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)

Previously, men with erectile dysfunction (ED) were frequently treated with penile prosthesis implants or considered to have psychogenic impotence. Since the reports by Virag and Brindley in 1932 and 1983, pharmacotherapy, by self-injection programs has become a new therapeutic concept for impotent men. In clinical practice, this application model has been generally accepted as the "golden standard" in the treatment of ED. Papaverine was first used as monotherapy, but because of side-effects such as prolonged erection, priapism, and fibrosis of the corpus cavernosum, single use of the drug was abandoned. Instead, papaverine was introduced in mixtures, e.g. together with alpha adrenoceptor-blockers as phentolamine, and/or prostaglandin E1 (PGE1) in these "cocktails", the dose of papaverine is reduced to 10-15 mg compared to the high doses (80-120 mg) that were used initially. By having two or more drugs in the mixture, a facilitating cascade effect as probably obtained. PGE1 is the only drug that has been approved by the FDA and is today registered in more than 50 countries. Other combination therapies such as vasoactive intestinal polypeptide+ phentolamine, or calcitonin gene-related peptide+ PGE1, have been suggested as suitable alternatives for intracavernosal injection. Transdermal and intraurethral application models may be considered in selected patients. Recently, oral administration of a phosphodiesterase inhibitor (UK-92.480) was reported to improve penile erection in patients with psychogenic impotence. Further clinical results from controlled trials will probably explain if this new oral drug will compete with PGE1 or other agents in self-injection programs.
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PMID:Pharmacotherapy in erectile dysfunction agents for self-injection programs and alternative application models. 890 79

1. The effect of papaverine, a well known smooth muscle relaxant, was investigated on neural transmission within the enteric nervous system. Segments of guinea-pig ileum were placed in a partitioned bath to enable drugs, including papaverine, to be applied to enteric nerve pathways without interfering with the recording of the smooth muscle contraction. Ascending excitatory enteric nerve pathways were activated by electrical field stimulation in the anal compartment (10 Hz for 2 s, 45 mA, 0.5 ms pulse duration) and the resulting contraction of the intestinal circular muscle in the oral compartment was recorded isotonically. 2. Tetrodotoxin (0.6 microM) and hexamethonium (100 microM) both abolished, or greatly reduced, the contractions when applied to either compartment indicating that nicotinic synapses are involved in this pathway. 3. Papaverine (0.3-30 microM) applied independently to each compartment depressed in a concentration-dependent manner, the nerve-mediated contractions. The IC50 of this inhibitory effect was 3.53 microM for the oral and 4.76 microM for the anal compartments, respectively. Two other phosphodiesterase (PDE) inhibitors, 3-isobutyl-1-methylxanthine (IBMX 10-300 microM) and theophylline (30-1000 microM) added to the anal compartment also inhibited the nerve mediated contractions. Papaverine applied to the anal bath, after IBMX 100 microM (or theophylline 300 microM) further inhibited the nerve-mediated contractions, but was less effective than when applied alone. 4. Phentolamine (1 microM), an alpha-adrenoceptor antagonist, reduced the inhibitory effect of papaverine, but not that of IBMX (100 microM) or theophylline (300 microM). A combination of phentolamine and IBMX (or theophylline) prevented the inhibitory effect of papaverine. 5. Tetrodotoxin, but not papaverine or hexamethonium, inhibited the contraction elicited by electrical stimulation just anal to the partition indicating that papaverine did not affect the generation or conduction of nerve action potentials. 6. Verapamil (1 microM) and nifedipine (1 microM), two smooth muscle relaxants which act by blocking L-type calcium channels, only inhibited the contractions when applied directly to the recording (oral) compartment. This indicates that L-type Ca2+ channels are probably not involved in synaptic transmission in these ascending pathways and thus that the PDE inhibitors do not inhibit synaptic transmission by acting on these channels. omega-Conotoxin GVIA (10 nM), a potent inhibitor of the N-type Ca2+ channels, blocked the nerve-mediated contractions applied to either compartment. Whether the PDE inhibitors exert their inhibitory actions via these channels remains to be established. 7. The results indicate that the PDE inhibitors, papaverine, IBMX and theophylline inhibit excitatory enteric neural pathways by depressing synaptic transmission. The inhibitory effect of papaverine (but not IMBX or theophylline) involves, at least in part, the release of noradrenaline from sympathetic nerves acting on alpha-adrenoceptors on enteric neurones.
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PMID:Effect of papaverine on synaptic transmission in the guinea-pig ileum. 920 46

