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 respiratory effects of caffeine and paraxanthine, two xanthine adenosine antagonists with phosphodiesterase (PDE) activity, CGS 15943, a non-xanthine adenosine antagonist lacking PDE inhibitory activity, and rolipram, a non-xanthine PDE inhibitor lacking adenosine antagonist activity, were characterized in unanesthetized, seated rhesus monkeys exposed to 10% O2 balanced in N2 (hypoxia). Ventilation was measured continuously by enclosing the monkey's head in a fitted helmet and using a pressure-displacement plethysmographic technique. Respiratory frequency (f) and minute volume (VE) increased during 15-minute periods of hypoxia, and intramuscular administration of caffeine (0.3 and 1.0 mg/kg), paraxanthine (0.3 and 1.0 mg/kg) and CGS 15943 (0.03 and 0.1 mg/kg) attenuated the ventilatory response to hypoxia. In contrast, rolipram (0.003-0.03 mg/kg) did not significantly alter the ventilatory response to hypoxia. Drug effects also were characterized in monkeys exposed to air (normoxia) or 3%, 4% and 5% CO2 balanced in air (hypercapnia). Doses of caffeine, paraxanthine or CGS 15943 that attenuated the ventilatory response to hypoxia had no significant effect on f or VE during conditions of normoxia or hypercapnia. The results indicate that adenosine may play a major role in the function of peripheral, O2-sensitive mechanisms during hypoxia.
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PMID:Attenuation of hypoxia-induced increases in ventilation by adenosine antagonists in rhesus monkeys. 763 51

The effects of caffeine and several selective phosphodiesterase (PDE) inhibitors on ventilation and on schedule-controlled behavior were studied in rhesus monkeys. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to air (normocapnia) and to elevated levels of CO2 (3, 4 and 5%) mixed in air (hypercapnia) was measured after cumulative doses of each drug. In other monkeys, behavioral effects were studied by administering cumulative doses preceding sequential periods of fixed-ratio or fixed-interval responding. The nonselective PDE inhibitors, caffeine and 3-isobutyl-1-methylxanthine, and the type IV-selective PDE inhibitors, rolipram and Ro 20-1724, had pronounced respiratory-stimulant effects during conditions of normocapnia and hypercapnia, and their potencies in increasing ventilation corresponded with their potencies as PDE inhibitors. The type III-selective PDE inhibitor, CI-930, had only modest respiratory-stimulant effects at the highest dose studied, and the type V-selective PDE inhibitor, zaprinast, had no respiratory effect. CGS 15943, a selective adenosine antagonist lacking PDE-inhibitory effects, also had only modest respiratory-stimulant effects at the highest dose studied. In contrast to their relative potencies and efficacies in stimulating respiration, caffeine and 3-isobutyl-1-methylxanthine were less efficacious than CGS 15943 in increasing fixed-interval responding, and CI-930, rolipram and Ro 20-1724 only decreased fixed-interval responding. Zaprinast had little or no behavioral effect. The results support the interpretation that inhibition of type IV PDE plays a prominent role in the respiratory-stimulant effects of xanthines, whereas the behavioral-stimulant effects are more closely related to antagonism of adenosine receptors.
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PMID:Comparative effects of caffeine and selective phosphodiesterase inhibitors on respiration and behavior in rhesus monkeys. 768 4

To study the effects of progesterone on placental vascular tone, we used isolated (1-2 mm in diameter) placental arteries and veins from term uncomplicated pregnancies. These vessels, incubated in Krebs buffer (pH 7.4) under 5% O2-5% CO2 (balance N2, PO2 approximately 35 torr) and precontracted with serotonin were exposed to incremental doses of progesterone (0.01-30 mumol/L) in the presence or absence of endothelium, 10 mumol/L indomethacin (inhibits prostaglandin synthesis), 10 mumol/L methylene blue (a soluble guanylate cyclase inhibitor), 100 mumol/L nitro-L-arginine (inhibits L-arginine metabolism), 1 mmol/L isobutylmethylxanthine (a cAMP phosphodiesterase inhibitor), or 30 mumol/L mifepristone (RU 38486, an antiprogestin). Progesterone elicited an acute dose-dependent relaxation in both arteries and veins that was not altered by removal of the endothelium or pretreatment with indomethacin, nitro-L-arginine, or methylene blue, excluding a role for prostaglandins, L-arginine products, or cGMP in mediating this relaxation. However, isobutylmethylxanthine significantly enhanced the relaxation in response to progesterone, suggesting a role for cAMP. RU 38486 inhibited the relaxation by 50-100%, depending on the progesterone dose, consistent with a role for progesterone receptors. These results suggest that progesterone causes a dose-dependent endothelium-independent relaxation of human placental arteries and veins. This relaxation seems to be mediated by a receptor-activated cAMP mechanism and could be physiologically important in maintaining low resistance and adequate blood flow in the placental circulation.
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PMID:Properties of a progesterone-induced relaxation in human placental arteries and veins. 785 92

