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)

After incubation with 3H-noradrenaline, strips of human pulmonary arteries from patients undergoing surgery for lung tumour were superfused with physiological salt solution containing cocaine and corticosterone. Forskolin, AH 21-132 (a cAMP phosphodiesterase inhibitor), 8-Br-cAMP and isoprenaline did not affect the basal tritium efflux from the strips, but produced a concentration-dependent facilitation of the tritium overflow evoked by transmural electrical stimulation (2 Hz). The facilitatory effect of isoprenaline was potentiated by forskolin which produced a shift to the left of the concentration-response curve of isoprenaline. It is concluded that cAMP plays a role in the modulation of noradrenaline release in the human pulmonary artery and that presynaptic beta-adrenoceptors appear to be coupled to an adenylate cyclase in the sympathetic nerve terminals.
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PMID:Involvement of cAMP in modulation of noradrenaline release in the human pulmonary artery. 299 30

The role of cyclic AMP on endothelial cell proliferation was investigated, since these cells can be exposed to high concentrations of physiological and pharmacological agents that alter cyclic AMP metabolism. Cloned bovine aortic endothelial cells were plated at 25,000 cells/35mm dish and grown for 5 days in the presence of phosphodiesterase (PDE) inhibitors, forskolin, or cyclic AMP analogs. The PDE inhibitors dipyridamole, ZK 62 711, isobutylmethylxanthine (IBMX) and theophylline inhibited cell growth in a concentration-dependent manner. Dipyridamole produced a 30% and a 50% inhibition at 5 microM and 12.5 microM, while higher concentrations were cytotoxic. At its therapeutic plasma concentration range (50-100 microM) theophylline inhibited cell proliferation by 15-25%, while IBMX and the highly specific cyclic AMP phosphodiesterase inhibitor, ZK 62 711 inhibited growth by 60-80% and 40-50%, respectively. Forskolin (5 microM) increased cyclic AMP levels and cyclic AMP-kinase activity ratios by 2.5-fold and 2-fold. In the absence of PDE inhibitors forskolin produced a 20% growth inhibition at 0.5 microM and a 60% inhibition at 10 microM. The forskolin dose-response curve was not altered by theophylline, but was shifted to the left by approximately 10-fold with dipyridamole and ZK 62 711 and 5-fold with IBMX. Forskolin (5 microM), by itself produced a 1.8-fold increase in cyclic AMP. In the presence of 5 microM theophylline, dipyridamole, IBMX, and ZK 62 711, cyclic AMP was increased by forskolin 2.0, 2.6, 3.5, and 6.6-fold, respectively. 8-Bromo cyclic AMP and dibutyryl cyclic AMP produced a 55% and 60% growth inhibition at 100 microM. The cyclic GMP analogs were less effective inhibitors of growth (15-30%). Our results demonstrate that cyclic AMP analogs and pharmacological agents that elevate intracellular cyclic AMP levels inhibit cell growth and suggest that cyclic AMP may be an important endogenous regulator of endothelial cell proliferation.
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PMID:Forskolin, phosphodiesterase inhibitors, and cyclic AMP analogs inhibit proliferation of cultured bovine aortic endothelial cells. 300 97

Forskolin caused a concentration dependent relaxation of rabbit detrusor muscle strips. The relaxant effect of forskolin was potentiated by the cyclic AMP sensitive phosphodiesterase inhibitor, Ro20-1274. Pretreatment with the beta-adrenergic antagonist, propranolol, did not inhibit the relaxation of rabbit detrusor induced by forskolin, whereas the relaxation response to forskolin was inhibited in part by the adenylate cyclase inhibitor, SQ22536. Forskolin also increased cyclic AMP levels significantly in rabbit detrusor muscle. These data suggest that detrusor muscle relaxation by forskolin may be mediated by cyclic AMP and that forskolin may activate adenylate cyclase without stimulating beta-adrenergic receptors in detrusor muscle.
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PMID:Relaxant effect of forskolin in rabbit detrusor smooth muscle: role of cyclic AMP. 301 24

Forskolin has been reported to stimulate cAMP formation and reduce intraocular pressure in rabbit and primate eyes. In view of recent evidence for the involvement of cAMP in modulation of transmitter release at adrenergic synapses, we have investigated the presynaptic effects of forskolin and other cAMP activators on field-stimulated secretion of 3H-norepinephrine (3H-NE) in the isolated, perfused rabbit iris-ciliary body. Forskolin (10(-7)-10(-5) M) was found to markedly enhance stimulation-evoked 3H-NE release without affecting basal (spontaneous) release. The response to forskolin was potentiated by the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX; 0.5 mM) and was mimicked by the cell-permeant cyclic nucleotide analog 8-bromo-cAMP. 8-bromo-cGMP also produce a small enhancement of stimulus-evoked 3H-NE secretion, whereas IBMX alone had little effect on either stimulated or basal secretion. These results suggest that cAMP may play an important neuromodulatory role in regulation of norepinephrine release at intraocular synapses, and raise the possibility that the ocular hypotensive response to forskolin in rabbit eyes may be mediated, in part, by enhanced adrenergic neurosecretion.
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PMID:Potentiation of sympathetic neurosecretion by forskolin and cyclic AMP in the rabbit iris-ciliary body. 301 36

