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 inhibitors of the cGMP-inhibited, low-Km cAMP phosphodiesterase--milrinone and OPC 3911--and an inhibitor of a non-cGMP-inhibited low-Km cAMP phosphodiesterase--rolipram--were used to evaluate the functional importance of the two cAMP phosphodiesterase activities in vascular smooth muscle and in platelets. Vinpocetine, an inhibitor of a calcium-calmodulin-dependent phosphodiesterase was also studied. OPC 3911 and milrinone relaxed the contracted rat aorta, inhibited ADP-induced platelet aggregation and also enhanced isoprenaline-induced relaxation as well as the antiaggregatory effects of adenosine. In platelets, OPC 3911 and milrinone increased cAMP levels, but in the rat aorta the increase was significant only for milrinone (OPC 3911 P = 0.062). In both tissues OPC 3911 and milrinone enhanced the increase in cAMP caused by activators of adenylate cyclase (isoprenaline/adenosine). Rolipram had no effects on aggregation or cAMP levels in platelets and no overadditive effects in combination with adenosine. Rolipram had little effect on relaxation and cAMP levels, did not alter isoprenaline-induced relaxation of guanfacin-contracted rat aorta, but showed synergistic effects with isoprenaline in raising cAMP levels. In PGF2 alpha-contracted aorta rolipram enhanced relaxation caused by isoprenaline. Vinpocetine had a relaxant effect without affecting cAMP levels, but had no effect on platelets. These results support the concept that the cGMP-inhibited phosphodiesterase is an important modulator of vascular smooth muscle tone and platelet function. The role of the non-cGMP-inhibited phosphodiesterase in these tissues is less obvious.
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PMID:Effects of isozyme-selective phosphodiesterase inhibitors on rat aorta and human platelets: smooth muscle tone, platelet aggregation and cAMP levels. 217 33

In this study three forms of cyclic nucleotide phosphodiesterase (PDE) isolated from rabbit aorta were pharmacologically characterized, and the consequence of selective inhibition of calmodulin-stimulated PDE (CaM-PDE) and cGMP specific PDE (cG-PDE) was evaluated using PDE inhibitors. The cG-PDE (F1) was selectively inhibited by M&B 22948 (IC50 = 0.5 microM) and dipyridamole (IC50 = 7 microM). The cAMP-PDE (cA-PDE, F3) was inhibited more effectively by the cA-PDE inhibitor milrinone than by other PDE inhibitors. The cA-PDE preparation appeared to contain both cG-inhibited PDE and cG-insensitive PDE based on an additive inhibition of the activity by milrinone and SQ 65442, respective inhibitors of these enzymes. Vinpocetine, 8-methoxymethyl isobutylmethylxanthine (8-MeOMeMIX) and M&B 22948 effectively inhibited CaM-PDE (F2). Vinpocetine was a more selective inhibitor of CaM-PDE than M&B 22948 or 8-MeOMeMIX. CaM-PDEs isolated from rabbit aorta and bovine brain exhibited a similar sensitivity to these inhibitors. Seventy-two percent of the cGMP-hydrolyzing activity of this rabbit aortic CaM-PDE preparation was immunoadsorbed to monoclonal antibody (ACC-1) against CaM bound to brain CaM-PDE. Vinpocetine, 8-MeOMeMIX and M&B 22948 at concentrations (30 and 100 microM) which inhibit CaM-PDE greater than 60% increased cGMP but not cAMP levels in l-norepinephrine (NE) preincubated rabbit aortic slices. At concentrations selectively inhibiting cG-PDE, dipyridamole and M&B 22948 increased cGMP levels in untreated slices but failed to increase cGMP levels significantly in NE-treated slices. By contrast, vinpocetine failed to increase cGMP significantly in untreated slices, although it increased cGMP levels in NE or KCl preincubated slices. These data indicate that, in activated (precontracted) aorta, CaM-PDE is a major enzyme, whereas in untreated aorta cG-PDE is a predominant enzyme for the hydrolysis of cGMP. This study also shows a usefulness of selective inhibitors in identifying different forms of PDE and similar drug sensitivities and immunoadsorption of aortic and brain CaM-PDEs by a monoclonal antibody.
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PMID:Effects of selective inhibitors on cyclic nucleotide phosphodiesterases of rabbit aorta. 255 21

Effect of a novel compound, 14-ethoxycarbonyl-(3 alpha, 16 alpha-ethyl)-14,15-eburnamenine (vinpocetine, TCV-3B), on the cyclic nucleotide metabolism and in vitro response of a vascular strip was investigated. The concentration of vinpocetine producing relaxation of the canine basilar arterial strip induced by 30 microM arachidonate peroxide was 3 microM. Cyclic GMP content in the vascular strip increased dose-dependently by addition of vinpocetine, and 2.5-fold elevation of cyclic GMP content in the vascular strip was observed by 10 microM vinpocetine. Administration of vinpocetine concentrations ranging from 1 to 100 microM did not produce a significant increase in cyclic AMP of the vascular strip. Vinpocetine did not stimulate guanylate cyclase, but selectively inhibited Ca2+-calmodulin dependent phosphodiesterase (Ca2+-PDE). Increase in cyclic GMP by vinpocetine is due to inhibition of Ca2+-PDE because Ca2+-PDE is known to hydrolyze cyclic GMP preferentially. Our results suggest that vinpocetine, a selective Ca2+-PDE inhibitor, produces relaxation of the vascular strip by the increase in cyclic GMP.
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PMID:[Effect of vinpocetine (TCV-3B), a vasodilator agent, on cyclic nucleotide metabolism]. 613 34

