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)

Microelectrodes were used to investigate the possible involvement of cAMP and Ca2+ ions in the parathyroid hormone's, bPTH(1-34), effect on the membrane potential of rat osteoblasts in primary culture. Parathyroid hormone (10(-7) M) depolarized cell membrane by 25.0 +/- 6.1 mV (mean +/- standard deviation, SD; n = 17). Blocking Ca2+ influx with the Ca channel blocker cobalt revealed two phases in the hormone effect: a rapid and slight membrane hyperpolarization followed by sustained depolarization. In addition, cobalt significantly (p less than 0.01) decreased the magnitude of the PTH depolarizing action. The addition of dibutyryl-cAMP (10(-3) M) to the perfusion solution also resulted in a biphasic effect. At a lower concentration (10(-4) M), dibutyryl-cAMP produced only membrane hyperpolarization, suggesting a cAMP dose dependence of the opposite membrane potential changes. Forskolin (10(-5) M) and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX) (10(-4) M) mimicked the depolarizing effect of PTH. IBMX at a low concentration (5 x 10(-6) M) potentiated the depolarizing effect of PTH. Increases in [Ca2+]i using Ca2+ ionophore A23187 and intracellular injection of CaCl2 or inositol trisphosphate decreased the PTH depolarizing action, whereas intracellular injection of EGTA enhanced this effect. These results indicate that PTH evokes a biphasic change in rat osteoblast membrane potential that seems to be mediated by an increase in cAMP and modulated by intracellular calcium.
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PMID:Early effects of parathyroid hormone on membrane potential of rat osteoblasts in culture: role of cAMP and Ca2+. 246 41

The role of cyclic AMP in the regulation of melatonin production was investigated in cultured Syrian hamster pineal glands. Forskolin markedly increased cyclic AMP production in pineal glands collected either late in the light period or in the dark period. The effect of forskolin was synergistically enhanced by 3-isobutylmethylxanthine, a phosphodiesterase inhibitor; however, increase in cyclic AMP after isoproterenol was only apparent in the presence of 3-isobutylmethylxanthine. Since beta-adrenergic agonists are able to stimulate melatonin production late in the dark period only, these data suggest that, in the hamster pineal gland, there may be intracellular mechanisms in addition to a cyclic AMP increase required for induction of melatonin production by beta-adrenergic agonists.
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PMID:The in vitro activation of cyclic AMP production by either forskolin or isoproterenol in the Syrian hamster pineal during the day is not accompanied by an increase in melatonin production. 246 73

1. Isolated segments of the guinea-pig ileum were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent was determined by h.p.l.c. with electrochemical detection. Test substances were applied via the arterial perfusion medium. 2. Isoprenaline (0.1 microM) increased the outflow of 5-HT and 5-HIAA maximally by about 75% and this was antagonized by propranolol (0.1 microM). Forskolin (1-10 microM) increased the outflow of 5-HT by approximately 105% and that of 5-HIAA by approximately 55%. The phosphodiesterase inhibitor AH 21-132 (0.1-1 microM) increased the outflow of 5-HT and 5-HIAA by about 70%. Isoprenaline (1 nM) and AH 21-132 (10 nM), which alone had no effect, increased the outflow of 5-HT and 5-HIAA by 75%, when applied in combination. 3. Clonidine (1 microM) reduced the outflow of 5-HT by 45%, an effect blocked by tolazoline (1 microM), but not by prazosin (0.1 microM). 4. The effects of isoprenaline, forskolin and clonidine were also observed in the presence of tetrodotoxin (1 microM) demonstrating a direct modulation of 5-HT release from the enterochromaffin cells. 5. In conclusion, the release of 5-HT from enterochromaffin cells is facilitated by activation of beta-adrenoceptors and inhibited via alpha 2-adrenoceptors. Enhancing intracellular cyclic AMP, by direct stimulation of adenylate cyclase with forskolin or by inhibition of phosphodiesterase, also facilitates the release of 5-HT. The beta-adrenoceptor-mediated effect on 5-HT release appears to involve an increase in cyclic AMP, as the effect of isoprenaline was potentiated after inhibition of phosphodiesterase.
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PMID:Adrenergic modulation of the release of 5-hydroxytryptamine from the vascularly perfused ileum of the guinea-pig. 246 31

