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 forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin were investigated using [125I]bovine serum albumin (125I-BSA). Forskolin, forskolin 7-ethyl carbonate and 7-desacetylforskolin, which are potent activators of adenylate cyclase, greatly potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. On the other hand, 14,15-dihydroforskolin and 1,9-dideoxyforskolin, which are weak or inactive as activators of adenylate cyclase, did not have any significant effect on bradykinin and prostaglandin E1-induced plasma exudations. The phosphodiesterase inhibitors, ZK 62711, dipyridamole, HL 725, and 3-isobutyl-1-methylxanthine potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. Papaverine had biphasic effects on the bradykinin-response and slight inhibitory effects on the prostaglandin E1-response. 8-Bromo cyclic AMP in the doses of 0.01 to 1 microgram potentiated the bradykinin-induced plasma exudation, but had no effect at doses of 10 and 100 micrograms. 8-Bromo cyclic AMP at all doses significantly inhibited the prostaglandin E1-induced response. The results suggest that the effects of forskolin and its analogs on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin derive from activation of cyclic AMP-generating systems.
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PMID:Effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin. 631 36

The effects of papaverine and verapamil were studied in spontaneously beating right atria of guinea pigs, rabbits and rats and on segments of sinoatrial node tissue from rabbits. Papaverine (10(-4)M) produced a significant negative chronotropic effect in guinea pigs and rats, with a lesser effect in rabbits. Papaverine antagonized the positive chronotropic response to transmural nerve stimulation (TNS) of the sinoatrial node of rabbit atria in a concentration-dependent manner. The chronotropic response to 5 X 10(-7)M norepinephrine was enhanced in the presence of 10(-6)M papaverine, but was noncompetitively antagonized at concentrations above 10(-5)M. The negative chronotropic response to TNS was unaltered by papaverine except at concentrations at or above 5 X 10(-5)M; however, the negative chronotropic response to 5 X 10(-6)M methacholine was not altered by 10(-4)M papaverine. A local anesthetic (lidocaine) inhibited both the positive and negative chronotropic TNS response at a concentration that had no effect on the response to exogenous norepinephrine. Verapamil (10(-7) to 10(-6)M) had no significant effect on either the positive or negative chronotropic response to TNS. The effects of papaverine on TNS are attributed to the influence of at least three actions: 1) phosphodiesterase inhibition, 2) local anesthetic activity and 3) physiological antagonism of norepinephrine. The effects of 2 X 10(-4)M papaverine on action potentials of rabbit sinoatrial node cells were studied. Papaverine decreased the maximum diastolic potential, increased the action potential overshoot and transformed the normal ramp configuration of slow diastolic depolarization into a concave shape.
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PMID:Influence of papaverine on spontaneous activity of isolated right atria from small mammals. 636 76

The present studies were conducted to further investigate a role of cyclic nucleotides for organic anion transport in rat kidney cortical slices by using papaverine as a phosphodiesterase inhibitor. Papaverine was chosen for this study because this drug is an organic cation, a transport system of which is thought to be clearly separable from an organic anion transport system. Papaverine inhibited not only p-aminohippuric acid (PAH) accumulation in the slices but also urate one. Pretreatment of the slices with papaverine was effective for significant inhibition of PAH accumulation during subsequent incubation in the absence of papaverine. The present results suggest that a relationship may exist between cyclic nucleotides and organic anion transport in rat kidney cortical slices, although further work is necessary before the above evaluation can be given.
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PMID:Effect of papaverine on organic anion transport in rat kidney cortical slices. 647 Sep 31