Several drugs have been used to stimulate human sperm motility, including 3-deoxy-adenosine, caffeine, and pentoxifylline. Pentoxifylline is an inhibitor of the phosphodiesterase and may stimulate sperm motility by increasing the intracellular levels of cAMP. In this study we have evaluated the effect of pentoxifylline in the outcome of the sperm penetration assay into zona-free hamster oocytes. Twenty-seven semen samples, obtained for diagnostic purposes, were used. After the motile sperm were selected by the swim-up technique, the samples were divided into two aliquots. One aliquot was incubated with 1 mg ml-1 of pentoxifylline at 37 degrees C, 5% CO2 for 30 min. The control aliquot was incubated with culture medium. The samples were then washed and resuspended in fresh, pentoxifylline-free medium, at a sperm concentration of 10 x 10(6) cells ml-1. One hundred microlitres of each sperm suspension was then deposited under oil and 30-40 zona-free hamster oocytes were added. After 6 h of gamete coincubation, the percentage of penetrated oocytes and the number of decondensed sperm heads were evaluated. The percentage of acrosome-reacted sperm was evaluated using the Pisum sativum lectin. The percentage of zona-free hamster oocytes penetrated was increased after pentoxifylline-treatment. The percentage of acrosome reacted sperm and the number of decondensed sperm heads per egg were not different between the control and the pentoxifylline-treated groups. The results suggest that the beneficial effect of pentoxifylline upon the sperm cells is not mediated by stimulation of the acrosome reaction.
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PMID:Pentoxifylline increases sperm penetration into zona-free hamster oocytes without increasing the acrosome reaction. 827 10

Boar spermatozoa loaded with the Ca2+ probe fluo-3 were incubated in various Tyrode's-based media similar to those used for in vitro fertilization (IVF), and samples were then analysed by two-colour flow cytometry; propidium iodide was included in the media to detect membrane-damaged ("dead") cells. If media contained bicarbonate/CO2 (a component thought to promote capacitation), part of the live sperm population experienced a considerable influx of Ca2+ into both head and tail compartments. The percentage of responding cells reached a maximum after about 30 min, but both during and after this period there was also a steady increase in the number of dead cells. This bicarbonate-mediated increase in cell death took place in the absence of external Ca2+. Evidence was obtained that the entry of propidium iodide was preceded by a change in permeability of the plasma membrane, detectable by leakage of carboxydichlorofluorescein, and it was therefore deduced that the Ca2+ influx detected by fluo-3 was due to destabilization of the plasma membrane. A similar response could be produced by both caffeine and papaverine (best known as phosphodiesterase inhibitors), but neither cyclic AMP nor activators of adenylate cyclase had any effect. There was no influence of substrate on the process, but, in comparison to poly(vinyl alcohol), serum albumin enhanced it. The precise relevance of this destabilization to capacitation is not yet clear, but it seems significant that the process is mediated or enhanced by components often specifically included in IVF media, and that different individual cells respond after different times.
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PMID:Flow cytometric studies of bicarbonate-mediated Ca2+ influx in boar sperm populations. 839 Dec 78

