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 elevated calcium content found in red cells from patients with sickle cell anemia may be of pathophysiologic importance in the hemolysis and vasoocclusion which characterize this disorder. Cetiedil, an antisickling agent, has been reported to inhibit the activity of enzymes that are stimulated by the calcium regulatory protein calmodulin. To investigate the mechanism by which cetiedil modifies calcium-mediated erythrocyte function, the effect of the drug on the active transport of calcium into inside-out erythrocyte vesicles was examined and its influence on the activities of phosphodiesterase and Ca-ATPase studied. Cetiedil, in the presence of calmodulin, significantly inhibited calcium transport into inside-out vesicles that were prepared with erythrocytes from normal controls and from patients with sickle cell anemia. However, in the absence of calmodulin, no inhibition was observed. Likewise, cetiedil inhibited calmodulin-stimulated, but not basal, activities of phosphodiesterase and Ca-ATPase. These data, along with previous reports, suggest that cetiedil does not act by lowering the intracellular calcium content. It is, therefore, likely that the beneficial effect of cetiedil is due to its ability to protect the red cell from the deleterious consequences of an elevated concentration of intracellular calcium.
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PMID:Inhibition of erythrocyte calcium transport by cetiedil. 282 42

The aim of this study was to investigate whether increasing calcium sensitivity of myofibrils plays a role in the positive inotropic activity of the cardiotonic agent sulmazole. We studied the effects of the stereoisomers of sulmazole on cardiac contractility in vivo and in vitro, arterial blood pressure, cardiac (Na-K)ATPase activity, cAMP/cGMP-phosphodiesterase activity of cardiac and smooth muscle tissue and calcium sensitivity of skinned myocardial fibres. Both stereoisomers of sulmazole were equipotent vasodilators in vivo and this can be explained by their equipotent cAMP- and cGMP-phosphodiesterase inhibitory activities in smooth muscle tissue. However, (+)sulmazole was a much stronger positive inotropic agent than (-)sulmazole in vivo and in vitro. This difference in inotropic activity cannot be explained by cAMP- or cGMP-phosphodiesterase inhibition or (Na-K)ATPase inhibition in cardiac tissue. Only (+)sulmazole produced a dose-dependent increase in calcium sensitivity of skinned myocardial fibres. Therefore, the calcium sensitizing effect on myofibrils evoked by (+)sulmazole might be responsible for the difference in inotropic activity observed between the stereoisomers of sulmazole.
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PMID:Increase in calcium sensitivity of cardiac myofibrils contributes to the cardiotonic action of sulmazole. 282 14

The two clinically important classes of antimycotic drugs, the polyenes and azoles, act on the plasma membrane of the cell. The primary modes of action are believed to be through interaction with sterols (polyenes) and alteration in sterol composition of the membrane (azoles). In this report we show that, at growth inhibitory concentrations, the polyenes (nystatin and amphotericin) and azoles (miconazole and ketoconazole) also inhibit plasma membrane enzymes. There was extensive (greater than 75%) inhibition of the Candida albicans plasma membrane enzymes ATPase, glucan synthase, adenyl cyclase and 5'-nucleotidase, when assayed in situ. The antifungals papulacandin and echinocandin, which inhibit glucan synthesis, also inhibited plasma membrane enzymes in situ; glucan synthase (greater than 90%), 5'-nucleotidase (greater than 80%) and ATPase (70-80%). Purified plasma membrane was prepared from yeast cells of C. albicans by two different techniques: concanavalin A stabilization and coating of spheroplasts with silica microbeads. In the purified plasma membrane vesicles prepared from concanavalin A the adenyl cyclase and phosphodiesterase were extensively (greater than 90%) inhibited by the three different classes of antifungal drugs; variable inhibition was observed with ATPase (70-100%). The 3',5'-cyclic phosphodiesterase of the plasma membrane purified by the microbeads method was almost completely inhibited by all of the antifungals tested and there was partial inhibition of ATPase (20-85%) and adenyl cyclase (30-90%).
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PMID:The effects of azole and polyene antifungals on the plasma membrane enzymes of Candida albicans. 283 Mar 94

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.
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PMID:Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents. 283 2