Previous results (J. Pharm. Dyn., 7, 342, 1984) from this laboratory indicated that papaverine, a classical phosphodiesterase inhibitor, inhibited the transport of organic anions such as p-aminohippurate (PAH) and urate in rat kidney cortical slices. The transport of papaverine itself, an organic cationic drug, in the kidney is not yet understood. The purpose of this study was to examine the interaction of papaverine with incubated slices and basolateral membrane vesicles prepared from rat kidney cortex, in terms of the possibility of the intracellular action of papaverine in kidney cells. Papaverine was taken up against a concentration gradient by kidney cortical slices and by liver slices. The uptake of papaverine by the former slices was depressed by hypothermia and anoxia with metabolic inhibitors, but that of the drug by the latter slices was not affected by hypothermic condition. Tetraethylammonium (TEA) as a prototype for organic cationic drugs did not depress papaverine transport. TEA also had no effect on the inhibitory effect of papaverine on PAH accumulation in kidney cortical slices. Papaverine, however, inhibited TEA accumulation prominently. Kinetic studies using the slices indicated that papaverine increased the Km for TEA accumulation and decreased Vmax. Then, papaverine inhibition was a "mixed type". TEA uptake by basolateral membrane vesicles was markedly inhibited by papaverine, but PAH uptake by the vesicles was not affected by the drug. The present results indicate that papaverine may be at least partly transported by the same system which handles TEA, but some aspect of the transport system for papaverine may be qualitatively different from that for TEA. Additional studies are required, however, to unequivocally establish the relationships between papaverine and TEA renal transport mechanisms.
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PMID:Transport of papaverine in rat kidney cortical slices. 653 Jun 47

Anti-aggregating activity of 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG 626) was tested using rabbit platelets in vitro. EG-626 alone, when added before, prevented platelet aggregation induced by ADP, as did PGI2, papaverine and dipyridamole. Spontaneous disaggregation was also accelerated when EG-626 was added after the maximal aggregation induced by ADP. EG-626 alone also inhibited platelet aggregation induced by collagen and arachidonic acid. ID50s of these agents in ADP-induced aggregation were 7-9 nM for PGI2, 223 microM for EG-626, 266 microM for papaverine and 957 microM for dipyridamole. When EG-626 was used in combination with PGI2, a threshold dose (50 microM) of EG-626 potentiated the antiaggregation effect of subthreshold dose (3 nM) of PGI2 upto 100% inhibition in collagen-induced platelet aggregation. The marked potentiating effect of EG-626 was accompanied by an accumulation of cyclic AMP in the platelets. These effects might be due to inhibition of phosphodiesterase. Papaverine and dipyridamole, other phosphodiesterase inhibitors, also potentiated the anti-aggregating activity of PGI2. The activity of papaverine, however, was one eighth of EG-626 and that of dipyridamole was much less. The most effective combination of PGI2 and EG-626 to induce 50% inhibition was obtained with 20% of ID50 of each agent, whereas that of PGI2 and papaverine or dipyridamole was 39 or 41%, respectively.
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PMID:Potentiation of anti-aggregating activity of PGI2 by 7-ethoxycarbonyl-6,8-dimethyl-4-hydroxymethyl-1(2H)-phthalazinone (EG-626) in rabbit platelets in vitro. 699 30

1. The effects of nicardipine on the secretion of pancreatic juice were investigated in dog isolated, blood-perfused pancreas, and compared with those of papaverine, aminophylline and secretin. 2. Intra-arterial administration of nicardipine (1-10 micrograms) elicited a dose-dependent increase in pancreatic secretion. Papaverine (0.1-1 mg), aminophylline (0.3-3 mg) and secretin (0.03-0.1 units) also elicited increased secretion. The secretory activity of nicardipine (10 micrograms) was approximately equal to that of 0.5 mg of papaverine, 1.5 mg of aminophylline and 0.03 units of secretin. 3. The concentration of bicarbonate in the pancreatic juice induced by nicardipine was increased, but the protein concentration was only increased slightly. These effects are analogous to those of secretin. 4. Nicardipine-induced secretion was not modified by pretreatment with relatively large doses of phentolamine, propranolol, atropine, guanethidine, haloperidol or metiamide. 5. Secretin-induced secretion was significantly potentiated by infusion of papaverine, but not by infusion of nicardipine or aminophylline. 6. These results suggest that nicardipine acts on the exocrine cells in the dog pancreas, at least in part, through the increase of intracellular cyclic AMP concentration by inhibiting phosphodiesterase activity.
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PMID:Effects of nicardipine on pancreatic exocrine secretion in the dog. 716 2