We show that bubbles containing different gases (N2, He, Ne, Ar, or an O2-CO2-N2 mixture) are equally potent platelet agonists. The synergistic effect of different platelet antagonists does not seem to be affected by the type of gas in the bubbles. In contrast to aggregation in platelet-rich plasma (PRP), bubbles cause only a weak response in gel-filtered platelets (GFP), i.e., comparison of aggregation in protein-rich and protein-poor platelet suspensions may shed light on the role of different plasma proteins. Extracellular fibrinogen promotes bubble-induced platelet aggregation similar to known physiologic agonists, whereas albumin counteracts this aggregation. Bubble-induced aggregation is inhibited in GFP-fibrinogen by 2-deoxy-D-glucose plus antimycin A, suggesting dependency on ATP generation in the platelets and evidence for direct exposure of the "cryptic" fibrinogen receptor by bubbles. Hyperbaric compression and subsequent rapid, inadequate decompression of PRP caused little change in the aggregation response to gas bubbles and epinephrine at 1 bar, but reduced the response to ADP. Bubbles tended not to form before the surface film was broken. Pressure-induced aggregation was apparently metabolically active and not due to passive agglutination; electron microscopic studies and PRP with added glutaraldehyde did not show platelet activation, clumping, or reduced platelet count. In contrast to aggregation caused by pressure, bubble-induced aggregation in PRP at 1 bar (after treatment in the pressure chamber) was nearly completely inhibited by theophylline, a phosphodiesterase inhibitor that increases intracellular platelet cyclic AMP.
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PMID:Bubble-induced aggregation of platelets: effects of gas species, proteins, and decompression. 839 14

This study characterized in rhesus monkeys the effects of selected adenosine agonists on ventilation during normal atmospheric conditions and during conditions of hypercapnia, hypoxia and hyperoxia. In seated, unanesthetized monkeys prepared with a head plethysmograph, ventilation during exposure to air, CO2 (3, 4 and 5%) mixed in air (hypercapnia), 10% O2 mixed in N2 (hypoxia) and 100% O2 (hyperoxia) was measured during cumulative dosing with each drug. The nonselective (A1/A2) agonist, 5'-N-ethylcarboxamidadenosine (NECA), the peripherally active, A2-selective agonist, CGS 21680 [2-(carboxyethylphenylamino)adenosine-5'-carboxamide], and the A1-selective agonists, N6-cyclohexyladenosine and N6-cyclopentyladenosine, increased respiratory frequency (f), but had no significant effect on minute volume (VE) during exposure to air. The relative potencies for increasing f corresponded closely with their potencies for binding at A2 receptors. NECA and CGS 21680 increased f in a dose-dependent manner during exposure to 3% CO2, but proportional increases in f were less pronounced as the concentration of CO2 increased. NECA and CGS 21680 also increased f during hypoxia, but neither had a significant effect on f during subsequent hyperoxia. The highest dose of CHA and CPA decreased f below control values during exposure to 5% CO2 and decreased f and VE during hyperoxia. In contrast, the adenosine antagonist, caffeine, and the selective phosphodiesterase inhibitor, rolipram, increased f and VE under all conditions. During hypercapnia, the magnitude of the increases in f was similar at each concentration of CO2 studied. Caffeine and rolipram increased f and VE during hypoxia, and f and VE remained elevated during hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of adenosine agonists on ventilation during hypercapnia, hypoxia and hyperoxia in rhesus monkeys. 849 37

We examined the hypothesis that an increase in the myocardial cyclic adenosine monophosphate (cAMP) by a phosphodiesterase III inhibitor, E-1020, may ameliorate the hemodynamic and biochemical changes in rabbit hearts after cardioplegic arrest, and that this enzyme-mediated process is temperature-sensitive. Sixty-one male Japanese white rabbits weighing 2.8 to 3.5 kg were used. Isolated hearts were prepared for modified Langendorff circulation using modified Krebs-Henseleit bicarbonate solution bubbled with a 95% O2-5% CO2 gas mixture. Thirty or sixty minutes of cardioplegia at 37 degrees C, or thirty minutes of cardioplegia at 15 degrees C was followed by normothermic reperfusion for 60 minutes. E-1020, 0.1 mmol/L was added to the cardioplegic solution (Bretschneider's HTK solution). The left-ventricular function was measured with a latex balloon placed in the left-ventricular cavity. The myocardial cAMP was higher, the total myocardial calcium was lower in hearts with E-1020 than in hearts with HTK alone (p < 0.05). E-1020 at 0.1 mmol/L did increase the myocardial concentration of cAMP and the functional recovery, and prevented the increase in the myocardial total calcium. Temperature affected the myocardium to preserve myocardial concentrations of adenine nucleotide compounds and cAMP. Our results suggest that a 0.1 mmol/L E-1020 adjunct to HTK solution at 37 degrees C completely prevents left-ventricular functional depression during 30 min of cardioplegia induced with non-oxygenated HTK, but decreases its potential efficacy at 15 degrees C. The protective effects disappear if the ischemic period lasts 60 min at 37 degrees C.
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PMID:Effect of phosphodiesterase III-inhibitor (E-1020) adjunct to Bretschneider's HTK cardioplegic solution on myocardial preservation in rabbit heart. 889 57

