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At least 1,297 records · Page 72Linked to original sources
PubMed1990

Effects of a new 1,3-thiazole derivative ZSY-39 on force of contraction and cyclic AMP content in canine ventricular muscle.

A newly synthesized 1,3-thiazole derivative ZSY-39 increased the force of contraction in a concentration-dependent manner in association with elevation of tissue cyclic AMP levels in the isolated canine ventricular trabeculae electrically driven at 0.5 Hz at 37 degrees C. ZSY-39 shortened the duration of isometric contractions mainly by abbreviation of the relaxation time. The maximal response to and EC50 of ZSY-39 were 0.7 (isoproterenol = 1.0) and 4.6 x 10(-5) M. Bupranolol (3 x 10(-7) M) did not affect the positive inotropic effect of ZSY-39. The time course of increases in the force of contraction induced by ZSY-39 (10(-4) M) coincided with that of cyclic AMP accumulation. The concentration-response curve for the increase in the force of contraction produced by ZSY-39 was superimposable on that of the elevation of cyclic AMP levels. Carbachol (3 x 10(-6) M) shifted the concentration-response curve for the increase in force by ZSY-39 to the right and downward, and decreased the accumulation of cyclic AMP induced by ZSY-39 (10(-4) M). ZSY-39 (10(-5) M) enhanced significantly the positive inotropic effect of isoproterenol. The relationship between the force of contraction and cyclic AMP levels after the administration of ZSY-39 was not modified by the addition of carbachol or isoproterenol. These findings indicate that cyclic AMP plays an important role in the positive inotropic effect of ZSY-39 on canine ventricular muscle.

Animals↗
PubMedDate not supplied

Myocardial extraction of cyclic AMP during pacing-induced angina.

The application of cyclic AMP as a marker of myocardial ischemia in humans with coronary artery disease has been investigated during pacing-induced angina. Cyclic AMP was determined by a radioimmunoassay. In 15 patients myocardial lactate extraction at rest (20 +/- 12%) converted to production levels (-30 +/- 23%) during angina (p less than 0.0005). Insignificant changes occurred in coronary venous plasma cyclic-AMP levels. The mean myocardial cyclic-AMP extraction at rest (0.3 +/- 8.7%) converted to small release values (-6.0 +/-11%) during angina (= n.s.). No significant correlation was found between myocardial lactate and cyclic-AMP uptake or release. Therefore, cyclic AMP is an insensitive marker in the evaluation of myocardial ischemia.

Angina Pectoris↗
PubMed1984

Adriamycin inhibits PTH-mediated but not PGE2-mediated stimulation of cyclic AMP formation in isolated bone cells.

We have examined the effect of adriamycin, an anthracycline antibiotic which modifies plasma membrane functions, on the cyclic AMP response to PTH and PGE2 in isolated osteoblastlike cells. Adriamycin blunted the increment in bone cell cyclic AMP caused by exposure to PTH. This effect appeared rapidly (within 3 min after bone cells were exposed to adriamycin) and disappeared soon after exposure of adriamycin-treated cells to adriamycin-free incubation medium. Inhibition was evident over the entire time course of PTH action, at low as well as high PTH concentrations, and was one-half maximal at 31 microM adriamycin. It could not be attributed to alterations in cyclic AMP exodus, degradation or interference with the cyclic AMP assay, nor to impaired cell viability. Adriamycin also reduced the stimulatory effect of PTH on adenylate cyclase activity in a crude plasma membrane preparation. By contrast, adriamycin failed to modify the effects of PGE2 on cyclic AMP generation in intact bone cells, and on adenylate cyclase activity in broken cells. Moreover, concentrations of adriamycin that blunted the effect of PTH on adenylate cyclase activity did not inhibit the stimulatory effects of sodium fluoride or of GppNHp. These results suggest that adriamycin selectively alters the interaction between PTH and its receptor or impairs the transmission of information from hormone-receptor complex to adenylate cyclase (or both), perhaps by binding to specific lipid domains in the plasma membrane. Structural analogues of adriamycin, which vary in their lipophilic properties, also varied in their capacity to perturb the cyclic AMP response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMed1997

Increased cyclic AMP response to forskolin in Epstein-Barr virus-transformed human B-lymphocytes derived from schizophrenics.

