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)

The effects of elevated levels of adenosine 3',5'-cyclic monophosphate (cAMP), in cultured endothelial cells from bovine aorta, on the ATP-induced increases in the intracellular free calcium concentration [( Ca2+]i) and the release of prostaglandin I2 (PGI2) and endothelium-derived relaxant factor (EDRF) were investigated. Endothelial cAMP production was assessed in terms of cAMP release in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine; this release was increased fivefold by isoproterenol (1 microM), 1.6-fold by isoproterenol (0.1 microM), and 1.5-fold by the stable PGI2 analogue iloprost (10 microM). [Ca2+]i, measured with the fluorescent probe indo-1, was increased by ATP (1 microM) from 150 +/- 20 (SE) to 410 +/- 50 nM. Neither isoproterenol nor iloprost changed [Ca2+]i in unstimulated cells, but they significantly reduced [Ca2+]i levels in the presence of ATP. Similar inhibitions of increases in [Ca2+]i as by iloprost and isoproterenol (0.1 microM) were evoked by dibutyryl-cAMP (100 microM). Release of PGI2 was enhanced from 3.9 +/- 0.5 to 34.6 +/- 6 ng.min-1.5 x 10(6) cells-1 by ATP (3 microM); in the presence of isoproterenol, the ATP-stimulated release was reversibly reduced to 18.1 +/- 4.9 ng/min. Release of EDRF was assayed in terms of its stimulatory action on purified soluble guanylate cyclase. EDRF release in the first minute after stimulation with ATP (10 microM) was significantly attenuated by isoproterenol from 32.3 +/- 4.8 to 23.0 +/- 4.6 nmol.min-1.mg-1 (activity of soluble guanylate cyclase).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:cAMP attenuates autacoid release from endothelial cells: relation to internal calcium. 169 98

Atrial natriuretic factor (ANF, 10(-7) M) and, even more potently, sodium nitroprusside (SNP, 10(-5)-10(-3) M) stimulated cGMP formation in human peritoneal macrophages. This suggests that the two forms of guanylate cyclase, the particulate form stimulated by ANF and the soluble form activated by SNP, coexist in this cell type. A fall in cAMP levels in parallel with the rise of cGMP levels provoked by ANF and SNP was noticed that was amplified by an increase in the concentration of the phosphodiesterase inhibitor, IBMX. Our finding that ANF, contrary to its action in other tissues, was unable to exert direct inhibitory effects on the adenylate cyclase activity in isolated macrophage membranes, together with the observation that SNP was able to mimic the effect of ANF on cAMP levels indicates that the cAMP-lowering effect of ANF is most likely mediated through the cGMP signal.
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PMID:Atriopeptins and nitroprusside provoke opposite changes in cGMP and cAMP levels in human macrophages. 169 68

Cicletanine is an antihypertensive/vasorelaxant/natriuretic agent of unknown mechanism. We wished (a) to determine if cicletanine interacts with guanylate cyclase activators that modulate vasomotor tone and sodium balance [i.e., atriopeptin II (AP II), endothelium-derived relaxing factor (EDRF), and sodium nitroprusside (SNP)], and (b) to define the subcellular basis for this interaction by quantitating the effects of cicletanine on low Km cyclic GMP phosphodiesterase (PDE) activity. In phenylephrine-contracted rat aortic smooth muscle, the vasorelaxant potency of cicletanine was increased twofold in the presence of a threshold-relaxant concentration of AP II, and functional cyclic GMP PDE inhibition was also evident from the three- to sixfold potentiation by cicletanine of AP II- or SNP-induced vasorelaxation. Vasorelaxation produced by cicletanine was not endothelium dependent, however. In further studies, intravenous (i.v.) administration of cicletanine or the low Km cyclic GMP PDE inhibitor, zaprinast, decreased blood pressure (BP) greater than or equal to 20% in conscious spontaneously hypertensive rats (SHR). These results are consistent with the additional finding that cicletanine inhibited Ca2(+)-calmodulin (CaM) cyclic GMP PDE and zaprinast-sensitive cyclic GMP specific PDE over a concentration range (10-600 microM) similar to that for vasorelaxation. Thus, inhibition of low Km cyclic GMP PDEs by cicletanine may be partly responsible for the vasorelaxant effect of cicletanine as well as the potentiation by cicletanine of the vasorelaxant actions of guanylate cyclase activators. The extent to which this mechanism contributes to the antihypertensive efficacy of cicletanine has not yet been fully determined.
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PMID:Inhibition of low Km cyclic GMP phosphodiesterases and potentiation of guanylate cyclase activators by cicletanine. 170 Feb 24

