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)

Effects of papaverine on sinus rate and atrial contractility were investigated using the isolated atrium preparation of the dog perfused with heparinized arterial blood led from a support dog. When papaverine was injected into the cannulated sinus node artery, positive chronotropic and inotropic responses were dose-relatedly produced from about 3 mug. At a dose level above 100 mug, papaverine induced initially slightly negative chronotropic and inotropic effects followed by marked positive ones. Papaverine-induced positive chronotropic and inotropic effects (P-PCIE) were not influenced by treatment with tetrodotoxin which blocked the action of nicotine. P-PCIE were slightly suppressed by an adrenergic beta-blocking agent, alprenolol, which blocked the action of norepinephrine. They were however potentiated by treatment with desmethylimipramine which completely blocked the action of tyramine. A large amount of MnCl2 suppressed the actions of both papaverine and norepinephrine. Papaverine-induced negative chronotropic and inotropic effects were not influenced by atropine treatment. In addition, papaverine slightly potentiated the negative chronotropic and inotropic responses to adenosine. From these results, it appears that papaverine has a direct stimulating property on sinus rate and atrial contractility which may be due to inhibition of phosphodiesterase and successive accumulation of cyclic AMP. Moreover, papaverine may partially cause catecholamine release from adrenergic nerve fibers and it may inhibit the adenosine uptake mechanism.
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PMID:Pharmacologic analysis of papaverine-induced positive chronotropic and inotropic effects. 125 18

The effects of papaverine, a smooth muscle relaxant agent, on the voltage-dependent Ca++ current were examined in isolated smooth muscle cells from the guinea pig trachea. The tight-seal whole cell voltage clamp technique was used. Papaverine (1-100 microM) inhibited the Ba++ inward current (IBa) through the voltage-dependent L-type Ca++ channel in a concentration-dependent fashion. The inhibitory effect of papaverine on IBa appeared to have both tonic and use-dependent components. In addition to the reduction of the maximal conductance of IBa, papaverine (20 microM) shifted the quasi-steady-state inactivation curve of IBa to more negative membrane potentials by approximately 10 mV. These effects of papaverine on IBa were completely reversible. Although it has been suggested that papaverine inhibited phosphodiesterase to increase intracellular cyclic AMP, phosphodiesterase inhibitors (theophylline, 500 microM, and 3-isobutyl-1-methylxanthine, 500 microM), isoproterenol (2 microM) and dibutyryl cyclic AMP (1 mM) did not affect IBa. Thus, papaverine inhibits IBa in a way independent of intracellular cyclic AMP. Papaverine also had inhibitory effects on other membrane currents (i.e., the voltage-dependent transient outward K+ current and the Ca(++)-activated oscillatory K+ current), which may result in an enhancement of the excitability of the cells. These results suggest that inhibition of the voltage-dependent L-type Ca++ channel is involved in the papaverine-induced relaxation of the tracheal smooth muscle.
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PMID:On the mechanism of papaverine inhibition of the voltage-dependent Ca++ current in isolated smooth muscle cells from the guinea pig trachea. 132 5

In intact ventricular strips from toad heart, we studied the relaxant or positive lusitropic effect of different interventions known to increase intracellular cAMP levels. Isoproterenol increased developed tension (DT), maximal rate of contraction (+T), and maximal velocity of relaxation (-T). From 10(-8) to 10(-4)M isoproterenol, -T increased proportionally more than +T being the ratio +T/-T significantly decreased. A single dose of isoproterenol (3 x 10(-8)M) increased cAMP levels from 0.174 +/- 0.022 to 0.329 +/- 0.039 pmoles/mg ww (P < 0.05), increased contractility by 69 +/- 13% and decreased +T/-T by 18.5 +/- 4.55%. Administration of 10(-3)M of dibutyryl cyclic AMP (dcAMP) significantly increased DT and +T and decreased the ratio +T/-T. Similar effects were obtained with milrinone, a specific cAMP phosphodiesterase inhibitor. Papaverine, a non selective phosphodiesterase inhibitor, failed to increase +T but significantly increased -T. In chemically skinned ventricular trabeculae, calcium sensitivity of the myofibrils was significantly increased by 10(-5)M of the phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine (IBMX). 10(-3)M dcAMP failed to affect calcium sensitivity of chemically skinned ventricular trabeculae when given alone, but produced a decrease in calcium sensitivity of the myofibrils in the presence of 10(-5)M of either IBMX or papaverine. The results would indicate that the relaxant effect of isoproterenol is mediated in toad ventricle by an increase in intracellular cAMP levels. They furthermore suggest that a decrease in myofilament sensitivity to calcium may be a mechanism by which cAMP produces its relaxant effect.
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PMID:Positive lusitropic effect and diminished myofibrillar sensitivity to calcium produced by cAMP on toad (Bufo arenarum Hensel) ventricle. 133 17