The effects of papaverine, cyclic AMP and MIX(3-isobutyl-1-methylxanthine, a phosphodiesterase inhibitor) on calcium uptake by a microsomal fraction from rat uterus were tested in the presence of 3 mM ATP. Papaverine potentiated calcium uptake in the presence of oxalate but inhibited it in the absence of oxalate. However, cyclic AMP and MIX did not influence calcium uptake, neither in the presence nor the absence of oxalate. These results suggest that calcium uptake by plasma membrane-derived vesicles in the absence of oxalate is inhibited by papaverine and that papaverine potentiated calcium uptake by the internal membranes in the presence of oxalate. They suggest also that the stimulatory action of papaverine involves a cyclic AMP-independent mechanism in addition to the mechanism via cyclic AMP.
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PMID:A dual action of papaverine on calcium uptake by microsomal fraction isolated from rat uterus. 721 34

1. In the present study we assessed the activity of antioquine, a bisbenzyltetrahydroisoquinoline alkaloid isolated from Pseudoxandra sclerocarpa, by examining its effects on the contractile activity of rat isolated aorta, specific binding of [3H]-(+)-cis-diltiazem, [3H]-nitrendipine and [3H]-prazosin to cerebral cortical membranes and the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta. 2. Contractions in rat aorta induced by high concentrations of KCl (80 mM) and noradrenaline (1 microM) were inhibited by antioquine in a concentration-dependent manner (0.1 microM- 300 microM). The alkaloid appeared more potent against KCl-induced contractions. This inhibitory effect was observed at both 37 degrees C and 25 degrees C. 3. Paradoxically, at the highest concentration tested (300 microM) antioquine induced a contractile response of similar magnitude in the presence and absence of extracellular calcium, at 37 degrees C. This activity was greatly attenuated at 25 degrees C. Antioquine-induced contractions were not inhibited by prazosin (0.1 microM), nifedipine (1 microM) or diltiazem (100 microM). On the contrary, prazosin and nifedipine slightly increased the contractions in the presence of extracellular calcium. Papaverine (100 microM) partially inhibited the contractile response to antioquine both in the presence and absence of extracellular calcium. 4. At 25 degrees C, in Ca(2+)-free solution, antioquine (300 microM) did not modify the contractile response (phasic and tonic) evoked by noradrenaline, but increased the phasic contraction induced by caffeine. At 37 degrees C, the contraction elicited by antioquine made it impossible to observe the noradrenaline-induced one. 5. Antioquine showed affinity for the [3H]-prazosin binding site and for the [3H]-(+)-cis-diltiazembinding site of the Ca2+-channel receptor complex, but had no effect at the dihydropyridine binding site in rat cerebral cortex.6. Antioquine weakly inhibited some PDE forms isolated from bovine aorta: a CaM-PDE (PDE I)which preferentially hydrolyzes cyclic GMP and is activated by calmodulin, and a rolipram-sensitive cyclic AMP-PDE (PDE IV) which hydrolyzed cyclic AMP. Antioquine did not exert any inhibitory effect on the other forms of PDE, a cyclic GMP selective form (PDE V) and a low Km cyclic AMP-PDEthat is inhibited by cyclic GMP (CGI-PDE, PDE III).7. The present work provides evidence that antioquine has properties both as a calcium entry blocker(possibly through the benzothiazepine recognition site in the calcium channel) and as a contractile agent.Its mechanism of action as a contractile agent is not related to Ca2+-entry and is hypothetically similar to that of calyculin-A or okadaic acid. The possible involvement of a-adrenoceptors in this paradoxical effect cannot be excluded. The rigidity of the molecule provides an interesting model for analyzing this contractile mechanism and the intracellular processes involved.
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PMID:Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta. 835 49