The interaction of hormones acting via the mobilization of calcium and stimulation of cAMP levels in cells was examined by determining the effects of carbachol and forskolin on cAMP and cGMP accumulation in mouse parotid gland. Treatment of isolated acini with either carbachol (0.01 to 20 microM) or forskolin (1 microM) alone produced little or no increase in cAMP levels; carbachol, however, augmented the effect of forskolin on cAMP accumulation approximately 3- to 4-fold. The effects of carbachol on forskolin-stimulated cAMP levels were further augmented approximately 10-fold in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (MIX) but not in the presence of "low Km" cGMP-inhibited phosphodiesterase inhibitor milrinone. Augmentation of cAMP levels also occurred in the presence of carbachol plus the beta-adrenergic agonist isoproterenol (0.01 microM). In either the presence or absence of forskolin, carbachol increased cGMP levels independently of the inclusion of MIX and in a fashion parallel to that observed for cAMP accumulation. In the presence of forskolin (1 microM), the concentration of carbachol that produced half-maximal effects on cAMP and cGMP levels was 0.62 and 0.72 microM, respectively. Similar values were obtained in the presence of MIX. Cyclic GMP levels were also enhanced by carbachol plus isoproterenol. Hydroxylamine, as well as dibutyryl-cGMP and 8-bromo-cGMP in combination with forskolin, mimicked the effects of carbachol plus forskolin on cAMP levels. LY83583 (6-anillino-5,8-quinolinedione), an agent that lowers cGMP by inhibiting guanylate cyclase, reduced basal levels of cGMP and also completely prevented the increase in cGMP caused by carbachol plus forskolin. In these experiments, however, the augmentation of forskolin-stimulated cAMP levels by carbachol was reduced by approximately 50%. Additional studies suggest that calcium is also required for carbachol augmentation of forskolin-stimulated cAMP accumulation by effects on the adenylate cyclase complex. Augmentation of cAMP levels by carbachol did not involve effects on cAMP degradation. The results suggest that, when cAMP synthesis is stimulated by forskolin or isoproterenol, the muscarinic agonist carbachol augments cAMP accumulation by mechanisms involving cGMP and calcium in mouse parotid gland.
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PMID:Regulation of cAMP metabolism in mouse parotid gland by cGMP and calcium. 170 Feb 70

Peptide hormones can stimulate cyclic GMP synthesis through either of two general mechanisms: some peptides activate the cytoplasmic form of guanylate cyclase via a coupling factor called EDRF (endothelium-derived relaxation factor), while others activate the membrane form by interacting directly with an extracellular binding domain of the cyclase molecule itself. We have investigated the mechanism(s) by which crustacean hyperglycemic hormone (CHH), a neuropeptide that regulates energy metabolism in crustaceans, elevates cyclic GMP levels in lobster muscle. Phosphodiesterase inhibitors potentiate the response in intact tissue. This indicates that the primary effect of the peptide is to activate a cyclase rather than inhibit a phosphodiesterase. Methylene blue, a specific inhibitor of the EDRF pathway, does not block the actions of CHH. In addition, nitroprusside, an agent that directly activates the EDRF pathway in vertebrate animals, does not activate guanylate cyclase either in intact or homogenized lobster muscle. This indicates that the EDRF pathway, although prominent in vertebrate muscle, is not found in crustaceans and further suggests that the membrane cyclase is the most likely target of CHH. Membrane and soluble cyclases can be isolated from homogenates of lobster muscle (in a 3.5:1 ratio), and both are stimulated by Mn2+ and inhibited by Ca2+. CHH has no effect on the soluble enzyme. Coupling of CHH receptors to the particulate cyclase, however, remains intact in isolated membranes, thus providing a new model system for the study of receptor/cyclase interactions.
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PMID:Activation of membrane guanylate cyclase by an invertebrate peptide hormone. 170 Jul 84

