spontaneous behavior, rectal temperature and brain cAMP levels of rats: interaction with rolipram. 303 38

TSH is a trophic factor for cultured rat thyroid cells (FRTL-5). In the present study we have investigated the mechanism by which TSH promotes cell growth and evaluated the possible role of the adenylate cyclase (AC)-cAMP system in this process. The mitogenic activity of several agents was evaluated by measuring their effect on cell number or 3H-thymidine incorporation into DNA. Forskolin and cholera toxin, two potent and specific activators of the AC, induced a dose dependent increase of 3H-thymidine incorporation. The maximal stimulation, observed at concentrations of 10 microM and 10 ng/ml, respectively, was beta 80% of that obtained with optimal concentrations of TSH. A similar effect was obtained with a Graves' IgG preparation (0.2 mg/ml) able to stimulate the thyroid AC or with 3-isobutyl-1-methyl-xanthine (IBMX, 0.5 mM), a phosphodiesterase inhibitor. 8-bromo cAMP (0.5 mM), a cAMP analog, also stimulated 3H-thymidine incorporation, and its potency was approximately 60% of that of TSH. Similar results were obtained when the mitogenic activity of these compounds was evaluated by cell number. Norepinephrine (NE, 10 microM), although devoid of AC stimulatory activity in these cells, also stimulated 3H-thymidine incorporation, but its potency was only 20-30% of that of TSH. Indomethacin (100 microM), an inhibitor of phospholipid and arachidonic acid metabolism, was able to inhibit the stimulatory effect of NE (84%), and to a lesser extent of TSH (63%) and cholera toxin, had minor effect on forskolin (24%), IBMX (16%) and Graves' IgG (8%), and no effect on 8-bromo cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of the adenylate cyclase-cAMP system on TSH-stimulated thyroid cell growth. 303 75

The effects of phosphodiesterase inhibitors and forskolin on steroid-induced germinal vesicle breakdown (GVBD) were investigated in brook trout (Salvelinus fontinalis) oocytes using an in vitro incubation technique. Follicles were first treated with a collagenase solution to remove the follicle wall. Denuded oocytes were examined, using scanning electron microscopy. In all experiments GVBD was induced by the use of 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one. Cyclic adenosine 3',5'-monophosphate (cAMP) levels were measured (by protein-binding assay) in control and forskolin-treated oocytes. Collagenase treatment removed a majority of the follicle wall, as shown by scanning electron microscopy. Partially denuded (PD) oocytes were slightly more sensitive to steroid treatment than intact follicles (IF), as shown by ED50 values; but PD oocytes did not respond to gonadotropin (GTH) stimulation. Both 3-isobutyl-1-methyl-xanthine (IBMX) and SQ20,006 (Squibb) blocked GVBD, but IBMX was more inhibitory. Forskolin also blocked steroid-induced GVBD. Kinetics of inhibition studies were performed using IBMX, forskolin, and cycloheximide. IBMX and cycloheximide inhibited GVBD if added during the first 18 h following steroid stimulation, whereas forskolin blocked GVBD if added within 12 h after steroid treatment. Forskolin, at levels that block GVBD in vitro, significantly increased cAMP in both IF and PD oocytes, but the response of IF was greater than that of PD oocytes.
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PMID:Steroid-induced final maturation in brook trout (Salvelinus fontinalis) oocytes in vitro: the effects of forskolin and phosphodiesterase inhibitors. 304 Jan 36

The effects of pertussis toxin, forskolin and phosphodiesterase inhibitors on the antinociceptive action of intrathecal purines were examined to investigate the possible involvement of adenylate cyclase in spinal antinociception. Pretreatment with pertussis toxin (0.25 and 0.5 microgram) inhibited the antinociceptive action of L-phenyl-isopropyladenosine (L-PIA), N6-cyclohexyladenosine (CHA) and 5'-N-ethylcarboxamide adenosine (NECA) in the tail flick and hot plate tests. Forskolin (10-30 micrograms) reduced the effect of CHA and NECA in the hot plate test. Ro 201724 (30 micrograms) and Rolipram (20 micrograms) inhibited CHA in the tail flick and hot plate tests, but did not affect NECA in either test. These results suggest (1) spinal antinociception by purines is mediated by interactions with G-proteins (Gi linked to adenylate cyclase and/or Go linked to ion channels) (2) spinal antinociception by CHA is due to inhibition of adenylate cyclase (3) a separate mechanism, which does not involve stimulation of adenylate cyclase, may be involved in the spinal action of NECA.
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PMID:Role of G-proteins and adenylate cyclase in antinociception produced by intrathecal purines. 314 8