Papaverine is a nonspecific smooth muscle relaxant and a phosphodiesterase inhibitor. Its effects on biliary excretion of lipids and horseradish peroxidase were investigated in a single-pass isolated perfused rat liver model. A constant infusion of papaverine (1.6 mumol/min; 40 mumol/L) significantly increased bile flow (microliters per minute per gram of liver) before (2.03 +/- 0.09 vs. 1.0 +/- 0.06) and after sodium taurocholate infusion (2.77 +/- 0.10 vs. 1.88 +/- 0.11). However, papaverine significantly and reversibly reduced biliary excretion of phospholipids and cholesterol (nanomoles per minute per gram of liver) after a 1.0 mumol/min sodium taurocholate infusion, from 7.45 +/- 0.83 and 1.42 +/- 0.15 to 1.75 +/- 0.18 and 0.39 +/- 0.06, respectively (p less than 0.01), whereas secretion of bile acids was unaffected. When a 1-min pulse of horseradish peroxidase (25 mg) was infused in isolated perfused rat liver after a continuous infusion of N6,O-2'-dibutyryladenosine 3',5'-cyclic monophosphate (0.25 mumol/min; 6.25 mumol/L), horseradish peroxidase appeared in bile in an early (4 to 6 min) and late (20 to 25 min) peak. Papaverine significantly reduced the late peak, from 1.211 +/- 0.264 to 0.498 +/- 0.107 (p less than 0.01). Papaverine had no significant effects on either cyclic AMP or cyclic GMP in the liver and bile, although it has been reported that papaverine is a phosphodiesterase inhibitor. These findings indicate that papaverine inhibits biliary excretion of lipids but not bile acids, and they suggest that papaverine has an inhibitory effect on transcytotic vesicle transport independent of an increase of cyclic nucleotides in hepatocytes.
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PMID:Papaverine inhibits transcytotic vesicle transport and lipid excretion into bile in isolated perfused rat liver. 139 83

The morphological change of several neuroblastoma cell lines induced by griseolic acid, a novel and potent inhibitor of cyclic nucleotide phosphodiesterase (PDE), was examined. In the cell lines tested, Neuro-2a (a murine neuroblastoma cell line) showed dose-dependent (1 microM-1 mM) neurite extension. Griseolic acid markedly increased the intracellular cyclic AMP level of Neuro-2a cells, suppressed DNA synthesis (82% at 1 mM), and induced multipolar (multiple-neurite-bearing)-type neuritogenesis. A similar type of neurite outgrowth was induced by 8-bromo-cyclic AMP, which also elevated the intracellular cyclic AMP concentration. In contrast, when Neuro-2a cells were treated with retinoic acid, neurite formation was of the monopolar (single-neurite-bearing) type. Papaverine and theophylline, which have been frequently used as PDE inhibitors, failed to induce these morphological changes up to 1 mM, probably owing to the lesser potency of these compounds as compared with griseolic acid on the inhibition of PDE. Retinoic acid, theophylline, and papaverine were ineffective at elevating the intracellular cyclic AMP level. These results suggest that multipolar-type cell shape change in Neuro-2a cells is correlated with the accumulation of intracellular cyclic AMP and that griseolic acid is a useful compound to induce neuroblastoma cells into terminal differentiation.
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PMID:Multiple neurite formation in neuroblastoma cell lines by griseolic acid, a potent inhibitor of cyclic nucleotide phosphodiesterases. 164 54

