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)

Forskolin and milrinone both increase cyclic AMP concentrations to enhance cardiac contractility and cause vascular dilation in vitro and in vivo. However, forskolin acts via direct stimulation of adenylate cyclase while milrinone inhibits phosphodiesterase (PDE-III) activity. The forskolin analog, 7-desacetyl-7-(O-propionyl)-hydroxyl-aminocarbonyl-forskolin (P87-7692) has also been shown to directly stimulate adenylate cylase and increase cyclic AMP production in isolated cardiac tissue; however, the in vivo activity of this compound has not been described. Thus, the purpose of this study was to compare the cardiovascular effects of equivalent doses of these compounds and to further characterize the cardiotonic activity of P87-7692 in the anesthetized dog. It was found that both i.v. (3-30 micrograms/kg) and intracoronary (0.1-30 micrograms) administration of milrinone, forskolin, and P87-7692 caused dose-related positive inotropic, coronary, and peripheral vasodilator effects in anesthetized dogs; however, P87-7692 produced significantly greater and more sustained cardiotonic activity following a single 30-micrograms/kg, i.v., bolus injection when compared to the same dose of milrinone and forskolin. Analysis of the dose-response relationship between the changes in contractile force and heart rate for these compounds revealed that a 50% augmentation in contractile force was associated with increases in heart rate of 2.1% for milrinone, 6.4% for P87-7692, and 13.7% for forskolin. These data indicate an improved separation between the chronotropic and inotropic effects for P87-7692 as compared to forskolin. All three compounds also produced coronary vasodilation in vivo and in vitro; however, P87-7692 consistently showed greater activity relative to the same doses of milrinone and forskolin. Moreover, P87-7692 was significantly (p less than 0.05) more potent at relaxing KC1-precontracted canine coronary rings, with an EC50 of 2.1 x 10(-7) M as compared to 1.1 x 10(-6) M for forskolin and 3.2 x 10(-6) M for milrinone. The results of these studies indicate that structural modification of the forskolin molecule can increase the separation between positive inotropic and chronotropic effects, improve the overall hemodynamic profile, and prolong the duration of cardiotonic activity for this class of compounds.
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PMID:Cardiotonic and coronary vasodilator responses to milrinone, forskolin, and analog P87-7692 in the anesthetized dog. 138 77

The vasoinhibitory effect of FK 453 was examined in isolated rabbit aorta. FK 453 inhibited contractile responses to norepinephrine, angiotensin-I and KCl. Pretreatment of the tissue with FK 453 failed to affect the relaxing effect of verapamil on the KCl response and the inhibitory effect of prazosin on the phenylephrine response. FK 453 inhibited both the residual norepinephrine response and the subsequent Ca2+ response in a Ca(2+)-free medium containing EGTA and nifedipine. The inhibitory effect of a combined treatment with either FK 453 plus nitroglycerin or FK 453 plus theophylline, but not with FK 453 plus M & B 22,948 (2-o-propoxyphenyl-8-azapurine-6-one; May & Baker), was much greater than that of any single treatment. Pretreatment with FK 453 also potentiated relaxing effects of nitroglycerin and isoproterenol on the PGF2 alpha response. The effect of a combined treatment with FK 453 plus theophylline, but not with FK 453 plus M & B 22,948, was much greater than that of any single treatment. FK 453 also inhibited the activity of phosphodiesterase from canine aorta to convert cyclic [3H]-GMP and cyclic [3H]-AMP to 5'-GMP and 5'-AMP, respectively. These results suggest that the inhibitory action of FK 453 is not due to inhibition of voltage-operated Ca2+ channels or alpha-adrenoceptors, but due to increase in cyclic GMP level.
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PMID:Characteristics of vasoinhibitory action of FK 453 (a pyrazolo-pyridine derivative), a new antihypertensive agent with diuretic action in isolated rabbit aorta. 140 48

