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 mode for the antispasmodic action of suloctidil was examined using aorta strips of rats in vitro. Both 10 microM suloctidil and 0.1 microM verapamil non-competitively inhibited the norepinephrine (NE)-induced contraction, of which pD'2 values were 4.61 +/- 0.41 and 6.16 +/- 0.22, respectively. Prazosin at 1 nM competitively inhibited the NE-induced contraction, and its pA2 value was 9.84 +/- 0.15. In the depolarized aorta, suloctidil competitively inhibited the CaCl2-induced contraction at the concentrations of 0.1 and 1.0 microM, of which the pA2 value was 5.96 +/- 0.26. However, 10 microM suloctidil inhibited the CaCl2-induced contraction in a non-competitive manner, and its pD'2 value was 5.01 +/- 0.14. The pA2 values for papaverine, verapamil and cinnarizine were found to be 5.23 +/- 0.10, 7.53 +/- 0.09 and 7.11 +/- 0.11 in CaCl2 induced contraction, respectively. In a Ca2+ free medium, 1 microM NE caused a transient contraction, which was maximum (23.8 +/- 2.2% of that in a normal solution) at 0.4 min after the application of NE. Subsequent application of 2.5 and 10 mM CaCl2 evoked a gradual contractile response, of which the maximum was 103.1 +/- 4.2% and 133.8 +/- 10.3% of that in a normal solution, respectively. Initial phasic contraction induced by NE in a Ca2+ free medium was not affected by 10 microM suloctidil nor by 0.1 microM verapamil, while this contraction was significantly suppressed by 1 nM prazosin. The tonic contraction, however, induced by re-application of CaCl2 was significantly suppressed by 10 microM suloctidil, 0.1 microM verapamil and 1 nM prazosin. Furthermore, 1.0 microM suloctidil and 0.1 microM verapamil significantly suppressed the 45Ca uptake into the depolarized aorta 5 and 10 min after the addition of 45CaCl2. On the contrary, suloctidil had no influence on the phosphodiesterase activity prepared from the aorta of rats even at 10 microM, whereas 1.0 microM papaverine inhibited the enzyme activity. It is concluded that suloctidil and verapamil inhibit the contractions of the isolated rat aorta induced by NE and CaCl2 through the inhibition of the influx of Ca2+ without affecting the intracellular Ca2+ release.
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PMID:[Effect of suloctidil on the contractions of isolated rat aortic strips induced by norepinephrine and CaCl2]. 632 88

Previous studies on the mode of action of flavoxate have shown that the drug exerts a selective and direct muscle relaxant activity. In order to study the mode of action of flavoxate, the following activities were investigated: calcium blocking, inhibition of cyclic AMP phosphodiesterase (PDE), local anaesthetic activity, the effects on the synthesis and release of prostaglandins. In the K+-depolarized guinea-pig taenia coli, contracted by CaCl2, flavoxate and papaverine showed a moderate calcium antagonistic activity. Anticholinergic drugs, such as atropine and emepronium, did not exert a similar action. The antispasmodic activity of a drug can be correlated with inhibition of cyclic AMP phosphodiesterase, and since papaverine is a potent PDE inhibitor, we tested flavoxate for this activity. Flavoxate exerted a PDE inhibitory activity about three and five times greater than that of aminophylline in tissues homogenates of guinea-pig ureter and urinary bladder, respectively. It also showed the same local anaesthetic activity of lidocaine. Finally, the synthesis and release of prostaglandins by urinary bladder muscle in vitro have been investigated before and after treatment with flavoxate. Myolytic activity of papaverine and flavoxate do not involve inhibition of prostaglandins synthesis in rat urinary bladder in vitro. Therefore, the mode of action of flavoxate can be related to a superimposition of myotropic, calcium antagonistic and local anaesthetic activity.
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PMID:Pharmacological studies on the mode of action of flavoxate. 632 16