A novel vasodilating agent, vinpocetine (14-ethoxycarbonyl-(3 alpha,16 alpha-ethyl)-14,15-eburnamenine) inhibits Ca2+-dependent phosphodiesterase, selectively, among the three forms of cyclic nucleotide phosphodiesterase identified in the rabbit aorta. The concentration of vinpocetine producing 50% inhibition of Ca2+-dependent phosphodiesterase activity was approximately 21 microM, both in the presence and absence of Ca2+-calmodulin (CaM). Increasing the concentration of CaM in the presence of Ca2+ did not prevent vinpocetine-induced inhibition of Ca2+-dependent phosphodiesterase, thereby indicating that vinpocetine inhibited the enzyme by interacting with the enzyme and not with CaM. To determine the influence of vinpocetine-induced inhibition of Ca2+-dependent phosphodiesterase on cyclic nucleotide metabolism in vascular smooth muscle, cyclic nucleotide levels in isolated rabbit aortic strips were also investigated. Addition of vinpocetine produced dose-dependent increases in only the cyclic GMP levels and there was no significant effects on the cyclic AMP levels. These results provide pharmacological evidence that Ca2+-dependent phosphodiesterase mainly hydrolyzes cyclic GMP in vascular smooth muscle. Vinpocetine may induce vascular relaxation by increasing cyclic GMP contents in vascular smooth muscle through selective inhibition of Ca2+-dependent phosphodiesterase.
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PMID:Effects of vinpocetine on cyclic nucleotide metabolism in vascular smooth muscle. 632 4

Cavinton was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.
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PMID:[Mechanism of action of vinpocetine]. 908 41

The effect of selective phosphodiesterase (PDE) inhibitors was studied on neural transmission within the enteric nervous system employing a two-compartment bath (containing the oral and the anal end of a segment of guinea-pig ileum, respectively). Ascending excitatory enteric nerve pathways were activated by electrical field stimulation (10 Hz for 2 s, 45 mA, 0.5 pulse duration) in the anal compartment and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded. The partitioned bath enables PDE inhibitors and other drugs to be applied to enteric nerve pathways (in the anal compartment) without interfering with the recording of the smooth muscle contraction in the oral compartment. The PDE 4 inhibitors rolipram (0.01-10 microM) and Ro-20-1724 (0.01-10 microM) significantly (P<0.01) inhibited (10-91% and 9-83%, respectively) the nerve-mediated contractions. When both rolipram and Ro-20-1724 were tested after phentolamine (1 microM) or yohimbine (0.1 microM), they were significantly (P<0.01) less effective. By contrast prazosin (1 microM) was ineffective. Vinpocetine (50 microM), milrinone (30 microM) and zaprinast (100 microM), which inhibit PDE 1, 3 and 5, respectively, did not modify the nerve-mediated contractions. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-Br-cyclic AMP) or N6,2'-O-dibutyryladenosine 3',5' cyclic monophosphate (dibutyryl cyclic AMP), two analogues of cyclic AMP, at lower concentrations (0.1-1 microM) significantly (P<0.01) inhibited (15-73% and 5-49%, respectively) the nerve-mediated contractions, while at higher concentrations (10-100 microM) they caused a significant (P<0.01) potentiating (48-68% and 77-78%, respectively) effect. These results indicate that inhibition of PDE 4 (but not PDE 1, PDE 3 or PDE 5) produces a depression of neural transmission within the enteric nervous system, possibly by releasing noradrenaline acting at alpha2-adrenoceptors on enteric neurons.
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PMID:Effect of selective phosphodiesterase inhibitors on synaptic transmission in the guinea-pig ileum. 968 45

The present study investigates the potential role of the Ca2+-calmodulin-dependent type I phosphodiesterase (PDE)-cGMP-protein kinase G (PKG) pathway in spontaneous [Ca2+]i oscillations in GH3 cells using fura-2 single cell videoimaging. Vinpocetine (2.5-50 microM), a selective inhibitor of type I PDE, induced a concentration-dependent inhibition of spontaneous [Ca2+]i oscillations in these pituitary cells, and at the same time produced an increase of the intracellular cGMP content. The cell permeable cGMP analog N2,2'-O-dibutyryl-cGMP (dB-cGMP) (1 mM) caused a progressive reduction of the frequency and the amplitude of spontaneous [Ca2+]i oscillations when added to the medium. KT5823 (400 nM), a selective inhibitor of cGMP-dependent protein kinase (PKG), produced an increase of baseline [Ca2+]i and the disappearance of spontaneous [Ca2+]i oscillations. When KT5823 was added before vinpocetine, the PKG inhibitor counteracted the [Ca2+]i lowering effect of the cGMP catabolism inhibitor. Finally, the removal of extracellular Ca2+ or the blockade of L-type voltage-sensitive calcium channels (VSCC) by nimodipine produced a decrease of cytosolic cGMP levels. Collectively, the results of the present study suggest that spontaneous [Ca2+]i oscillations in GH3 cells may be regulated by the activity of type I PDE-cGMP-PKG pathway.
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PMID:Involvement of phosphodiesterase-cGMP-PKG pathway in intracellular Ca2+ oscillations in pituitary GH3 cells. 1008 77