We examined regulation of histamine release from canine hepatic and fundic mucosal mast cells in short-term culture. We found that beta- but not alpha-adrenergic agonists markedly inhibited concanavalin A (ConA)-stimulated histamine release. Inhibition by epinephrine was reversed by the beta-antagonist propranolol, but not by the alpha-adrenergic antagonists phentolamine or yohimbine. The beta 2-selective antagonist ICI 115881 reversed the effects of epinephrine, whereas the beta 1-antagonists practolol and betaxolol had little effect. Prostaglandin E2 (PGE2), but not its analogue enprostil, inhibited ConA-stimulated histamine release. This difference may relate to the ability of PGE2, but not enprostil, to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) production. Forskolin, cAMP analogues, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also effectively inhibited ConA-stimulated histamine release. Neither adrenergic agonists nor PGE2 inhibited histamine release stimulated by the combination of phorbol 12-myristate-13-acetate plus the calcium ionophore A23187. These data suggest that inhibition was mediated via cAMP-dependent mechanisms and was exerted on primary cell activation, rather than on postreceptor activating events.
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PMID:Beta-adrenergic and prostanoid inhibition of canine fundic mucosal mast cells. 246 93

The regulation of bile acid transport in rat ileum was studied in vitro using the adenylate cyclase stimulator forskolin, or 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor. Forskolin 20 microM as well as 100 microM IBMX enhanced mucosal cyclic AMP to 3-fold the control levels. As a physiological response, net fluid absorption in everted ileal sacs was reduced. Taurocholate (10-500 microM) transfer in everted perfused segments of rat ileum was measured using a three compartment dual label method suitable for measuring active transport. Transport asymmetry with absorption exceeding its counterflux by 26-fold, was measured at 500 microM taurocholate. Forskolin increased absorption of taurocholate still further, by 68%, and reduced the serosal to mucosal flux. Enhanced intracellular accumulation of taurocholate indicated a stimulatory action of forskolin on active transport at the mucosal brush-border membrane. In uptake studies, accumulation of taurocholate was enhanced by 100 microM IBMX also. Forskolin-induced uptake stimulation could also be shown for chenodeoxycholate and cholate. In the presence of the neuronal blocker tetrodotoxin, uptake stimulation was still effective. Results indicate that the ileal bile acid transporter is included within the group of sodium-dependent cotransporters of the rat small intestine which are subject to a cyclic AMP-related stimulation at the mucosal cellular level.
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PMID:Stimulation of bile acid active transport related to increased mucosal cyclic AMP content in rat ileum in vitro. 246 77

Ventricular myocytes isolated from the hypertrophied hearts of thyrotoxic adult rats have an increase in mean protein content per myocyte (6.3 +/- 0.2 vs. 4.4 +/- 0.2 ng) compared with euthyroid cells. Viability and adenine nucleotide profiles are similar in both populations, but NAD content of the hyperthyroid myocytes is depressed (4.9 +/- 0.2 vs. 5.5 +/- 0.2 nmol/mg for controls) and UTP is higher (1.2 +/- 0.09 vs. 0.9 +/- 0.04 nmol/mg). Binding of (-)-[125I]iodocyanopindolol to intact hyperthyroid myocytes is increased by 42% compared with controls, with no change in the dissociation constant (Kd). This elevation in beta-receptor number is correlated to enhanced beta-agonist-induced adenosine 3',5'-cyclic monophosphate (cAMP) production. The half-maximal effective concentration (EC50) for the euthyroid isoproterenol dose-response curve is 2.14 x 10(-7) M but is decreased to 2.51 x 10(-8) M in hyperthyroid cardiac cells. Basal adenylate cyclase activity is apparently not affected by thyroid hormones, since basal cAMP levels for both groups are identical (5 pmol/mg) and both rise roughly twofold in the presence of a phosphodiesterase inhibitor. Forskolin-induced cAMP production and cAMP-specific phosphodiesterase activity are similar as well. In contrast to beta-adrenergic response, there are no significant differences in alpha 1-antagonist [3H]prazosin binding parameters between hyperthyroid and euthyroid cardiomyocytes.
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PMID:Hyperthyroid adult rat cardiomyocytes. I. Nucleotide content, beta- and alpha-adrenoreceptors, and cAMP production. 248 Jul 17

In the first part of this presentation, data is reported on the hemodynamic effects of forskolin given to patients with dilated cardiomyopathy in a concentration of 3 micrograms/kg/min and 4 micrograms/kg/min. At the lower dosage, forskolin had no effect on dP/dtmax, cardiac index, ejection fraction, or myocardial oxygen consumption. With small dosages of dobutamine, however, an increase of all four parameters has been observed in the same group of patients. Systemic vascular resistance and left ventricular enddiastolic pressure fell with forskolin given at the lower concentration. Forskolin administered at a dosage of 4 micrograms/kg/min induced an increase in dP/dtmax by 19% and a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. Therefore, forskolin may serve as a vasodilating substance in lower concentrations, but cannot be used as a positive inotropic compound because of the subjective symptoms. In the second part, a study is reported in which an anti-ischemic effect of the phosphodiesterase inhibitor enoximone was observed in patients with proven significant coronary heart disease. With respect to the hemodynamic parameters, the most striking findings were the decreases in left ventricular enddiastolic pressure and systemic vascular resistance. Furthermore, when left ventricular stroke work index was plotted as a function of the left ventricular enddiastolic pressure, enoximone shifted the left ventricular function curve to the left. Therefore, the anti-ischemic effect of enoximone may not only be due to a reduction in preload and afterload but may rather reflect an effect on diastolic compliance. Studies with intracoronary injections of enoximone and animal experiments support this hypothesis.
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PMID:Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. 253 Sep 74

