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)

MDL 17,043 (1,3-dihydro-4-methyl-5-[4-(methylthio)-benzoyl]-2H-imidazol-2-one) is a new drug with cardiotonic properties. Its effects on several biochemical systems considered to be important in myocardial contraction were investigated and compared with those produced by amrinone and theophylline. Dog cardiac phosphodiesterases (PDEs) were separated into three major forms and labeled PDE I, II, and III according to the order of elution during isolation by column chromatography. PDE I and II, considered to be "high-Km" enzymes for cyclic AMP, were not inhibited by MDL 17,043, amrinone, or theophylline in concentrations of 50 microM. PDE III, a "low-Km" enzyme, was strongly inhibited by MDL 17,043. Kinetic studies showed the inhibition to be characteristic of partial competitive inhibition. At 0.25 microM cyclic AMP, 1.3 microM MDL 17,043 caused 50% inhibition of PDE III (I50), while the I50 for amrinone and theophylline were estimated to be 19.5 microM and 119 microM, respectively. Dog kidney Na+, K+-ATPase was inhibited 54% by 100 microM MDL 17,043 while amrinone caused an 18% inhibition at the same concentration. Ca2+-ATPase and Ca2+ uptake by dog sarcoplasmic reticulum vesicles were unchanged by MDL 17,043 concentrations up to 300 microM and 100 microM, respectively. It is suggested that the inhibition of PDE III is related to the cardiotonic effects produced by MDL 17,043 and amrinone, although inhibition of Na+, K+-ATPase may also play a role at high concentrations of these drugs.
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PMID:Biochemical studies on the mechanism of cardiotonic activity of MDL 17,043. 617 50

Aprindine, an antiarrhythmic agent with structural similarities to lidocaine and procainamide, has proved effective in treatment of patients with ventricular premature depolarizations, ventricular tachycardia, and supraventricular arrhythmias. While its effects at an electrophysiologic level have been elucidated, its mechanism of action at a biochemical level has remained largely undefined. The data in this communication demonstrate that aprindine inhibits the activation of bovine brain cyclic 3':5'-nucleotide phosphodiesterase (EC 3.1.4.17) by calmodulin. This inhibition is specific for the calmodulin-stimulated enzyme, as no effect of aprindine is seen when phosphodiesterase is assayed in the absence of calmodulin. The inhibition is competitive with respect to substrate (cyclic AMP) and calmodulin concentrations. In the presence of 10 nM calmodulin, the ID50 for aprindine is 18 microM. This inhibition is not the result of aprindine acting as a calcium chelator because increasing the calcium concentration does not reverse the inhibitory effect. Aprindine also inhibits calmodulin-stimulated Ca-ATPase (ATP phosphohydrolase EC 3.6.1.3) activity, but again has no effect on the enzyme in the absence of calmodulin. Aprindine has hydrophobic properties which may be responsible for the inhibitory effect. Sufficient concentrations of aprindine are achieved in myocardial tissues to interfere with the ability of calmodulin to stimulate a number of enzymes present in the heart.
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PMID:Aprindine inhibits calmodulin-stimulated phosphodiesterase and Ca-ATPase activities. 618 51

Vanadate increases renal Na and water excretion. The mechanism whereby vanadate impairs water transport was examined in the toad bladder. Vanadate did not alter baseline water transport but caused a significant inhibition of water transport elicited by high doses of AVP. The inhibition of AVP stimulated water flow by vanadate was dose dependent with inhibition present with concentration as low as 10(-7) and maximal inhibition occurring at 10(-5) M. Vanadate also inhibited water transport stimulated by cyclic AMP or by phosphodiesterase inhibition indicating that vanadate has an effect beyond cyclic AMP step, in addition to whatever effect it might have on adenylate cyclase. The inhibitory effect of vanadate on AVP stimulated water flow was not altered by prior Na-K-ATPase or prostaglandin inhibition. Since vanadate has been shown to stimulate adenylate cyclase in other tissues we examined whether addition of vanadate 10 minutes after addition of AVP would enhance water transport. Vanadate caused a transient enhancement of AVP stimulated water flow. These data demonstrate that vanadate can inhibit or stimulate water flow in the toad bladder.
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PMID:Effect of vanadate on water transport by the toad bladder. 618 17