Bicarbonate/CO2 is believed to be the key in vitro effector of sperm capacitation, a process which induces major changes in the sperm plasma membrane in preparation for fertilization. In a flow cytometric study, we examined the effect of bicarbonate on boar spermatozoa using merocyanine, an impermeant lipophilic probe which binds to plasma membranes with increasing affinity as their lipid components become more disordered. We found that bicarbonate causes a rapid increase in the ability of live boar spermatozoa to bind merocyanine. First detected about 100 sec after exposure to bicarbonate and largely complete by 300 sec, this increase appears to result from individual cells within the sperm population switching from a low merocyanine-binding state to a high binding state. The majority of live spermatozoa are capable of responding in this way, and do so in proportion to bicarbonate concentration, half-maximal response being induced by about 3 mM bicarbonate; however, overall population response varies greatly between ejaculates. Increased merocyanine stainability is observed over the whole surface area of the cell, and is reversible both with respect to temperature (it is only manifested above 30 degrees C) and with respect to presence of bicarbonate. A similar effect can be induced by phosphodiesterase inhibitors such as isobutylmethylxanthine, and enhanced by a permeant cyclic nucleotide analogue. We conclude that bicarbonate causes a major alteration in sperm plasma membrane lipid architecture, apparently by perturbing enzymic control processes. This novel action of bicarbonate may represent an initial permissive event in the capacitation sequence.
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PMID:Bicarbonate/CO2, an effector of capacitation, induces a rapid and reversible change in the lipid architecture of boar sperm plasma membranes. 891 50

The effects of chronic caffeine administration on ventilation and schedule-controlled behavior were studied in 12 adult rhesus monkeys. In seated subjects prepared with a head plethysmograph, ventilation was measured during exposure to air (normocapnia) and to elevated levels of CO2 (3%, 4% and 5%) mixed in air (hypercapnia). Acute administration of caffeine (10.0-30.0 mg/kg i.m.) produced marked, dose-dependent increases in ventilation during conditions of normocapnia and hypercapnia. However, daily administration of caffeine (10.0 mg/kg i.m.) for 8 consecutive days resulted in tolerance to its respiratory-stimulant effects that was surmountable with higher doses. Caffeine-tolerant subjects also were cross-tolerant to theophylline, an active metabolite of caffeine, and to rolipram and Ro 20-1724, selective phosphodiesterase inhibitors. When chronic administration was terminated and the acute effects of caffeine were redetermined, sensitivity returned to levels obtained before chronic administration within 9 days. Drug effects on behavior were studied in monkeys trained to respond under a fixed-interval schedule of stimulus termination. Acute administration of caffeine (1.0-30.0 mg/kg i.m.) produced significant rate-increasing effects on fixed-interval responding, but chronic administration resulted in tolerance that was insurmountable, such that no dose increased responding above control rates. Although the time course for development and loss of tolerance to the behavioral effects of caffeine corresponded closely with respiration, cross-tolerance did not extend to the behavioral effects of rolipram. Chronic caffeine administration had little effect on caffeine metabolism or clearance, which indicated that caffeine tolerance was pharmacodynamic. The results suggest that different neurochemical mechanisms mediate the effects of caffeine on respiration and behavior, and that inhibition of type IV phosphodiesterase plays a prominent role in caffeine-induced respiratory stimulation.
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PMID:Effects of chronic caffeine administration on respiration and schedule-controlled behavior in rhesus monkeys. 933 24


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