Papaverine (0.3-100 microM) more potently inhibited phenylephrine (1 microM)-induced contraction than 65 mM K+-induced contraction of the aorta, while it equally inhibited contractions induced by 65 mM K+ and carbachol (1 microM) in ileal smooth muscle. In phenylephrine-treated aorta, papaverine (1-10 microM) increased the cAMP and cGMP content. However, in carbachol-treated ileum, 30 microM papaverine partially increased the cAMP content while it maximally relaxed the preparation. In fura2-loaded aorta, papaverine (0.3-10 microM) inhibited both the contraction and the increase in intracellular Ca2+ level ([Ca2+]i) induced by phenylephrine in parallel. However, papaverine inhibited carbachol-induced contraction with only a small decrease in [Ca2+]i. Papaverine (1-30 microM) inhibited the carbachol-induced increase in oxidized flavoproteins, an indicator of increased mitochondrial oxidative phosphorylation, in ileal smooth muscle whereas it did not change the phenylephrine-induced increase in the aorta. These results suggest that papaverine inhibits smooth muscle contraction mainly by the accumulation of cAMP and/or cGMP due to the inhibition of phosphodiesterase in the aorta whereas, in ileal smooth muscle, papaverine inhibits smooth muscle contraction mainly by the inhibition of mitochondrial respiration.
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PMID:The difference in the inhibitory mechanisms of papaverine on vascular and intestinal smooth muscles. 976 29

Papaverine, despite being a potent phosphodiesterase inhibitor, actually blocks adipocyte lipolysis. The present study was designed to clarify the mechanism of the inhibitory effect of papaverine on lipolysis. Lipolysis, stimulated by either 10 microM isoproterenol or 5 mM dibutyryl cAMP, was significantly inhibited by papaverine (100 microM and above). Papaverine, however, did not affect the isoproterenol-induced increase in the protein kinase A (A-kinase) activity ratio. In cell-free extract from non-stimulated adipocytes, cAMP-stimulated A-kinase activities were almost completely blocked by H-89, a potent inhibitor of A-kinase, but not by papaverine. Thus, the inhibitory effect of papaverine on lipolysis could be responsible for a deficit in step(s) distal to A-kinase activity. Hormone-sensitive lipase activities in the infranatant fraction of centrifuged homogenates of cells, which were maximally stimulated with isoproterenol were significantly reduced. This result indicates that hormone-sensitive lipase redistributes from cytosol to its substrate in lipolytically stimulated cells. Papaverine completely blocked the isoproterenol-induced decrease in lipase activity in the infranatant fraction. These results suggest that papaverine blocks lipolysis through its inhibitory effect on the redistribution of hormone-sensitive lipase.
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PMID:Inhibition of adipocyte lipolysis by papaverine: papaverine can inhibit the redistribution of hormone-sensitive lipase. 1089 95

Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildenafil are PDE inhibitors. Papaverine is a non-specific inhibitor of these enzymes; sildenafil is an orally active, potent and selective inhibitor of GMP-specific PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic fibers through alpha(1) adrenoceptors, produces detumescence, thus making alpha adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed alpha(1)-alpha(2) adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on alpha(2) adrenoceptors in the central nervous system and blocks adrenergic influences at peripheral level.
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PMID:Erectile dysfunction: from biochemical pharmacology to advances in medical therapy. 1091 32