We investigated the possible mechanisms involved in the positive inotropic activity of Ro 13-6438 (R-6-chloro-1,5-dihydro-3- methylimidazo -[2,1-b] quinazolin -2[ 3H]-one), a structurally novel cardiotonic agent with vasodilating properties. The positive inotropic response to Ro 13-6438 of the isolated guinea pig papillary muscle was accompanied by inhibition of myocardial phosphodiesterase (PDE) activity and elevation of intracellular cyclic AMP (cAMP) levels Ro 13-6438 had no effect on Na+,K+-stimulated or Ca2+-stimulated ATPase activity and did not influence the rate of 45Ca uptake in cardiac membrane vesicles. Ro 13-6438 caused a concentration-dependent increase in the upstroke velocity, overshoot, and duration of slow action potentials evoked in partially depolarized papillary muscles. Pretreatment of guinea pigs with reserpine did not prevent the effects of Ro 13-6438 on slow action potentials, but slightly decreased its positive inotropic activity. The muscarinic agonist carbachol reversed the Ro 13-6438-induced enhancement of contractility and changes in the slow action potential in an atropine-sensitive manner. These results indicate that the positive inotropic effects of Ro 13-6438 are correlated with PDE inhibition, increased cAMP levels, and an increase of the slow action potential in ventricular myocardium. It is suggested that the elevated cAMP levels resulting from the Ro 13-6438-induced inhibition of PDE enhance the slow inward Ca2+ current.
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PMID:Studies on the mechanism of positive inotropic activity of Ro 13-6438, a structurally novel cardiotonic agent with vasodilating properties. 620 81

Localization and quantification studies were carried out on bay-scallop (Aequipecten irradians) striated-muscle troponin C- and troponin I-like proteins. Indirect immunofluorescence microscopy of scallop myofibrils stained with either rabbit anti-(scallop troponin I) or anti-(scallop troponin C) antibodies shows staining of all I-bands observed. The results of quantification studies using sodium dodecyl sulfate poly-acrylamide-gel electrophoresis of untreated scallop myofibrils, washed scallop myofibrils, and isolated scallop thin filaments indicate an actin/tropomyosin/troponin-C molar rationn of 7:1:1. The molar ratio for troponin I could not be determined in untreated myofibrils because of interfering bands; in washed myofibrils a value of 0.6 mol of troponin I/mol of tropomyosin was found. Purified scallop troponin C binds Ca2+ and interacts with scallop troponin I to relieve troponin I-induced inhibition of actomyosin ATPase. Although scallop troponin C is an acidic protein, it appears to be less acidic than troponin C from higher organisms. A calmodulin-like protein has been isolated from scallop striated muscle that activates bovine brain phosphodiesterase to the same extent as does brain calmodulin. Its amino acid composition and its electrophoretic mobility on alkaline 6 M-urea/polyacrylamide gels differs from that of scallop troponin C, and it appears not to be associated with thin filaments.
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PMID:The stoichiometry and location of troponin I- and troponin C-like proteins in the myofibril of the bay scallop, Aequipecten irradians. 624 69

The hypothesis that bisacodyl induces inotestinal fluid accumulation by increasing mucosal PGE2 content, inhibiting (Na + K) ATPase, and stimulating adenyl cyclase activities was tested in rats. Eighteen hours after its intragastric administration, bisacodyl (5.9 mg/kg body wt) decreased significantly jejunal and colonic (Na + K) ATPase activity: 36.4 +/- 1.4 (SE) and 28.3 +/- 1.4, respectively, as compared to 42.1 +/- 1.6 and 37.0 +/- 2.9 mumol/mg protein/hr in saline-treated rats. Bisacodyl administration increased significantly jejunal and colonic PGE2 content and stimulatd jejunal and colonic adenyl cyclase activity as compared to those in control rats. Jejunal and colonic cAMP content was not significantly increased by bisacodyl. Four hours after its administration, bisacodyl increased intestinal PGE2 content but failed to stimulate adenyl cyclase activity. Pretreatment with indomethacin prevented the increase in PGE2 content and the stimulation of adenyl cyclase induced by bisacodyl. Only jejunal phosphodiesterase activity was stimulated by bisacodyl (10 mg/kg body wt). The results reported thus suggest that intestinal inhibition of (Na + K) ATPase activity, increase of mucosal PGE2 content, and possibly also stimulation of adenyl cyclase activity might contribute to the net water accumulation induced by bisacodyl. It is also suggested that the stimulation of adenyl cyclase activity is mediated by increase in mucosal PGE2 content.
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PMID:Effects of bisacodyl on cAMP and prostaglandin E2 contents, (Na + K) ATPase, adenyl cyclase, and phosphodiesterase activities of rat intestine. 624 58

Some properties of the soluble phosphatidylinositol phosphodiesterase (monophosphatidylinositol inositolphosphohydrolase, EC 3.1.4.10) of rabbit iris smooth muscle are described. Studies on its subcellular distribution showed that in this tissue the phosphodiesterase is not exclusively cytosolic. Thus, under our experimental conditions about 58% of the enzyme activity was found in the soluble fraction and the remainder was particulate. When the latter was treated with deoxycholate about 59% of the enzyme activity, compared to 86% of that of ATPase, was still bound to the particulate fraction. The kinetic properties of the enzyme (30--50% (NH4)2SO4 fraction) were examined. Maximum breakdown was 7.7 mumol/h per mg protein and occurred at pH 5.6. The products of [14C]arachidonic acid-labelled phosphatidylinositol were 1,2-diacylglycerol and a mixture of 86% myoinositol 1-phosphate and 14% myoinositol 1,2-(cyclic)phosphate. The enzyme has an absolute requirement for Ca2+. Addition of Ba2+, La3+, Mg2+, Mn2+, EGTA or EDTA at 0.05--5 mM concentrations; Sr2+ at higher concentrations (greater than 0.25 mM) markedly inhibited the phosphodiesterase activity and this inhibition was completely reversed by Ca2+. The enzyme is specific for the phosphoinositides.
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PMID:Studies on the properties of a soluble phosphatidylinositol-phosphodiesterase of rabbit iris smooth muscle. 625 Jun 28