Tiaramide hydrochloride (THC) is a benzothiazoline derivative with a remarkable antianaphylactic activity: in anaesthetized guinea-pig it shows protecting effects against histamine (H)- and bradykinin (Bk)-induced bronchoconstriction, preventing increase of lung resistance and decrease of dynamic compliance. At the same time THC inhibits formation of circulating thromboxane A2 brought about by H and Bk. THC is also able to antagonize the contractions induced by CaCl2 on isolated guinea-pig tracheal spirals and its mode of action seems to be of the competitive type. Furthermore THC abolishes the "tonic" phase of K+-induced contractions of guinea-pig taenia coli which are dependent on inward movement of calcium, whereas the "phasic" component of the contractions is left unaltered. THC is a very weak inhibitor of 3'-5' cyclic adenosine monophosphate phosphodiesterase which is affected only at very high dosage (10(-2) M). The calcium antagonistic activity of THC may explain both its bronchodilating and antianaphylactic properties.
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PMID:New pharmacological aspects on the antiasthmatic activity of tiaramide-HCl. 689 Aug 32

A Golgi-rich fraction has been isolated from rat ascites hepatoma AH-130 cells. Unlike the usual procedure for isolating Golgi complexes from liver and other tissues, a hypotonic solution including 2 mM CaCl2 was used as the homogenization medium for the ascites hepatoma cells, followed by a combination of differential and discontinuous sucrose gradient centrifugations. Electron microscopic observation revealed that the isolated fraction consisted of cisternae, vesicles and tubular elements which were similar to those structures described previously for the Golgi fraction isolated from rat liver. Galactosyl- and sialyl-transferases were concentrated about 55- and 75-fold, respectively, in this fraction compared with the homogenate, indicating that these enzymes are useful markers for the Golgi complex of rat ascites hepatoma AH-130 cells, as they are for those of other normal tissues. The preparation was virtually free of cytochrome oxidase, but contained minor amounts of acid phosphatase, alkaline phosphatase and phosphodiesterase I activities. Electrophoretic analysis on sodium dodecylsulfate-polyacrylamide gels showed that the hepatoma Golgi membranes were resolved into at least 23 protein bands, which were apparently different from the electrophoretic profile of the plasma membrane isolated from the same hepatoma cells.
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PMID:Isolation and characterization of the Golgi complex from rat ascites hepatoma AH-130 cells. 714 13

Mechanical force regulates gene expression and cell proliferation in a variety of cell types, but the mechanotransducers and signaling mechanisms involved are highly speculative. We studied the fibroblast signaling mechanism that is activated when cells are switched from mechanically stressed to mechanically relaxed conditions, i.e., stress relaxation. Within 10 min after initiation of stress relaxation, we observed a transient 10-20-fold increase in cytoplasmic cyclic AMP (cAMP) and a threefold increase in protein kinase A activity. The increase in cAMP depended on stimulation of adenylyl cyclase rather than inhibition of phosphodiesterase. Generation of cAMP was inhibited by indomethacin, and release of arachidonic acid was found to be an upstream step of the pathway. Activation of signaling also depended on influx of extracellular Ca2+ because addition of EGTA to the incubations at concentrations just sufficient to exceed Ca2+ in the medium inhibited the stress relaxation-dependent increase in free arachidonic acid and cAMP. This inhibition was overcome by adding CaCl2 to the medium. On the other hand, treating fibroblasts in mechanically stressed cultures with the calcium ionophore A23187-stimulated arachidonic acid and cAMP production even without stress relaxation. In summary, our results show that fibroblast stress relaxation results in activation of a Ca(2+)-dependent, adenylyl cyclase signaling pathway. Overall, the effect of stress relaxation on cAMP and PKA levels was equivalent to that observed after treatment of cells with forskolin.
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PMID:Stress relaxation of fibroblasts activates a cyclic AMP signaling pathway. 751 67