1. The effect of the flavonoids genistein (3-100 microM), kaempferol (3-60 microM) and quercetin (1-100 microM) on KCl (60 mM)-induced tonic contraction in rat smooth muscle was assayed. In the same way, the modification of these effects in the presence of an inhibitor of protein kinase (PKA) (Rp-cAMPS), an inhibitor of phosphodiesterase (papaverine) and beta-adrenoreceptor blocking agents (propranolol and atenolol) was studied. 2. The flavonoids totally relaxed the KCl-induced tonic contraction (IC50: genistein 20.2 +/- 2.0 microM, n = 11; kaempferol 10.1 +/- 1.6 microM, n = 8; quercetin 13.2 +/- 1.2 microM, n = 8). 3. The incubation with Rp-cAMPS (10 and 100 microM) 30 min prior to KCl shifted the dose-response curve of the flavonoids to the right, increasing their IC50 up to 27.8 +/- 3.8 and 31.9 +/- 7.3 microM, respectively, for genistein; 24.7 +/- 0.2 and 19.6 +/- 4.9 microM, respectively, for kaempferol; 18.8 +/- 2.2 and 18.4 +/- 1.5 microM, respectively, for quercetin. 4. Papaverine (3-100 microM) also relaxed the contraction induced by KCl and this effect was significantly displaced to the right with Rp-cAMPS (10 microM) (IC50 12.1 +/- 2.2 vs. 16.5 +/- 3.1 microM). Papaverine (3 microM) added to the organ bath 15 min before the contractile agent increased the relaxing effect of the flavonoids and significantly decreased their IC50 (genistein 20.2 +/- 2.0 vs. 9.8 +/- 1.4 microM; kaempferol 10.1 +/- 1.6 vs. 6.6 +/- 0.7 microM; quercetin 13.2 +/- 1.2 vs. 7.8 +/- 1.4 microM). 5. The incubation with atenolol (10 microM) did not alter the relaxing effect of the flavonoids. In the same experimental conditions, propranolol (10 microM) did not modify the effect of genistein and kaempferol, but shifted the response curve of quercetin significantly to the right (13.2 +/- 1.2 vs. 17.7 +/- 3.4 microM). 6. The results suggest that genistein, kaempferol and quercetin produced the relaxation of uterine smooth muscle by increasing intracellular cAMP. Beta-adrenoceptors could also be involved in the effect of quercetin.
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PMID:Involvement of cAMP and beta-adrenoceptors in the relaxing effect elicited by flavonoids on rat uterine smooth muscle. 1096 41

We investigated cystic fibrosis transmembrane conductance regulator (CFTR) activation by clinically used phosphodiesterase inhibitors (PDEis) in Calu-3 cell monolayers alone and in combination with A2B adenosine receptor stimulation. This receptor pathway has previously been shown to activate wild-type and mutant CFTR molecules. Several PDEis, including milrinone, cilostazol (Pletal), papaverine, rolipram, and sildenafil (Viagra), produced a short circuit current (Isc) that was glibenclamide-sensitive, achieving 20-85% of forskolin-stimulated Isc. Papaverine, cilostazol, and rolipram also augmented both the magnitude and the duration of Isc following low dose stimulation of adenosine receptors with Ado (0.1-1.0 microM, P < 0.01). Subsequent studies demonstrated that very low concentrations of cilostazol or papaverine (approximately 1/2 peak serum concentrations) were sufficient to activate Isc, and both agents markedly augmented Ado-stimulated Isc (1 microM, P < 0.01). Our results provide evidence that select PDEis, at concentrations achieved as part of systemic therapies, can activate CFTR-dependent Isc in Calu-3 cell monolayers. These studies also indicate that PDEis have the capacity to augment an endogenous CFTR-activating pathway in an "in vivo"-like model system, and supports future investigations of these agents relevant to cystic fibrosis.
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PMID:Adenosine receptors and phosphodiesterase inhibitors stimulate Cl- secretion in Calu-3 cells. 1271 75