The calcium channel-blocking activity and associated cardiovascular effects of diproteverine, a novel compound derived from papaverine, were investigated. Electrophysiological measurements in sheep Purkinje fibres showed diproteverine to reduce the amplitude of the slow action potential (IC30 = 2 microM) and to shorten the duration of the fast action potential at 50% repolarisation (IC30 = 2.5 microM). Higher concentrations (4-5 times) were required to block block the sodium channel, as assessed by a reduction in Vmax of the fast action potential. Papaverine was found to possess marginal membrane channel-blocking activity and to be much more potent than diproteverine as a cAMP-phosphodiesterase inhibitor. The most significant haemodynamic property of diproteverine, seen in anaesthetised dogs and conscious dogs pretreated with atropine, was to cause a reduction in heart rate. This appeared to be a particular feature of diproteverine as the other calcium antagonists studied produced either a smaller decrease in heart rate or tachycardia as a reflex response to hypotension. In a chronic myocardial infarct model in dogs, diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischaemic area of the myocardium. Diproteverine resembled diltiazem in its effects on coronary blood flow, with both these agents being preferable to nifedipine and verapamil, which caused coronary steal in this model. The combination of the reduction in heart rate, to lower cardiac oxygen demand, with the beneficial action on coronary blood flow should result in diproteverine being particularly beneficial for the treatment of angina pectoris.
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PMID:Diproteverine (BRL 40015): a new type of calcium antagonist with potential antianginal properties. 205 33

Papaverine, an inhibitor of cAMP phosphodiesterase, reduced yields of infectious vesicular stomatitis virus in HEp-2 cells approximately 100-fold if added to cultures at a concentration of 30 microM before and after virus infection. The extent of papaverine-induced suppression of viral growth was dependent on drug dose and treatment regimen. Cells progressively recovered their viral permissive state after removal of drug. The cyclic nucleotide, cGMP, nullified the inhibitory effect of papaverine if added to cells during drug treatment. Pulse labeling experiments with [35S]methionine showed that papaverine compromises production of all virus-specific proteins in infected cells without adversely affecting host cell protein synthesis. Treatment of cells with papaverine strongly inhibited the production of viral RNA and both cellular RNA and DNA. It was found that VSV causes an immediate but transient stimulation of DNA synthesis in HEp-2 cells which is prevented by papaverine treatment. This drug also selectively blocked primary transcription of VSV in vivo and to a lesser extent in vitro RNA polymerase activity of the virion-bound transcriptase. The finding that papaverine has a strong inhibitory effect on viral biosynthesis including early transcription suggests that VSV replication may depend on host factors that regulate intracellular levels of cyclic nucleotides such as cAMP.
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PMID:Inhibitory effect of papaverine on RNA and protein synthesis of vesicular stomatitis virus. 241 Oct 62

We attempted to determine whether there is a possible link between the effect of papaverine on p-aminohippurate (PAH) accumulation, on cyclic nucleotide content and on certain other cellular functional parameters in rat kidney cortical slices in vitro. Papaverine at a concentration of 0.1 mM almost completely inhibited PAH accumulation in the slices. However, cyclic guanosine 3', 5'-monophosphate (cyclic GMP) and cyclic adenosine 3', 5'-monophosphate (cyclic AMP) levels in the slices were not significantly affected by papaverine at 0.1 mM, though papaverine at a concentration of 1 mM increased the cyclic GMP level without affecting the cyclic AMP level. Papaverine (0.1 mM) produced a decrease in the sodium gradient and in the adenosine triphosphate (ATP) level in the slices. Calcium uptake by mitochondria, isolated from kidney cortex, was apparently decreased in the presence of 0.1 mM papaverine. These results suggest that the inhibition of phosphodiesterase probably does not explain the action of papaverine on PAH accumulation in the slices. The inhibition of PAH accumulation by papaverine is partly a reflection of the fall in the sodium gradient in the slices treated with papaverine. In addition, a depression of ATP level in the slices and an inhibition of mitochondrial calcium uptake may be related to a possible mechanism of action of papaverine on PAH accumulation.
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PMID:Influence of papaverine on cyclic nucleotide level and cellular metabolism in rat kidney cortex in terms of its inhibitory effect on p-aminohippurate transport. 242 72