Forskolin, epinephrine, and prostaglandin I2 were used to examine the adenylate cyclase-phosphodiesterase system of intact thrombopathic and normal canine platelets. The results provide indirect support for the hypothesis that the elevation of intraplatelet c-AMP in this unique hereditary defect is due to impaired phosphodiesterase activity. The inhibitory (Nj) and stimulatory (Ns) components of adenylate cyclase appeared functionally intact. Cytosolic fractions of normal and thrombopathic platelets had similar cAMP hydrolytic activities. The failure of intact forskolin-stimulated thrombopathic platelets to return elevated cAMP to non-stimulated levels after 15 min, despite significant phosphodiesterase activity in cytosolic fractions, implies that the platelet isoenzymes are under regulatory control.
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PMID:Evidence for regulatory control of canine platelet phosphodiesterase. 302 25

Unstimulated efflux of cyclic AMP from perfused dog adrenal glands was not altered by 0.1 microM of forskolin and was slightly increased by 0.3 and 1.0 microM of forskolin. ACh stimulated efflux of cyclic AMP which preceded CA release and the efflux was dose-dependently enhanced by forskolin. Forskolin did not affect the spontaneous CA release but enhanced ACh-evoked catecholamine (CA) release. There was a close correlation between the dose relationship of forskolin enhancement of stimulated-cyclic AMP efflux and that of evoked-CA release. ACh-evoked CA release in the presence of forskolin was further potentiated by R020-1724, a phosphodiesterase inhibitor. CA release evoked by excess K+, or by caffeine in the presence or absence of external Ca2+ was also potentiated by forskolin. These results suggests that cyclic AMP generation may increase in response to stimulation of adrenal chromaffin cells and that the resulting increase of the nucleotide may function as a facilitating modulator of CA release.
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PMID:Forskolin enhancement of acetylcholine-evoked cyclic AMP formation and catecholamine release in perfused dog adrenals. 302 49

Forskolin, a direct activator of the catalytic subunit of adenylate cyclase (AC), and the cyclic nucleotide analogs dibutyryl cAMP (dBcAMP), 8-bromo cAMP (8-BrcAMP) and dibutyryl cGMP (dBcGMP) were tested for their ability to reverse the hypothermia or hypokinesia of mice depleted of presynaptic endogenous monoamines by pretreatment with reserpine, alpha-methyl-p-tyrosine and p-chlorophenylalanine. Forskolin and the cAMP analogs decreased the rectal temperature and inhibited locomotor activity in normal mice. In mice depleted of brain monoamines forskolin reversed the hypothermia and hypokinesia; dBcAMP and 8-BrcAMP antagonized the hypothermia but were only marginally effective in reversing the hypokinesia. DBcGMP was inactive. The antihypothermic action of forskolin or salbutamol was enhanced by the novel antidepressant and cAMP selective phosphodiesterase inhibitor rolipram (4RS-[3-cyclopentyloxy-4-methoxy-phenyl]-2-pyrrolidone). As an indirect effect via release of endogenous monoamines stimulating postsynaptic receptors was precluded by the monoamine-depleting pretreatment, forskolin and the cAMP analogs are thought to exert their antidepressant action by directly increasing brain cAMP availability. This is achieved by forskolin via activation of the catalytic subunit of AC and by the cAMP analogs via substitution for cAMP. These findings suggest that antidepressant activity is crucially linked to enhanced cAMP availability within brain effector cells. The successful treatment of endogenously depressed patients with rolipram supports this assumption.
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PMID:Effects of forskolin and cyclic nucleotides in animal models predictive of antidepressant activity: interactions with rolipram. 302 33