1. In electrically driven guinea pig left atria, micromolar concentrations (2 mumol/l to 80 mumol/l) of N-chlorobenzyl derivatives of amiloride (o-chlorobenzamil and 3',4'-dichlorobenzamil) produced quantitatively similar positive inotropic effects. Contracture developed with 3',4'-dichlorobenzamil. Endogenously released catecholamines contributed 30% to the positive inotropic effect of o-chlorobenzamil but did not contribute at all to the effect of 3',4'-dichlorobenzamil. When tested in the presence of the inhibitor of phosphodiesterase isobutylmethylxanthine, o-chlorobenzamil antagonized its positive inotropic effect, whereas 3',4'-dichlorobenzamil potentiated it. o-Chlorobenzamil also antagonized the positive inotropic effect of ouabain in that it shifted its concentration-effect curve to the right. Moreover, o-chlorobenzamil prevented the appearance of ouabain toxicity in terms of a rise in the resting force. 2. Also, in electrically driven guinea pig papillary muscle, micromolar concentrations (5 mumol/l to 30 mumol/l) of both N-chlorobenzyl derivatives of amiloride produced a positive inotropic effect. This effect was more marked with 3',4'-dichlorobenzamil than with o-chlorobenzamil and was associated for both compounds with lengthening of relaxation time. 3. o-Chlorobenzamil and 3',4'-dichlorobenzamil influenced, though not to the same extent, several systems involved in the onset and in the control of cardiac contractility. 3',4'-Dichlorobenzamil inhibited with the same potency Na-K-ATPase, sarcotubular Ca-ATPase, Na-Ca-exchange carrier, cAMP-dependent phosphodiesterase isolated from bovine heart and oxidative phosphorylation of mitochondria isolated from rat liver. Low micromolar concentrations of o-chlorobenzamil mainly inhibited Na-Ca-exchange carrier and cAMP-dependent phosphodiesterase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of N-chlorobenzyl analogues of amiloride on myocardial contractility, Na-Ca-exchange carrier and other cardiac enzymatic activities. 283 72

Rapid, unidirectional Ca2+ influx was examined in isolated brown adipocytes by short incubations (30 s) with 45Ca2+. Ca2+ uptake was found to be large in the resting brown adipocyte, but was markedly inhibited when the cells were presented with norepinephrine. Specific alpha 1-adrenergic stimulation was without effect on Ca2+ uptake. The effect of norepinephrine (which had an EC50 of 140 nM) could be inhibited by beta-adrenergic blockade and could be mimicked by forskolin (an adenylate cyclase activator) and theophylline (a phosphodiesterase inhibitor). Exogenous free fatty acids such as octanoate and palmitate (classical stimulators of respiration in brown adipocytes) were also able to dramatically inhibit Ca2+ uptake by the cells. The artificial mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP) induced a large reduction in cellular Ca2+ uptake (even in the presence of the ATPase inhibitor oligomycin), and in the presence of FCCP the inhibitory effect of norepinephrine on Ca2+ uptake was significantly reduced. The effect of beta-adrenergic stimulation on Ca2+ uptake was not directly caused by the large increase in respiration that occurs in response to norepinephrine because the respiratory inhibitor rotenone did not affect the Ca2+ response of the cells to the hormone. The evidence suggests that beta-adrenergic stimulation of brown adipocyte metabolism leads to a partial inhibition of Ca2+ uptake into the mitochondrial Ca2+ pool and we discuss the possibility that this represents the effect of a reduced membrane potential (and thus reduced Ca2+ uniport activity) in the partially uncoupled mitochondria of the thermogenically active brown adipocyte.
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PMID:Beta-adrenergic modulation of Ca2+ uptake by isolated brown adipocytes. Possible involvement of mitochondria. 283 96

K-252a, an indole carbazol compound of microbial origin, inhibited activation of bovine brain phosphodiesterase induced by calmodulin (CaM), sodium oleate, or limited proteolysis with almost equal potency. Kinetic analysis revealed that the CaM-activated phosphodiesterase (CaM-PDE) was competitively inhibited by K-252a with respect to CaM. On the other hand, inhibition of the trypsin-activated phosphodiesterase was competitive with respect to cyclic AMP. Addition of a lower amount of phosphatidylserine or sodium oleate to the reaction medium was efficacious in attenuating the inhibition of the CaM-PDE by W-7, compound 48/80, or calmidazolium but, in contrast, had no effect on the inhibition by K-252a. Furthermore, CaM-independent systems such as [3H]nitrendipine receptor binding or Na+ + K+-ATPase were influenced less by K-252a compared with W-7, compound 48/80 and calmidazolium. In conclusion, K-252a is an inhibitor of CaM-dependent cyclic nucleotide phosphodiesterase and it appears that it inhibits the enzyme not only via CaM antagonism but possibly also by interfering with the enzyme.
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PMID:The effect of K-252a, a potent microbial inhibitor of protein kinase, on activated cyclic nucleotide phosphodiesterase. 285 86