Ionizing radiation (IR) enhances double-strand-break (DSB)-repair fidelity in plasmids processed in normal lymphoblasts but not in lymphoblasts from ataxia telangiectasia (A-T) patients. Putatively, signal-transduction pathways mediate this DNA-repair induction. Because IR inhibition of DNA synthesis is defective in A-T cells and is mediated by a calmodulin (caM)-dependent pathway, we evaluated the involvement of caM-dependent pathways in DSB-repair induction. Human lymphoblasts were gamma-irradiated with or without treatment with caM antagonists and the cells' abilities to repair shuttle pZ189 carrying a single DSB (linDNA) were assessed. In untreated controls, IR enhanced DSB-rejoining fidelity if transfection occurred promptly but diminished fidelity if transfection was delayed. Treatment with two caM antagonists, W-7 and W-13, prior to irradiation blocked this IR-enhancement of DSB-rejoining fidelity. Vinpocetine, a caM-dependent phosphodiesterase inhibitor, and 8-bromo-cAMP also inhibited IR enhancement of repair fidelity, but caM-dependent protein kinase II inhibitor KN62 had no effect. Other protein kinase inhibitors, staurosporine and genistein, also did not inhibit IR enhancement of DSB repair fidelity. However, staurosporine blocked the twofold reduction in DSB-repair fidelity seen if linDNA transfection was delayed 2 h after irradiation. These findings point to the involvement of caM/cAMP-dependent pathway(s) in mediating IR-enhancement of DSB-rejoining fidelity in mammalian cells.
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PMID:Calmodulin antagonists and cAMP inhibit ionizing-radiation-enhancement of double-strand-break repair in human cells. 1085 32

Vinpocetine (ethyl apovincaminate) discovered during the late 1960s has successfully been used in the treatment of central nervous system disorders of cerebrovascular origin for decades. The increase in the regional cerebral blood flow in response to vinpocetine administration is well established and strengthened by new diagnostical techniques (transcranial Doppler, near infrared spectroscopy, positron emission tomography). The latest in vitro studies have revealed the effect of the compound on Ca(2+)/calmodulin dependent cyclic guanosine monophosphate-phosphodiesterase 1, voltage-operated Ca(2+) channels, glutamate receptors and voltage dependent Na(+)-channels; the latest being especially relevant to the neuroprotective action of vinpocetine. The good brain penetration profile and heterogenous brain distribution pattern (mainly in the thalamus, basal ganglia and visual cortex) of labelled vinpocetin were demonstrated by positron emission tomography in primates and man. Multicentric, randomized, placebo-controlled clinical studies proved the efficacy of orally administered vinpocetin in patients with organic psychosyndrome. Recently positron emission tomography studies have proved that vinpocetine is able to redistribute regional cerebral blood flow and enhance glucose supply of brain tissue in ischemic post-stroke patients.
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PMID:Role of sodium channel inhibition in neuroprotection: effect of vinpocetine. 1111 77

Characterisation of cyclic nucleotide-hydrolysing phosphodiesterases (PDEs) in recombinant systems has highlighted regulatory properties indicative of distinct physiological roles for these enzymes. The present study investigated the role of PDEs in the adenosine 3'5'-monophosphate (cAMP) response to the hypothalamic neuropeptides corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) in acutely dispersed rat adenohypophysial cells. Ca(2+)-activated PDE (PDE1) and Ca(2+)-independent, rolipram-sensitive PDE (PDE4) accounted for close to 90% of cAMP-hydrolysing activity in the adenohypophysis. Messenger RNA transcripts of PDE1 (isotypes 1A and 1C) and PDE4 (isotypes B and D3) were detected by RT-PCR. The PDE blockers rolipram and IBMX enhanced cAMP accumulation induced by CRF or CRF and AVP. Vinpocetine, an inhibitor of low K(m) PDE1 isotypes, did not alter the response to CRF but enhanced the effect of the combined CRF/AVP stimulus. Thus, PDE4s terminate the cAMP response to moderate stimulation, while low-affinity PDE1 becomes important when the concentrations of CRF and AVP are characteristic of exposure to intensive stress.
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PMID:Functional plasticity of cyclic AMP hydrolysis in rat adenohypophysial corticotroph cells. 1188 89


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