CK-2289 is an inhibitor of type III cyclic 3'5'-adenosine monophosphate phosphodiesterase with potential utility in the treatment of congestive heart failure. We compared CK-2289 to milrinone and enoximone in several pharmacological models. Intravenous administration of CK-2289 to pentobarbital-anesthetized dogs (0.03 to 1 mg/kg) produced dose-related increases in myocardial dP/dTmax and decreased mean arterial blood pressure, similar to milrinone and enoximone. However, CK-2289 was 3-9 times more potent than either agent as a positive inotrope. Intraperitoneal and oral administration of CK-2289 and milrinone to mice produced central nervous system depression. Administered intravenously. CK-2289 and milrinone (1 mg/kg) inhibited, whereas enoximone (1 mg/kg) enhanced, guinea-pig gastric acid secretion. CK-2289 (0.01 to 0.3 mg/kg) and milrinone (0.03 to 1 mg/kg), given intravenously, did not affect neurotransmission to the rabbit sciatic nerve-gastrocnemius muscle preparation. Neither CK-2289 nor milrinone (100 microM) inhibited sympathetic neurotransmission, alpha 1-, muscarinic and thromboxane receptors. Both compounds relaxed canine arteries and veins. CK-2289 was devoid of effects on non-vascular smooth muscles of guinea-pig vas deferens and uteri and rabbit bronchi. CK-2289 (1 to 100 microM), milrinone and enoximone inhibited human platelet aggregation produced by adenosine diphosphate and sodium arachidonate. These data suggest that CK-2289 should be devoid of adverse renal, neural, smooth or skeletal muscle or gastrointestinal side effects associated with milrinone and enoximone therapy.
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PMID:Pharmacological comparison of CK-2289, an inodilator agent, with milrinone and enoximone. 165 60

The inhibitory effect of adenosine (ADO) and pentoxifylline (POF) was studied alone and in combination on the N-formyl-methionyl-leucyl-phenylalanine (FMLP) stimulated superoxide anion production of human polymorphonuclear leukocytes (PMNL). The pharmacological analysis of the results of these experiments demonstrated greater than additive and independent interaction of the drugs, representing potentiation. These results reflect differences between the sites of action of ADO and POF. Accordingly, the ADO receptor antagonist 8-phenyltheophylline only diminished the inhibition mediated by ADO, but totally failed to affect POF. Therefore, we hypothesize that POF acts as a phosphodiesterase inhibitor, potentiating the increase in cyclic AMP induced by ADO due to the stimulation of the adenylate-cyclase of human PMNL.
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PMID:Pentoxifylline does not act via adenosine receptors in the inhibition of the superoxide anion production of human polymorphonuclear leukocytes. 165 78

Enzymatically dissociated ganglia from the myenteric plexus of the guinea-pig small intestine were used to investigate changes in levels of cyclic 3',5'-adenosine monophosphate (cAMP) in response to stimulation of adenylate cyclase by forskolin and inhibition of phosphodiesterase by 3-isobutyl-1-methylxanthine (IBMX). A linear relation with a positive correlation coefficient greater than 0.98 was found between: (1) amount of cAMP and number of ganglia; (2) amount of protein and number of ganglia; (3) amount of DNA and amount of protein; (4) amount of DNA and number of ganglia. Basal levels of cAMP were 2.25 +/- 0.21 fmol per ganglion for 900 ganglia. Forskolin stimulated a dose-dependent increase in cAMP over a concentration range of 0.05 to 50 microM, with a level of 18.6 +/- 4.9 fmol/ganglion at 50 microM forskolin. The inactive forskolin analog 1,9-dideoxyforskolin did not elevate cAMP. Addition of IBMX to the incubation medium stimulated a dose-dependent increase in cAMP over a concentration range of 0.1-1000 microM, with a level of 17.58 +/- 3.38 fmol/ganglion at 1000 microM IBMX. Application of 1 mM IBMX strongly potentiated the stimulating action of forskolin on cAMP levels. Our results derived from direct determination of cAMP changes in small intestinal myenteric ganglia are consistent with existing electrophysiological evidence for second messenger function of cAMP in slow synaptic modulation of excitability in AH/Type 2 neurons of the enteric nervous system.
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PMID:Determination of levels of cyclic AMP in the myenteric plexus of guinea-pig small intestine. 171 66