1. The effects of three phosphodiesterase inhibitors (papaverine, isobutyl methyl xanthine (IBMX) and SKF 94120) were examined on tension responses and cyclic nucleotide content (both cyclic AMP and cyclic GMP) of normal and Triton X-100 skinned isolated trachealis of the guinea-pig. 2. The three inhibitors were approximately equipotent in eliciting concentration-dependent relaxation of histamine-induced contractions of the trachealis. 3. Papaverine-induced relaxation was associated with concentration-related increases in the levels of both cyclic nucleotides. 4. IBMX at low concentrations (1 mumol l-1) produced significant relaxation (36%) of histamine-contracted trachealis without changing cyclic nucleotide levels. At a ten fold higher concentration IBMX-induced relaxation (95%) was associated with a selective increase in tissue cyclic GMP levels. Only at the highest concentration tested (100 mumol l-1) did IBMX increase cyclic AMP levels significantly. 5. SKF 94120 (1 mumol l-1) elicited a 23% relaxation of the contracted trachealis without altering the tissue content of either cyclic nucleotide. At the two higher concentrations tested (10 and 100 mumol l-1), SKF 94120-induced relaxation was accompanied by a selective increase in the levels of cyclic AMP. 6. In the skinned trachealis Ca2+ (10 and 20 mumol l-1)-induced contractions were significantly inhibited by the calmodulin antagonist calmidazolium (10 mumol l-1) and by cyclic AMP (10 mumol l-1), the catalytic subunit of cyclic AMP-dependent protein kinase (0.1 mumol l-1) and cyclic GMP (10 mumol l-1). 7. Papaverine (100 mumol l-1) significantly inhibited (31 +/- 6%) the Ca2+-induced contractions of the skinned trachealis. Both IBMX and SKF 94120 were without effect. It is concluded that cyclic nucleotide-dependent mechanisms have an inhibitory action on the biochemical processes that lead to contraction of the guinea-pig trachealis. The results suggest that a functional sarcoplasmic reticular and/or plasma membrane is essential for the expression of IBMXand SKF 94120-induced relaxation. This is not the case for papaverine. The results also highlight the fact that significant relaxant responses of airway smooth muscle can be produced by phosphodiesterase- inhibiting drugs without concomitant elevations in tissue cyclic nucleotide content.
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PMID:Effects of phosphodiesterase inhibitors on normal and chemically-skinned isolated airway smooth muscle. 244 91

CI-914 is a novel positive inotropic agent whose cardiotonic activity is not due to inhibition of Na+, K+-ATPase or to stimulation of cardiac beta-receptors. CI-914 also has no direct effect on sarcoplasmic reticulum, mitochondria or adenylate cyclase activity. CI-914 does, however, exert a potent inhibitory effect on cardiac phosphodiesterase activity. In evaluating the effect of this agent on the different molecular forms of phosphodiesterase present in cardiac muscle, CI-914 was found to selectively inhibit PDE III, which is a low Km, cAMP-specific form of the enzyme (IC50 = 6.1 microM). This inhibitory effect was found to be competitive with respect to the substrate. Papaverine and theophylline on the other hand were found to inhibit all three forms of phosphodiesterase present in cardiac muscle. The role of phosphodiesterase inhibition in mediating the positive inotropic response to CI-914 is supported by the finding that this agent: (i) significantly elevates cyclic AMP levels in ventricular tissue; (ii) shifts the normal concentration-response to the beta-receptor stimulant isoproterenol to the left: and (iii) restores contractility to K+-depolarized papillary muscles.
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PMID:Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent. 300 93


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