Inotropic response to four different types of pharmacological stimuli were compared in isolated right ventricular papillary muscles from newborn (24-48 h of age), immature (14-16 days), and adult (6-7 mo) rabbits. Forskolin, a direct activator of adenylate cyclase, produced a 12.5-fold increase in the maximal rate of tension development in the newborn group. The maximum response to isoproterenol was only 45% of the maximum forskolin response, suggesting incomplete physiological coupling of myocardial beta-adrenergic receptors to adenylate cyclase at birth. In contrast to the substantial inotropic response to agents that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) generation (forskolin and isoproterenol), a selective inhibitor of cAMP hydrolysis (milrinone) was relatively ineffective in the newborn group. Sulmazole, a drug that enhances calcium sensitivity of the contractile proteins, produced its greatest inotropic effect in immature myocardium. Cytosolic high-affinity cAMP phosphodiesterase activity was partially purified from ventricular homogenates by anion-exchange chromatography. The kinetics of cAMP hydrolysis (Km and Vmax) and inhibitory potency of milrinone were comparable in each age group. Thus the age-related differences in inotropic responsiveness may not be attributable to postnatal changes in myocardial cytosolic high-affinity cAMP phosphodiesterase activity.
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PMID:Inotropic responses change during postnatal maturation in rabbit. 340 92

Calcium-tolerant myocytes were isolated from rat hearts. Isoproterenol produced a dose-dependent increase in glycerol output (lipolysis) that could be blocked by propranolol. The presence of glucose in the incubation medium enhanced the release of glycerol from myocytes but had no effect on the decline in triacylglycerol content. No incorporation of radioactivity from [U-14C]glucose into glycerol could be detected. In incubations with isoproterenol, there was a stoichiometric relationship between the glycerol output and the decrease in triacylglycerol levels. The addition of the phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine resulted in an increase in the basal glycerol output and an enhancement of the isoproterenol-stimulated lipolytic rate. Forskolin and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate also produced a concentration-dependent stimulation of lipolysis in myocytes. Therefore, lipolysis in isolated myocytes must be regulated by adenosine 3',5'-cyclic monophosphate-dependent mechanisms. These results demonstrate that lipolysis can be observed in myocardial cells and that the lipolytic response to isoproterenol cannot be secondary to a physiological (inotropic) response since these myocyte preparations are quiescent.
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PMID:Stimulation of lipolysis in rat heart myocytes by isoproterenol. 403 87

The interaction between forskolin and vasoactive intestinal polypeptide (VIP) in the regulation of cyclic AMP production in GH3 pituitary tumour cells was investigated. Both forskolin (10nM-10 microns) and VIP (10pM-10nM) increased the cyclic AMP content of GH3 cells. Forskolin (50-100nM) was additive with VIP in stimulating cyclic AMP accumulation when low concentrations (less than 1 nM) of the peptide were used, but exhibited a synergistic interaction with higher VIP concentrations (10-100 nM). These effects on cyclic AMP accumulation were reflected in a leftward shift in the concentration-response curve for VIP-stimulated prolactin release from GH3 cells, a process known to be regulated by intracellular cyclic AMP concentrations. The synergy observed did not appear to be related to changes in cyclic nucleotide phosphodiesterase activity, since it was even more marked in the presence of isobutylmethylxanthine, a phosphodiesterase inhibitor. Studies of the time-course of VIP-induced changes in GH3-cell cyclic AMP content revealed that, with high concentrations of VIP, production ceased within 2 min of addition. This attenuation of cyclic AMP synthesis was still observed in the presence of isobutylmethylxanthine, but was markedly inhibited by low concentrations of forskolin (50-100nM). The results suggest that VIP-induced cyclic AMP production rapidly becomes desensitized. This process, which is prevented by forskolin, may be related to changes in the ability of the guanine nucleotide regulatory protein to couple receptor occupancy to activation of adenylate cyclase.
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PMID:Vasoactive-intestinal-polypeptide-stimulated adenosine 3',5'-cyclic monophosphate accumulation in GH3 pituitary tumour cells. Reversal of desensitization by forskolin. 608 46