When the homogenate prepared from immature rat testes was incubated with [32P]NAD, several proteins (90, 39 and 20 kDa) were ADP-ribosylated in the absence of bacterial toxins. This observation suggested the existence of an endogenous ADP-ribosyltransferase and substrates. The data that the digested product by phosphodiesterase of ADP-ribosylated 20 kDa protein was 5'-AMP suggested that 20 kDa protein was mono(ADP-ribosyl)ated. In addition, the mono(ADP-ribosyl)ation of 20 kDa protein was enhanced by guanine nucleotides such as GTP, GDP and GTP[gamma S], and decreased by the concentrations of 10 mM Mg2+. In contrast, the incorporation of ADP-ribose moiety from NAD to both 90 and 39 kDa proteins was not changed by guanine nucleotides. On the other hand, mono(ADP-ribosyl)ation of 20 kDa protein was not observed in the homogenate prepared from other tissues of the same rats. Furthermore, we found that mono(ADP-ribosyl)ation of 20 kDa protein was decreased with the maturation of the rats and that an endogenous mono(ADP-ribosyl)transferase and 20 kDa protein were located in the nuclei.
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PMID:Reduction of mono(ADP-ribosyl)ation of 20 kDa protein with maturation in rat testis: involvement of guanine nucleotides. 189 5

Analogues of the 2',5'-linked adenylate trimers monophosphate (p5'A2'p5'A2'p5'A) containing 8-hydroxypropyladenosine, 8-bromoadenosine, and 8-hydroxyadenosine in the first, second, and third nucleotide positions were tested for their ability to bind to and activate RNase L of mouse L cells. p5'AHPr2'p5'AHPr2'p5'AHPr (pAHPr3) (1b) and p5'ABr2'p5'ABr2'p5'ABr (pABr3) (1d) were markedly decreased in ability to bind to the 2-5A dependent endonuclease. On the other hand, analogue of the 2',5'-linked adenylate trimer monophosphate substituted by 8-hydroxyadenosine in the first, second, and third nucleotide position was bound about as well as parent 2-5A [pppA(2'p5'A)2] (p3A3) (1e) to RNase L. Additionally, p5'AOH2'p5'AOH2'p5'AOH (pAOH3) (1c) was as active as parent 2-5A in the rRNA cleavage assay, while pAHPr3 (1b) and pABr3 (1d) were devoid of activity. The 8-substituted analogues of 2-5A were more resistant to the degradation by the (2',5') phosphodiesterase. Finally of particular interest was monophosphate, pAOH3 (1c) which possessed nearly 100% of the translation inhibitory activity of 2-5A triphosphate itself. These results suggest that changes in the base-sugar torsion angles of 2-5A may modulate both binding to and activation of mouse L cell RNase L.
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PMID:Purine 8-substitution modulates the ribonuclease L binding and activation abilities of 2',5'-oligoadenylates. 202 89

AMP and NaF each taken separately were shown to activate DNA polymerization catalyzed by Klenow fragment of DNA polymerase I by means of interaction of AMP or NaF with 3'----5'-exonuclease center of the enzyme. In the presence of NaF which is a selective inhibitor of 3'----5'-exonuclease center, AMP is an inhibitor of polymerization competitive with respect to dATP. Ki values and the pattern of inhibition with respect to dATP were determined for AMP, ADP, ATP, carboxymethylphosphonyl-5'-AMP, Pi, PPi, PPPi, methylenediphosphonic acid and its ethylated esters, phosphonoformic acid, phosphonoacetic acid and its ethylated esters as well as for some bicarbonic acids in the reactions of DNA polymerization catalyzed by Klenow fragment of DNA polymerase I (in the presence of NaF) and DNA polymerase alpha from human placenta in the presence of poly(dT) template and r(pA)10 primer. All nucleotides and their analogs were found to be capable of competing with dATP for the active center of the enzyme. Most of the analogs of PPi and phosphonoacetic acid are inhibitors of Klenow fragment competitive with respect to dATP. Nowever these analogs display a mixed-type inhibition in the case of human DNA polymerase alpha. We postulated a similar mechanism of interaction for dNTP with both DNA-polymerases. It is suggested that each phosphate group of PPi makes equal contribution to the interaction with DNA polymerases and that the distance between the phosphate groups is important for this interaction. beta-phosphate of NTP or dNTP is suggested to make negligible contribution to the efficiency of the formation of enzyme complexes with dNTP. beta-phosphate is likely to be an essential point of PPi interaction with the active center of proteins during the cleavage of the alpha-beta-phosphodiester bond of dNTP in the reaction of DNA polymerization.
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PMID:[Interaction of dNTP-binding sites of human DNA polymerase alpha and The Klenow fragment of Escherichia coli DNA polymerase I with nucleotides, pyrophosphate and their analogs]. 216 89

The phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine (IBMX) was able to elevate rat small intestinal cyclic AMP levels to 300% of basal values. Active jejunal D-glucose transport was enhanced parallel to the rise of intracellular cyclic AMP levels to 140% of control values at 100 mumol/l IBMX. Transport parameters, as determined in a three compartment model in vitro using a dual label method, indicate increased 'uphill' glucose transport at the site of the brush border membrane, higher intracellular accumulation of the sugar, with unchanged passive permeabilities. Phlorizin-inhibited D-glucose transport and L-glucose transfer in the rat were not affected by the persisting cyclic AMP elevation produced by IBMX. Stimulating effects could also be demonstrated with D-galactose as a substrate. IBMX 100 mumol/l also increased active D-glucose as well as 3-O-methylglucose transport in mouse jejunum. Stimulatory effects on intestinal hexose transport and mucosal cyclic AMP levels were also found with the adenylate-cyclase activator forskolin. In the present study, forskolin effects on jejunal mucosal cyclic AMP levels were enhanced in the presence of 100 mumol/l IBMX, resulting in a 20-fold increase compared to controls at 20 mumol/l forskolin. The concentration response for the effect of forskolin in the presence of 100 mumol/l IBMX on D-glucose transport did not produce a significant increase compared to transport stimulation with IBMX alone. At higher concentrations of forskolin however, glucose transport decreased to levels well below the IBMX controls. The elevation of cellular cyclic AMP levels had no effects on passive permeability.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Response of rat small intestinal active aldohexose transport to elevation of mucosal cyclic AMP by forskolin and 3-isobutyl-1-methylxanthine in vitro. 241 72

The purpose of this study was to investigate the possible roles of selective inhibition of cyclic nucleotide phosphodiesterase (PDE) isozymes, adenylate cyclase activation, and tissue cyclic 3',5'-adenosine monophosphate (cyclic AMP) elevation in the positive inotropic action of five new cardiotonic drugs. Three PDE isozymes (PDE I, II and III), homogenates, and slices of guinea pig ventricles were used. The inotropics amrinone, milrinone, AR-L 115BS, MDL 17,043, and RMI 82,249 all inhibited cyclic AMP hydrolysis by PDE III in a concentration-dependent manner, as did the PDE inhibitors aminophylline and 1-methyl-3-isobutylxanthine (MIX). All drugs except for AR-L 115BS inhibited PDE III at concentrations lower than those producing a standard inotropic response. A significant correlation (r = 0.80, P less than 0.05) was observed between PDE III inhibition and inotropic activity for six of the drugs. Only aminophylline and MIX, but none of the cardiotonic drugs, inhibited cyclic AMP hydrolysis by PDE I and II and cyclic 3',5'-guanosine monophosphate (cyclic GMP) hydrolysis (amrinone not tested) by PDE I. Further, none of the cardiotonic drugs inhibited the calmodulin-stimulated cyclic AMP hydrolysis by PDE I, indicating their lack of calmodulin antagonist activity. These drugs also did not stimulate adenylate cyclase activity but all increased net cyclic AMP formation from ATP in guinea pig ventricular homogenates through inhibition of cyclic AMP breakdown. Amrinone, milrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, raised cyclic AMP levels significantly (P less than 0.05) in guinea pig ventricular slices. Also, amrinone, MDL 17,043 and RMI 82,249, but not AR-L 115BS, potentiated forskolin-induced cyclic AMP increase. These data taken together suggest that the specific inhibition of cyclic AMP PDE III isozyme and the consequent elevation of tissue cyclic AMP levels in cardiac tissue are an important mechanism of action of amrinone, milrinone, MDL 17,043 and RMI 82,249. Because AR-L 115BS did not increase cyclic AMP levels, it is likely that another mechanism may participate in the inotropic response to AR-L 115BS.
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PMID:Effects of several newer cardiotonic drugs on cardiac cyclic AMP metabolism. 242 28


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