The present studies investigated the effect of parathyroid hypertensive factor (PHF) on intracellular calcium regulation in VSMC. Nifedipine inhibited the hypertensive effect of PHF in Sprague-Dawley (SD) rats in vivo. PHF amplified the L-type calcium current in vascular smooth-muscle cells (VSMCs) isolated from SD rat tail artery. PHF potentiated the tension induced by norepinephrine (NE) in the presence of normal added CaCl2 and inhibited the tension dependent on Ca2+ release from intracellular calcium store(s) induced by NE in SD rat tail artery helical strips. PHF potentiated the intracellular free calcium concentration ([Ca2+]i) increment induced by KCl in cultured VSMCs from SD rat tail artery. All of the in vitro cellular calcium effects of PHF temporally correlated with its delayed hypertensive effect in vivo. PHF did not affect the accumulation of inositol phosphates in SD rat tail artery. Infusion of theophylline blunted the hypertensive effect of PHF in SD rats, suggesting that PHF may stimulate phosphodiesterase (PDE) activity. We suggest that PHF may potentiate the effects of other vasoconstrictors on calcium channels and increase [Ca2+]i, which would then lead to an increase in the responsiveness of the VSMC to other vasoconstrictors, and therefore an increase in blood pressure. The action of PHF may involve stimulation of PDE activity.
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PMID:Mechanism of the vascular action of parathyroid hypertensive factor. 751 38

The regulation of intracellular free Ca2+ concentration was examined in single dissociated chick pineal cells using the fura-2 technique. Approximately 10% of cells examined exhibited spontaneous Ca2+ oscillations while the rest were quiescent. Application of salines containing 80 mM KCl evoked large increases in intracellular free Ca2+ that were dependent upon external Ca2+ ions. These responses were inhibited by 10 microM nifedipine indicating involvement of L-type Ca2+ channels. Application of the tumor promoter thapsigargin (2 microM) evoked increases in intracellular free Ca2+. These responses could be observed in the absence of external Ca2+ indicating mobilization of internal stores. In the absence of external Ca2+, the responses to thapsigargin gradually decayed due to depletion of internal Ca2+ pools. A subsequent exposure to saline containing 5.8 mM CaCl2 caused a rapid increase in intracellular Ca2+ that was consistently larger than the peak response to thapsigargin. Application of 100 nM vasoactive intestinal peptide (VIP), a neurohormone that stimulates melatonin secretion from pineal cells, induced a sustained increase in intracellular free Ca2+ in a subpopulation of cells. In a small number of cells, VIP evoked Ca2+ oscillations. Approximately half of the cells examined showed no response to VIP. Application of 200 microM norepinephrine, which inhibits melatonin secretion from the chick pineal, had no effect on intracellular free Ca2+ in any quiescent or spontaneously oscillating cells. Application of 5 mM 8-Br-cAMP evoked sustained increases in intracellular Ca2+. Similar effects were obtained with the phosphodiesterase inhibitors papaverine (50 microM) or isobutylmethylxanthine (100 microM). Application of 200 nM forskolin, an activator of adenylate cyclase, evoked increases in intracellular free Ca2+ that could be detected in the presence of 10 microM nifedipine. The responses to forskolin gradually decayed in Ca(2+)-free external salines due to depletion of intracellular Ca2+ stores. Subsequent exposure to external Ca2+ caused a rapidly developing increase in intracellular Ca2+ that was larger than the peak response to forskolin. These results indicate that the regulation of intracellular free Ca2+ in chick pineal cells is complex. These cells exhibit Ca2+ oscillations and can mobilize both external and internal Ca2+ pools. Agents that increase intracellular cAMP cause mobilization of internal Ca2+ stores, possibly secondary to effects on other second messenger systems. Chick pineal cells, like many other cell types, possess mechanisms to allow for refilling of depleted internal Ca2+ stores. These results suggest new mechanisms for the regulation of melatonin synthesis and secretion and possible sites of action for the intrinsic circadian oscillator.
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PMID:Intracellular free Ca2+ in dissociated cells of the chick pineal gland: regulation by membrane depolarization, second messengers and neuromodulators, and evidence for release of intracellular Ca2+ stores. 780 49