Strips of the rabbit pulmonary artery preincubated with 3H-noradrenaline were superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Basal tritium efflux and electrically evoked tritium overflow were determined. The basal efflux of tritium was not affected by forskolin 0.01-10 mumol/l, 8-Br-cAMP and dibutyryl-cAMP 10-330 mumol/l, or the phosphodiesterase inhibitors rolipram 1-10 mumol/l and AH 21-132 l mumol/l; it was increased by AH 21-132 10-100 mumol/l. Forskolin concentration-dependently increased the evoked 3H overflow, and this effect was not attenuated by omission of cocaine. The facilitatory effect of forskolin was more pronounced at 0.66 Hz than at 2 Hz. Rolipram, AH 21-132, 8-Br-cAMP or dibutyryl-cAMP also produced a concentration-dependent increase in evoked 3H overflow (8-Br-cAMP was more effective than dibutyryl-cAMP in this respect). Except for the highest concentration investigated, AH 21-132 was more effective in facilitating evoked overflow than in increasing basal efflux. Forskolin, AH 21-132 or 8-Br-cAMP did not alter the percentages of 3H-noradrenaline and 3H-metabolites contained in basal tritium efflux or in stimulation-evoked tritium overflow. When a combination of AH 21-132 plus 8-Br-cAMP or AH 21-132 plus forskolin was administered, the facilitatory effect on evoked tritium overflow was more pronounced than with the single compounds alone. ACTH1-24 also facilitated the evoked tritium overflow. Combined exposure to ACTH1-24 plus forskolin, ACTH1-24 plus AH 21-132 or ACTH1-24 plus forskolin plus AH 21-132 resulted in a clearly more pronounced increase in evoked tritium overflow than exposure to the single compounds alone.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of cAMP for regulation of impulse-evoked noradrenaline release from the rabbit pulmonary artery and its possible relationship to presynaptic ACTH receptors. 609 33

The diterpene forskolin markedly activates adenylate cyclase in membranes from various rat brain regions and elicits marked accumulations of radioactive cyclic AMP in adenine-labeled slices from cerebral cortex, cerebellum, hippocampus, striatum, superior colliculi, hypothalamus, thalamus, and medulla-pons. In cerebral cortical slices, forskolin has half-maximal effects at 20-30 microM on cyclic AMP levels, both alone and in the presence of the phosphodiesterase inhibitor ZK 62771. The presence of a very low dose of forskolin (1 microM) can augment the response of brain cyclic AMP-generating systems to norepinephrine, isoproterenol, histamine, serotonin, dopamine, adenosine, prostaglandin E2, and vasoactive intestinal peptide. Forskolin does not augment responses to combinations of histamine-norepinephrine adenosine-norepinephrine, or histamine-adenosine. For norepinephrine and isoproterenol in rat cerebral cortical slices and for histamine in guinea pig cerebral cortical slices, the presence of 1 microM-forskolin augments the apparent efficacy of the amine, whereas for adenosine, prostaglandin E2, and vasoactive intestinal peptide, the major effect of 1 microM-forskolin is to increase the apparent potency of the stimulatory agent. In rat striatal slices, forskolin reveals a significant response of cyclic AMP systems to dopamine and augments the dopamine-elicited activation of adenylate cyclase in rat striatal membranes. The activation of cyclic AMP systems by forskolin is rapid and reversible, and appears to involve both direct activation of adenylate cyclase and facilitation and/or enhancement of receptor-mediated activation of the enzyme.
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PMID:Activation of cyclic AMP-generating systems in brain membranes and slices by the diterpene forskolin: augmentation of receptor-mediated responses. 612 72


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