Airway smooth muscle plasma membranes are rich in K+ channels of various types. Charybdotoxin (ChTX) is a potent blocker of the high-conductance Ca(++)-activated K+ channel in smooth muscle and produces a concentration-dependent contraction of guinea pig trachea. In the present study, pharmacologic experiments were performed on carbachol-contracted (0.34 microM) guinea-pig trachea contracted further with ChTX in order to determine if Ca(++)-activated K+ channels play a role in the responses to cAMP-dependent and cAMP-independent bronchodilators. Relaxation concentration response curves to the beta-agonists, isoproterenol and salbutamol; the phosphodiesterase inhibitor, aminophylline; the cAMP mimic, N6-2'-O-adenosine 3':5'-cyclic monophosphate the guanylate cyclase activator, sodium nitroprusside; and the K+ channel agonists, BRL-34915 and pinacidil, were obtained in the absence and presence of ChTX. The concentration response curves to isoproterenol and salbutamol were shifted to the right (approximately 27-fold and greater than 40-fold, respectively) by 180 nM ChTX, whereas concentration response curves to N6-2'-O-adenosine 3':5'-cyclic monophosphate and aminophylline were affected significantly less (shifted approximately 7.5-fold). Concentration response curves to the cGMP-dependent relaxant sodium nitroprusside were also altered by ChTX (17-fold rightward shift at 180 nM). In the presence of 60 nM ChTX, the concentration response curves to the above relaxants were shifted only 3- to 5-fold. In contrast, ChTX (60 and 180 nM) failed to produce a significant rightward shift in the concentration response curves to BRL-34915 or pinacidil. Relaxation to BRL-34915 was however, blocked by glybenclamide, suggesting differences in the mechanism of relaxation. Contraction of tissues with depolarizing concentrations of KCl (20-80 mM) inhibited responses to all bronchodilators. These results suggest that hyperpolarization of tracheal smooth muscle as a result of opening various types of K+ channels can lead to relaxation of carbachol-contracted tracheal smooth muscle.
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PMID:Selective inhibition of relaxation of guinea-pig trachea by charybdotoxin, a potent Ca(++)-activated K+ channel inhibitor. 170 Aug 17

In previous studies we have determined that both cultured neuronal and astrocyte glial cells prepared from the hypothalamus and brain stem of 1-day-old rats contain specific receptors for angiotensin II (ANG II). Astrocyte glial receptors are coupled to inositol phospholipid hydrolysis, but there is little indication of the intracellular messengers or signal transduction mechanisms coupled to the neuronal ANG II receptors. In the present study, we have determined that ANG II decreases cellular guanosine 3',5'-cyclic monophosphate (cGMP) levels in neuronal but not in astrocyte glial cultures. This effect is both time and concentration dependent and is inhibited by the ANG II-receptor antagonist [Sar1,Ile8]ANG II, showing the involvement of specific ANG II receptors. ANG II has no effects on particulate or soluble guanylate cyclase activities or on efflux of cGMP from neuronal cultures. However, the effects of ANG II on cellular cGMP content are abolished by pretreatment with the calcium channel blockers cadmium and nifedipine, and by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. These results suggest that calcium entry and possibly activation of a phosphodiesterase enzyme are involved in this ANG II-induced effect. This represents the first demonstration of a receptor-mediated effect of ANG II on an intracellular messenger in neuronal cultures. The functional role of cGMP as an intracellular messenger coupled to ANG II receptors in cultured neurons remains to be determined.
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PMID:Angiotensin II decreases cGMP levels in neuronal cultures from rat brain. 170 34