Compartmentalization of cAMP phosphodiesterases plays a key role in the regulation of cAMP signalling in mammals. In the present paper, we report the characterization and subcellular localization of TcPDE1, the first cAMP-specific phosphodiesterase to be identified from Trypanosoma cruzi. TcPDE1 is part of a small gene family and encodes a 929-amino-acid protein that can complement a heat-shock-sensitive yeast mutant deficient in phospho-diesterase genes. Recombinant TcPDE1 strongly associates with membranes and cannot be released with NaCl or sodium cholate, suggesting that it is an integral membrane protein. This enzyme is specific for cAMP and its activity is not affected by cGMP, Ca2+, calmodulin or fenotiazinic inhibitors. TcPDE1 is sensitive to the phosphodiesterase inhibitor dipyridamole but is resistant to 3-isobutyl-1-methylxanthine, theophylline, rolipram and zaprinast. Papaverine, erythro-9-(2-hydroxy-3-nonyl)-adenine hydrochloride, and vinpocetine are poor inhibitors of this enzyme. Confocal laser scanning of T. cruzi epimastigotes showed that TcPDE1 is associated with the plasma membrane and concentrated in the flagellum of the parasite. The association of TcPDE1 with this organelle was confirmed by subcellular fractionation and cell-disruption treatments. The localization of this enzyme is a unique feature that distinguishes it from all the trypanosomatid phosphodiesterases described so far and indicates that compartmentalization of cAMP phosphodiesterases could also be important in these parasites.
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PMID:Identification, characterization and subcellular localization of TcPDE1, a novel cAMP-specific phosphodiesterase from Trypanosoma cruzi. 1455 47

We have demonstrated that the relaxing mechanism of papaverine in phasic muscles such as ileum, urinary bladder, and uterus is different from tonic muscles such as aorta. In this study, we examined the inhibitory mechanism of papaverine on carbachol (CCh)-induced contraction in the bovine trachea. Papaverine inhibited muscle contraction and increase in [Ca(2+)](i) level induced by CCh. Papaverine increased cAMP content but not cGMP content. Papaverine did not affect CCh-induced oxidized flavoproteins fluorescence or reduced pyridine nucleotides fluorescence. Papaverine (30 microM) remarkably inhibited muscle tension, but slightly decreased creatine phosphate and ATP contents. Iberiotoxin restored the inhibitions of muscle contraction and [Ca(2+)](i) level induced by papaverine or dibutyryl-cAMP. These results suggested that the relaxing mechanism of papaverine in the bovine trachea is mainly due to increases of cAMP content by inhibiting phosphodiesterase and the mechanism is partially involved in the activation of BK channel by cAMP.
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PMID:Inhibitory mechanism of papaverine on carbachol-induced contraction in bovine trachea. 1598 26

The crude extract of aerial parts of St John's wort (Hypericum perforatum) (Hp.Cr) and its fractions were studied in vitro for its possible spasmolytic and bronchodilator activities to rationalize some of its medicinal uses. In rabbit jejunum preparations, Hp.Cr caused a concentration-dependent relaxation of both spontaneous and K+ (80 mm)-induced contractions at a similar concentration range (0.1-1.0 mg/mL), similar to that produced by papaverine, whereas verapamil was relatively potent against K+-induced contractions. Hp.Cr shifted the Ca2+ concentration-response curves (CRCs) to the right, similar to that caused by papaverine or verapamil and also caused leftward shift of isoprenaline-induced inhibitory CRCs, similar to papaverine. In guinea-pig tracheal preparations, Hp.Cr caused relaxation of carbachol and K+-induced contractions at similar concentrations (0.01-0.3 mg/mL) and also shifted the isoprenaline-induced inhibitory CRCs to the left, similar to that caused by papaverine. In rabbit aorta preparations at rest, Hp.Cr produced a moderate vasoconstriction, while exhibited vasodilator effect against phenylephrine and K+-induced contractions. Papaverine and verapamil also produced similar non-specific vasodilation, but were devoid of any vasoconstrictor effect. Hp.Cr caused suppression of atrial force of contractions at concentrations about 20 times higher than those that produced inhibitory effect in smooth muscle preparations, similar to papaverine. These results suggest that the spasmolytic effects of Hp.Cr are mediated through dual inhibition of calcium influx and phosphodiesterase (PDE)-like mechanisms, which might explain the medicinal use of St John's wort in the disorders of gastrointestinal and respiratory tracts. Furthermore, the presence of Ca2+ antagonist and PDE inhibitory-like constituents might also be contributing to some extent in the well established use of plant in depression.
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PMID:Antispasmodic and bronchodilator activities of St John's wort are putatively mediated through dual inhibition of calcium influx and phosphodiesterase. 1631 82


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