The effect of the adenylate cyclase activator forskolin on bone resorption and cyclic AMP accumulation was studied in an organ-culture system by using calvarial bones from 6-7-day-old mice. Forskolin caused a rapid and fully reversible increase of cyclic AMP, which was maximal after 20-30 min. The phosphodiesterase inhibitor rolipram (30 mumol/l), enhanced the cyclic AMP response to forskolin (50 mumol/l) from a net cyclic AMP response of 1234 +/- 154 pmol/bone to 2854 +/- 193 pmol/bone (mean +/- S.E.M., n = 4). The cyclic AMP level in bones treated with forskolin (30 mumol/l) was significantly increased after 24 h of culture. Forskolin, at and above 0.3 mumol/l, in the absence and the presence of rolipram (30 mumol/l), caused a dose-dependent cyclic AMP accumulation with an calculated EC50 (concentration producing half-maximal stimulation) value at 8.3 mumol/l. In 24 h cultures forskolin inhibited spontaneous and PTH (parathyroid hormone)-stimulated 45Ca release with calculated IC50 (concentration producing half-maximal inhibition) values at 1.6 and 0.6 mumol/l respectively. Forskolin significantly inhibited the release of 3H from [3H]proline-labelled bones stimulated by PTH (10 nmol/l). The inhibitory effect by forskolin on PTH-stimulated 45Ca release was significant already after 3 h of culture. In 24 h cultures forskolin (3 mumol/l) significantly inhibited 45Ca release also from bones stimulated by prostaglandin E2 (1 mumol/l) and 1 alpha-hydroxycholecalciferol (0.1 mumol/l). The inhibitory effect of forskolin on spontaneous and PTH-stimulated 45Ca release was transient. A dose-dependent stimulation of basal 45Ca release was seen in 120 h cultures, at and above 3 nmol of forskolin/l, with a calculated EC50 value at 16 nmol/l. The stimulatory effect of forskolin (1 mumol/l) could be inhibited by calcitonin (0.1 unit/ml), but was insensitive to indomethacin (1 mumol/l). Forskolin increased the release of 3H from [3H]proline-labelled bones cultured for 120 h and decreased the amount of hydroxyproline in bones after culture. Forskolin inhibited PTH-stimulated release of Ca2+, Pi, beta-glucuronidase and beta-N-acetylglucosaminidase in 24 h cultures. In 120 h cultures forskolin stimulated the basal release of minerals and lysosomal enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Use of forskolin to study the relationship between cyclic AMP formation and bone resorption in vitro. 302 78

Forskolin, a diterpene extracted from Coleus forskolii, stimulates the production of cAMP in a variety of cells and is potentially an important tool for studying the role of cAMP in the modulation of neuronal excitability. We studied the effects of forskolin on neurons of nudibranch molluscs and found that it caused characteristic, reversible changes in the amplitude and waveform of the transient K current, IA, and also activated an inward current similar to the cAMP-dependent inward current previously described in molluscan neurons. Forskolin altered the time course of IA activation and inactivation but did not affect the voltage dependence or the reversal potential of the current. IA normally inactivates exponentially, but in forskolin the time course of inactivation can be fit by the sum of 2 exponentials with an initial rate that is faster than the control and a final rate that is much slower. On depolarization in forskolin, IA begins to activate at the normal rate, but a slower component of activation is also seen. The changes in IA in the nudibranch cells were qualitatively different than the changes caused by forskolin in Aplysia bag cell neurons (Strong, 1984). Experiments were performed to determine whether these effects of forskolin require cAMP. Intracellular injection of cAMP, application of membrane-permeable analogs of cAMP, application of phosphodiesterase inhibitors, and intracellular injection of the active catalytic subunit of cAMP-dependent protein kinase did not affect the amplitude or waveform of IA. Also, the changes in IA that are caused by forskolin were not prevented or reversed by intracellular injection of an inhibitor of cAMP-dependent protein kinase. Cyclic AMP did, however, activate inward current at voltages near the resting potential. We conclude that the changes in IA and the activation of inward current represent separate affects of forskolin. The inward current appears to depend on an increase in intracellular cAMP, while the changes in IA do not. These experiments show that, in addition to activating adenylate cyclase, forskolin may have a separate direct affect on the transient K current.
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PMID:Forskolin's effect on transient K current in nudibranch neurons is not reproduced by cAMP. 302 41

The effects of compounds that activate adenylate cyclase and of cAMP on calcium-dependent action potentials recorded from mouse dorsal root ganglion neurons were assessed. Application of compounds that stimulate the adenylate cyclase system (forskolin, cholera toxin, and prostaglandin E1) increased action potential duration with an associated decrease in afterhyperpolarization. An adenylate cyclase inhibitor, 2',5'-dideoxyadenosine, partially inhibited the responses to forskolin and cholera toxin. cAMP analogs mimicked the effect of forskolin, and the phosphodiesterase inhibitor theophylline enhanced the response to forskolin. Following intracellular injection of the potassium channel blocker cesium, the forskolin response was reduced. Forskolin did not significantly alter resting membrane potential or conductance. The action potential responses to forskolin were voltage dependent, being reduced when the membrane was held at less negative (less than -50 mV) potentials. The data suggest that activators of adenylate cyclase and cAMP prolong calcium-dependent action potentials by blocking a voltage-dependent potassium conductance that is responsible, in part, for action potential repolarization and that inactivates at membrane potentials less negative than -50 mV.
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PMID:Activators of adenylate cyclase and cyclic AMP prolong calcium-dependent action potentials of mouse sensory neurons in culture by reducing a voltage-dependent potassium conductance. 303 Dec 36


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