1. Full inhibition of thrombin-induced platelet aggregation was elicited by the least maximal platelet inhibitory concentrations of nitric oxide (NO; 7 +/- 1 microM) or NO-donors which included sodium nitroprusside (NaNp; 80 +/- 13 microM) 3-morpholinosydnonimine (SIN-1; 3 +/- 0.1 microM) or endothelial cells (EC; 2.36 +/- 0.12 x 10(5) added 1 min before thrombin. Oxyhaemoglobin (oxyHb; 10 microM) administered 30s to 10 min after stimulation with thrombin caused a time-dependent reversal of the inhibition induced by these agents. OxyHb was ineffective when these agents were co-incubated with the non-selective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 0.05 mM). 2. OxyHb did not reverse the platelet inhibition with IBMX (0.2 mM) or that caused by a selective guanosine 3'; 5'-cyclic monophosphate (cyclic GMP) phosphodiesterase inhibitor 2-O-propoxyphenyl-8-azapurin-6-one, (M & B 22948; 20 microM). In addition, oxyHb did not reverse the inhibition with iloprost (1 nM) which inhibits platelet aggregation through stimulation of adenylate cyclase. 3. The inhibition of platelet aggregation by NO (7 +/- 1 microM) or NaNp (80 +/- 13 microM) was accompanied by a 13 fold increase in cyclic GMP levels occurring within 15 s of addition of these agents. In the continued presence of NO or NaNp, the reversing effect of oxyHb given 1 min after thrombin was associated with a pronounced decrease in cyclic GMP levels. 4. We conclude that the inhibition of platelet aggregation by activators of guanylate cyclase depends in the first few minutes on continuous stimulation of the enzyme in order to maintain intracellular concentrations of cyclic GMP, except when its breakdown is inhibited. 5. The addition of agents such as oxyHb after the inhibition of platelet aggregation offers another way of investigating the biochemical changes involved in maintaining platelets in an inactive state.
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PMID:The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO-donors. 170 9

The relaxant effect of vasoactive intestinal peptide (VIP) was investigated in isolated guinea-pig trachea in the presence of the phosphodiesterase (PDE) inhibitors, papaverine and 3-isobutyl-1-methylxanthine (IBMX), and the results were compared to those obtained with the cyclic AMP-dependent bronchodilators, isoproterenol and prostaglandin E2 (PGE2). The relaxant effect of VIP was greater when the magnitude of the leukotriene D4 (LTD4)-induced contraction was smaller. A similar effect was also observed for the relaxation induced by isoproterenol but not by PGE2. In the presence of papaverine (1 microM) and IBMX (3 microM), which reduced the 30 nM LTD4-induced contraction to the same extent, the relaxant effect of VIP was not changed, whereas the relaxant effects of isoproterenol and PGE2 were significantly potentiated. The potentiating effect of PDE inhibitors was also observed for the relaxation induced by the adenylate cyclase activator, forskolin, but not for the relaxation induced by the guanylate cyclase activator, sodium nitroprusside. These results suggest that the relaxation induced by VIP is different from that induced by cyclic AMP-dependent bronchodilator in the guinea-pig trachea.
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PMID:Effects of phosphodiesterase inhibitors on vasoactive intestinal peptide-induced relaxation of isolated guinea-pig trachea. 171 96

Atrial natriuretic factor (ANF, 10(-7) M) and sodium nitroprusside (SNP, 10(-5)-10(-3) M) stimulated cGMP production in human peritoneal macrophages (HPM). This suggests the existence of two separate forms of guanylate cyclase in HPM, e.g. the receptor-related form by ANF and the soluble form by SNP. In parallel with the rise in cGMP levels, both agents provoked a decrease in cAMP levels. Increasing the concentration of the phosphodiesterase inhibitor IBMX (0.2 mM to 1.0 mM) in the incubation media resulted in a significantly greater rise in cGMP levels which was accompanied by a profound decrease in cAMP levels. ANF did not exert any direct or GTP-related effect on cAMP production, which is in contrast to its action in other tissues. These results suggest that cAMP levels can be modulated through a cGMP signal, most likely at the production level. Results also give substantial evidence for the presence of a ANF receptor site on human peritoneal macrophages.
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PMID:Cyclic nucleotides in human macrophages: effects of atrial natriuretic factor and nitroprusside on cGMP and cAMP production. 172 23


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