The effect of the alpha-adrenergic blocker moxisylyte was examined on smooth muscle cells isolated from human corpus cavernosum, and compared with that of other adrenergic agents and papaverine. Isolated smooth muscle cells were shown to contract (reduction of the mean cell length) under noradrenaline and carbachol stimulations in a time-dependent and concentration-dependent manner (maximum at 30 seconds, EC50 [noradrenaline] = 5 nM., EC50 [carbachol] = 1 nM.). The contractile effect of noradrenaline was dose-dependently inhibited by moxisylyte (IC50 = 0.5 +/- 0.2 microM.) and by prazosin (IC50 = 0.9 +/- 0.2 microM.). The dose-response curves were parallel and no statistically significant difference could be shown between the IC50 values. The alpha 2-adrenergic antagonist tolazoline also inhibited noradrenaline-induced contraction, whereas the alpha-adrenergic agonist methoxamine did not change the mean cell length. As expected, isoproterenol caused relaxation of noradrenaline-precontracted cells by interaction with a beta 2-adrenergic receptor. Papaverine was also found to inhibit the contraction induced by noradrenaline in a dose-dependent manner (IC50 = 2 +/- 0.3 nM.). Tritiated-dihydroergocryptine (3H-DHE) specific binding was competitively inhibited by moxisylyte and prazosin with the same IC50 value of 0.01 microM. Methoxamine and tolazoline also inhibited this binding with lower affinity (IC50 = 0.1 +/- 0.02 microM.), while isoproterenol did not change specific binding. Scatchard plots from saturation experiments with 3H-DHE and with 3H-N-methyl scopolamine revealed the presence of 15 times more adrenergic than muscarinic binding sites (650,000 and 45,000 sites per cell, respectively). Together, these data support evidence for the presence of postsynaptic alpha 1-adrenergic receptors on smooth muscle cells from human corpus cavernosum. These receptors are coupled with the contraction of the cell and are blocked by the alpha 1-adrenergic antagonists moxisylyte or prazosin. They also show that the phosphodiesterase inhibitor papaverine and the beta-adrenergic agonist isoproterenol induced relaxation. This model constitutes a new approach to study the potential targets of the adrenergic agents in the erectile tissue.
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PMID:Adrenergic receptors on smooth muscle cells isolated from human penile corpus cavernosum. 839 43

The internal mammary artery (IMA) is the preferred conduit for myocardial revascularization, but it changes diameter in response to injury or thromboxane release to decrease myocardial blood supply. Papaverine, a phosphodiesterase (PDE) inhibitor, is injected in the IMA bed during surgery to prevent spasm. We evaluated the ability of papaverine and cyclic adenosine monophosphate PDE Type III (cAMP-PDE) inhibitors (amrinone, enoximone, and milrinone) in vitro to reverse the constriction of human IMA rings, induced by a thromboxane A2 analog, U46619, and evaluated amrinone's ability to modify the constricting effect of norepinephrine (NE). All cAMP-PDE inhibitors produced complete relaxation of U46619-induced contractions. The contractions necessary to produce 50% relaxation (EC50) were within therapeutic ranges. The vasodilatory potency of amrinone was greater after NE than after U46619 (EC50, 1.9 +/- 0.5 vs 4.3 +/- 2.2 x 10(-5)M; mean +/- SD; P < 0.05). Response to constriction after a submaximal dose of NE was attenuated to 38% (P < 0.001) from that observed in the control rings by a pretreatment with amrinone. These results suggest that cAMP-PDE inhibitors have the potential utility to reverse IMA spasm, and represent a potential therapeutic modality for IMA spasm after myocardial revascularization.
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PMID:The in vitro effects of phosphodiesterase inhibitors on the human internal mammary artery. 861 Sep 5


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