The effect of four slow Ca2+ channel blockers (felodipine, nifedipine, prenylamine and bepridil) that possess the ability to bind to calmodulin (CaM) section and to inhibit myosin light chain kinase (MLCK) on CaM-regulated Ca2+ pumping ATPase of cardiac sarcolemma (SL) and brain cyclic AMP phosphodiesterase (PDE) was studied. The ability of these drugs to inhibit Ca2+ pumping ATPase correlated with their inhibitory effect on CaM-activated Ca2+-dependent PDE. Nifedipine was unable to inhibit markedly both enzymes. Prenylamine also was a weak inhibitor, which was unexpected because of its CaM binding potency. Felodipine (10-50 microM) and bepridil (50 microM) markedly reduced activities of SL Ca2+ pumping ATPase and PDE. Striking differences were, however, demonstrated when Ca2+ and CaM concentrations, respectively, were increased. Previously it was reported that inhibition of the SL Ca2+ pumping ATPase by the CaM antagonist calmidazolium could be overcome by increasing Ca2+ concentrations (J. M. J. Lamers and J. T. Stinis, Cell Calcium 4, 281-294, 1983). Felodipine (10-50 microM) in the present study, appeared to be equipotent with calmidazolium in reducing Ca2+ pumping ATPase, but increasing Ca2+ up to 12.2 microM could not counteract this effect. Felodipine (2-10 microM) also inhibited brain PDE noncompetitively with respect to CaM contrary to the competitive effectors calmidazolium and bepridil. On the other hand, bepridil (10-20 microM) decreased or increased Ca2+ pumping ATPase activity depending on the Ca2+ concentration (0.29 and 12.2 microM, respectively) used. These findings suggest at least two types of CaM antagonists, which can be discriminated on basis of their inhibition patterns of PDE and heart SL Ca2+ pumping ATPase.
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PMID:Slow calcium channel blockers and calmodulin. Effect of felodipine, nifedipine, prenylamine and bepridil on cardiac sarcolemmal calcium pumping ATPase. 293 41

LY195115 selectively inhibited the peak III isozyme of cardiac cyclic nucleotide phosphodiesterase (PDE) eluted from DEAE-cellulose columns. Inhibition curves were biphasic, suggesting heterogeneity within this preparation. Since peak III PDE is reported to be derived from membranes, effects of LY195115 upon PDE associated with cardiac membranes were examined. LY195115-sensitive PDE measured in the various membrane fractions correlated well with the sarcoplasmic reticulum marker Ca2+-ATPase (r = 0.94; p less than 0.001), but not with Na+,K+-ATPase or azide-sensitive ATPase. Membrane disruption failed to reveal latent LY195115-sensitive PDE in sarcolemmal vesicles known to be primarily right side out. The results suggest that LY195115-sensitive PDE is located within sarcoplasmic reticulum membranes with a distribution similar or identical to that of Ca2+-ATPase. Accordingly, LY195115-sensitive PDE was referred to as SR-PDE. A subfraction of sarcoplasmic reticulum vesicles (free SR vesicles) was sufficiently homogeneous with respect to SR-PDE activity to carry out steady state kinetic studies. Double reciprocal plots of cAMP hydrolysis were linear, yielding Km and Vmax values of 0.46 +/- 0.03 microM and 700 +/- 90 pmol/min/mg of vesicle protein, respectively. LY195115 was a linear competitive inhibitor of SR-PDE with a Ki of 80 +/- 10 nM. -LogIC50 values for inhibition of SR-PDE by a series of structural analogues of LY195115 correlated highly with published -logED50 values for stimulation of cardiac contractility in vivo (r = 0.91, p less than 0.001). Consequently, in vivo effects of LY195115 upon the heart appear to result primarily from competitive inhibition of SR-PDE, or from binding to a site with a topography similar or identical to that of the catalytic site of SR-PDE.
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PMID:LY195115: a potent, selective inhibitor of cyclic nucleotide phosphodiesterase located in the sarcoplasmic reticulum. 294 29

We have characterized ATP-dependent Ca2+ transport into highly purified plasma membrane fraction isolated from guinea pig ileum smooth muscle. The membrane fraction contained inside-out sealed vesicles and was enriched 30-40-fold in 5'-nucleotidase and phosphodiesterase I activity as compared to post nuclear supernatant. Plasma membrane vesicles showed high rate (76 nmol/mg/min) and high capacity for ATP dependent Ca2+ transport which was inhibited by addition of Ca2+ ionophore A23187. The inhibitors of mitochondrial Ca2+ transport, i.e., sodium azide, oligomycin and ruthenium red did not inhibit ATP-dependent Ca2+ uptake into plasma membrane vesicles. The energy dependent Ca2+ uptake into plasma membranes showed very high specificity for ATP as energy source and other nucleotide triphosphates were ineffective in supporting Ca2+ transport. Phosphate was significantly better as Ca2+ trapping anion to potentiate ATP-dependent Ca2+ uptake into plasma membrane fraction as compared to oxalate. Orthovanadate, an inhibitor of cell membrane (Ca2+-Mg2+)-ATPase activity, completely inhibited ATP-dependent Ca2+ transport and the Ki was approximately 0.6 microM. ATP-dependent Ca2+ transport and formation of alkali labile phosphorylated intermediate of (Ca2+-Mg2+)-ATPase increased with increasing concentrations of free Ca2+ in the incubation mixture and the Km value for Ca2+ was approximately 0.6-0.7 microM for both the reactions.
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PMID:Characterization of Ca2+ uptake in plasma membrane vesicles isolated from guinea pig ileum smooth muscle. 295 Oct 13


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