The effect of forskolin on parathyroid hormone (PTH) stimulated bone resorption, as assessed in vitro by the release of 45Ca from prelabelled neonatal mouse calvarial bones, and cyclic AMP formation in mouse calvarial bones and osteoblast-like cells was investigated. Much higher concentrations (100-300-times) of PTH were required to stimulate cyclic AMP accumulation than to stimulate mineral mobilization in murine calvarial bones. PTH, in the absence of phosphodiesterase inhibitor, stimulated cyclic AMP formation in mouse calvarial bones at and above concentrations of 3-10 nmol/l with EC50 at 10-15 nmol/l. In the presence of forskolin (1 or 10 mumol/l) the minimal concentration required to obtain a cyclic AMP response to PTH was decreased by a factor of 30-100 and the EC50 value was decreased to 1-2 nmol/l. Similar results were seen in osteoblast-enriched cells. In addition, the magnitude of the PTH-induced cyclic AMP response was substantially potentiated by forskolin, both in calvarial bones and in isolated osteoblasts. Forskolin, in the absence of PTH, stimulated cyclic AMP levels in mouse calvaria at and above 1 mumol/l. In the presence of PTH, the response to forskolin was potentiated over the whole dose-response curve with apparent EC50 value at 1-2 mumol/l of forskolin. Forskolin (1 mumol/l) did not affect the magnitude of the 45Ca release response to PTH in 24 or 48 h cultures. In 96 h cultures, forskolin, in an additive manner, potentiated the effect of PTH on calcium mobilization. These results show that forskolin, in mouse calvarial bones and in isolated osteoblasts, in addition to directly stimulating cyclic AMP, can enhance receptor-mediated activation of adenylate cyclase. The finding that forskolin did not synergistically potentiate PTH-induced bone resorption suggests that there is no simple relationship between PTH-induced cyclic AMP formation and stimulation of bone resorption.
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PMID:Forskolin sensitizes parathyroid hormone-induced cyclic AMP response, but not the bone resorptive effect, in mouse calvarial bones. 253 71

We quantified the TSH-induced morphological change in FRTL-5 thyroid cells according to a morphological index corresponding to the mean cell area measured from microscopic photographs. Within 15 min, TSH induced, at 10 pM and higher concentrations, a decrease in morphological index together with a rise in cAMP levels in a TSH dose-dependent manner. Forskolin, 3-isobutyl-1-methylxanthine, and RO 20-1724, the latter two being phosphodiesterase inhibitors, mimicked these TSH effects, indicating that the rise in cAMP levels is responsible for the TSH effect. Extracellular ATP and its derivatives, known as purinergic receptor agonists, decreased cAMP levels and caused a complete reversal of the TSH morphological effect. Prior exposure of the cells to islet-activating protein (pertussis toxin), the depletion of extracellular Ca2+, or the addition of low doses of protein kinase-C inhibitors completely abolished the inhibitory action of ATP on the TSH effect, whereas phorbol 12-myristate 13-acetate, which activates protein kinase-C, mimicked the ATP action to some extent. Thus, although the TSH-induced change in cell morphology seems to be dependent on cAMP levels, the inhibition of TSH action by ATP seems to be mediated by at least two signal transduction pathways involving islet-activating protein substrate G-proteins: one inhibiting adenylate cyclase and the other involving Ca2+ and protein kinase-C.
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PMID:Extracellular adenosine triphosphate completely reverses the thyrotropin-induced morphological change in FRTL-5 cells. 254 96

The K+ current induced by isoprenaline acting on beta-adrenergic receptors in Xenopus laevis has been studied in oocytes still surrounded by their follicular cells and inner ovarian epithelium. Forskolin, an adenylate cyclase activator, induced a similar K+ current and when used at subliminal concentration it potentiated the current induced by isoprenaline. Inhibition of phosphodiesterase by methylisobutylxanthine also enhanced the response to isoprenaline. 8-Br-cAMP, a permeant analogue of cAMP also produced a K+ current. Acetylcholine produced a long lasting inhibition of the isoprenaline current. This inhibition was not seen in the presence of atropine. It is concluded that the K+ current induced by the activation of beta-adrenergic receptors in the oocyte is mediated by an intracellular rise of cAMP.
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PMID:beta-Adrenergic induced K+ current in Xenopus oocytes: role of cAMP, inhibition by muscarinic agents. 257 1


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