Amrinone, a new cardiotonic drug, has received attention as a better therapeutic agent than the cardiac glycosides in the treatment of congestive heart failure. In this study, the effects of amrinone on isolated rat uterus and its probable mechanism of action were investigated. At two different concentrations (0.1 and 0.5 mM), the inhibitory effects of amrinone on the spontaneous contractions of rat uterus were noted. In addition, amrinone (0.5 mM) was found to inhibit the tonic contractions induced by potassium sulphate (K2SO4)-Ringer solution (91.74%) and calcium chloride (CaCl2) (93.04%). These inhibitory effects were compared with regulators of the phosphodiesterase enzyme (PDE). It was concluded that amrinone could behave as a calcium antagonist and PDE inhibitor.
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PMID:The inhibitory effects of amrinone on isolated rat uterus. 785 49

F-0401 is a novel dihydropyridine (DHP) derivative with potent vasodilative and anti-aggregatory actions. In the present study, we examined the mechanisms of the actions of F-0401 and obtained the following findings: F-0401 suppressed [3H]nitrendipine binding to rat heart membrane (Ki value: 2.2 x 10(-7) M). CaCl2-induced contractions of rabbit aorta and guinea pig taenia coli were inhibited by F-0401 (pA2 values: 7.7 and 6.6). These results indicated that F-0401 had calcium antagonistic activity slightly less potent than that of the other DHP derivatives. In addition, F-0401 significantly inhibited the activity of thromboxane (TX) A2 synthetase (IC50 value: 2.5 x 10(-7) M) and [3H]PAF binding to rabbit platelets (Ki value: 1.4 x 10(-8) M). The other DHP derivatives tested did not affect TXA2 synthetic activity, and the PAF antagonism of the other derivatives were less than that of F-0401. Neither F-0401 nor the other DHP derivatives inhibited cAMP- or cGMP-dependent phosphodiesterase activity. These results revealed that F-0401 has calcium antagonistic, anti-PAF and TXA2 synthetase inhibitory actions in the same dose ranges.
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PMID:[Pharmacological profile of F-0401, a novel dihydropyridine derivative. (1) Mechanisms of action]. 834 21

A 19-amino acid residue peptide, Gly-Trp-Leu-Lys-Ile-Lys-Ala-Ala-Met-Arg-Trp-Gly-Phe-Phe-Val-Arg-Lys-Lys- Ala, corresponding to the basic amphiphilic alpha-helix (BAA) motif at the C-terminus of a recombinant tobacco calmodulin-binding protein, TCB60, was synthesized. The interaction of the synthetic binding domain with calmodulin (CaM) was analyzed by gel mobility shift assays, phosphodiesterase competition assays, and fluorescence, circular dichroism, and nuclear magnetic resonance spectroscopy. Mobility shift assays showed an apparent 2 kDa increase in CaM Mr in presence of synthetic peptide and CaCl2 in 4 M urea polyacrylamide gel electrophoresis. HPLC measurements of hydrolysis of cyclic AMP by CaM-dependent phosphodiesterase indicated the synthetic peptide competitively inhibits (Ki = 15-20 nM) stimulation of phosphodiesterase activity by CaM. Upon binding CaM, the fluorescence emission maximum of the synthetic peptide, which contained two tryptophanyl residues, shifted toward blue and increased in intensity. The circular dichroism spectra indicated the ellipticity of CaM increased at 208 and 222 nm upon complex formation with the synthetic peptide. 1H NMR studies showed that the peptide interacts with the aromatic residues in domains I and III of CaM. Taken together, these data provide direct evidence that the structurally conserved basic amphiphilic alpha-helix CaM-binding domain of the recombinant tobacco CaM-binding protein interacts with CaM at physiologically significant nanomolar concentrations and the microenvironments of both CaM and the synthetic binding domain are modified upon complex formation.
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PMID:Characterization of the basic amphiphilic alpha-helix calmodulin-binding domain of a 61.5 kDa tobacco calmodulin-binding protein. 904


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