Ouabain in concentrations from 20-100 micromoles produced a dose-related inhibition of in vitro stimulation of bone resorption by parathyroid hormone, 1,25-dihydroxyvitamin D3 and calcium ionophore A23187, as measured by 45Ca and [3H]-hydroxyproline release in 5-day cultures of fetal rat forelimb rudiments. The inhibitory effect on 45Ca release was completely reversed by subsequent incubation in ouabain-free medium. At a concentration of 100 micromoles ouabain virtually abolished active bone resorption; however, basal and stimulated bone cyclic AMP (cAMP) content were significantly increased above levels observed in the absence of ouabain. The increased cAMP content did not appear to be the result of phosphodiesterase inhibition. It is concluded that intact Na/K ATPase function is required for hormonally-stimulated bone resorptive processes and that the inhibitory effect of ouabain on bone resorption is produced at a point subsequent to cyclic AMP generation.
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PMID:Ouabain effects on hormonally-stimulated bone resorption and cyclic AMP content in cultured fetal rat bones. 625 6

The effects of dihydroxy bile acids on intestinal cyclic nucleotides, Na+-K+-ATPase, and net secretion, and of propranolol pretreatment on these actions were determined. Ileal and colonic loops were constructed in each of 12 rabbits, six of which were treated with propranolol preoperatively. In random order, normal saline, 6mM deoxycholic, chenodeoxycholic, or ursodeoxycholic acids were injected into the intestinal loops. Five hours after, net luminal secretion and mucosal adenylate cyclase, phosphodiesterase, cGMP, and Na+-K+-ATPase were determined. Deoxycholic and chenodeoxycholic acids each increased adenylate cyclase activity (< 0.01) and net secretion (p < 0.01), and decreased cGMP (p < 0.05). Ursodeoxycholic acid did not alter adenylate cyclase activity or secretion but increased cGMP (p < 0.05). Phosphodiesterase and Na+-K+-ATPase were unchanged. Propranolol reversed all of the bile acid effects. In conclusion, chenodeoxycholic and deoxycholic acid induce net intestinal secretion, probably via cAMP. Ursodeoxycholic acid does not affect cAMP but increases cGMP and does not promote net secretion.
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PMID:The effect of dihydroxy bile acids on intestinal secretion, cyclic nucleotides, and Na+-K+-ATPase. 625 79

The adenylate cyclase activation by bovine synthetic parathyroid hormone (bPTH) (1-34) was studied in vitro in kidney plasma membranes from D-deficient (D-Mb) or normal (D+Mb) rats. In D-Mb, the apparent affinity of parathyroid hormone (PTH) for membranes (170 +/- 30 nM) was significantly higher than that measured in D+Mb (55 +/- 5 nM). The maximum velocity of the PTH-stimulated adenylate cyclase was significantly higher in D+Mb than in D-Mb (163.0 +/- 13.7 and 93.4 +/- 6.7 pmol of cAMP/mg of protein/min, respectively). The action of vitamin D metabolites on the adenylate cyclase stimulation by PTH was then studied in vitro in D-Mb and D+Mb. In D-Mb, 25-hydroxyvitamin D3, 24,25-, and 1, 25-dihydroxyvitamin D3 significantly inhibited cAMP production in the presence of 0.87 microM of bPTH. Vitamin D3 had no effect. Maximal inhibition (86%) was observed for 1,25-dihydroxyvitamin D3. 1,25-Dihydroxyvitamin D3 decreased the maximum velocity of PTH-stimulated adenylate cyclase but did not modify the bPTH apparent affinity for D-Mb. The vitamin D3 metabolites tested did not modify the cyclase stimulation by isoproterenol, sodium fluoride, or 5'-guanylylimidodiphosphate. The presence of 1,25-dihydroxyvitamin D3 or 25-hydroxyvitamin D3 did not increase the (Na-K)-ATPase or the phosphodiesterase activities. In the presence of 1,25-dihydroxyvitamin D3 and bPTH, the apparent affinity of ATP for the catalytic moiety was not modified. The maximum velocity was decreased. These results suggest an in vitro interaction between hydroxylated vitamin D metabolites and kidney membranes PTH receptor.
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PMID:Renal parathyroid hormone-dependent adenylate cyclase in vitamin D-deficient rats. Inhibition by hydroxylated vitamin D3 metabolites. 625 64


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