Phorbol 12-myristate-13-acetate (PMA), a protein kinase C (PKC) activator, elevated basal cyclic AMP levels and enhanced isoproterenol-, prostaglandin E1- (PGE1), forskolin- and cholera toxin-stimulated cyclic AMP accumulation in Epstein-Barr virus (EBV)-transformed human B-lymphocytes. Staurosporine, a PKC inhibitor, significantly antagonized the increase in cyclic AMP accumulation produced by PMA, whereas the inactive phorbol ester, 4 alpha-phorbol 12,13-didecanoate (4 alpha PDD), had no effect. Basal levels of cyclic AMP and the accumulation of cyclic AMP produced by PMA, isoproterenol, PGE1, cholera toxin and the combination of these compounds with PMA were not significantly different between schizophrenics and controls. The cyclic AMP response to forskolin in the presence and absence of PMA was significantly greater in EBV-transformed human B-lymphocytes from schizophrenics. These results suggest that activation of adenylyl cyclase by forskolin is elevated in EBV-transformed B-lymphocytes derived from schizophrenics and that this elevation is further enhanced through a PKC-dependent phosphorylation mechanism.

Adult↗
PubMed1986

Cyclic AMP activation of a triglyceride lipase in broken cell preparations of rat heart.

The effect of CAM [cyclic AMP, Mg-ATP, and 3-isobutyl, 1-methylxanthine (MIX)] on triacylglycerol (TG) lipase activity in extracts from heparin-perfused rat heart was determined. TG lipase activity in homogenate, 10,000g supernatant, 105,000g supernatant, ammonium sulfate supernatant, and the eluate from heparin-Sepharose was increased between 62 and 151% when incubated with a combination of 0.3 mM cyclic AMP, 5 mM MgCl2, and 2 mM ATP. The addition of Mg-ATP + cyclic AMP caused a greater activation of TG lipase in the various fractions than did Mg-ATP + MIX or cyclic AMP + MIX. These results suggest that activation may be mediated by the classical cyclic AMP-protein kinase cascade. Control and CAM-stimulated activities were increased by heparin and inhibited by NaCl and protamine sulfate. In the absence of serum in the assay, the CAM system caused a relatively greater stimulation of lipolytic activity in each fraction compared to when serum was present in the assay. However, the absolute values were 6.1 to 16.3-fold greater with serum in the assay than without serum. In a similar manner, TG lipase activity was stimulated by CAM between 1.75 and 4.26-fold at pH 7.4, and only between 1.62 and 2.51-fold at pH 8.1. However, the absolute values at pH 8.1 were 6.77 to 31.83-fold greater than those seen at pH 7.4. These data demonstrate, for the first time, the cyclic AMP activation of a TG lipase above basal levels in cell-free fractions of rat heart. It is intriguing to speculate that the intracellular fraction of lipoprotein lipase may play a role in the hormonal regulation of cardiac TG lipolysis.

Animals↗
PubMed1979

Synaptic membrane proteins as substrates for cyclic AMP-stimulated protein phosphorylation in various regions of rat brain.

Synaptosomal plasma membranes from mammalian brain contain protein kinase activity which phosphorylates endogenous membrane proteins and is stimulated by cyclic AMP. Using polyacrylamide gel electrophoresis it was shown that at least ten proteins in the synaptosomal plasma membrane fraction could be phosphorylated by endogenous cyclic AMP-stimulated protein kinase activity. The number of proteins whose phosphorylation was stimulated by cyclic AMP was strongly influenced by the pH and Mg2+ concentration used in the phosphorylation reaction. A complex pattern of cyclic AMP-stimulated protein phosphorylation was obtained only with synaptosomal plasma membranes and a crude microsomal fraction. Mitochondrial and myelin fractions exhibited no cyclic AMP-stimulated protein kinase activity. Investigation of the distribution of substrates for cyclic AMP-stimulated phosphorylation among various brain regions failed to reveal any regional differences.

Animals↗
PubMed1981

Stimulation of alanine transport and metabolism by dibutyryl cyclic AMP in the hepatocytes from fed rats. Assessment of transport as a potential rate-limiting step for alanine metabolism.

(1) Cyclic AMP stimulated alanine transport in isolated hepatocytes by approx. 30%, in the range 0.2-5 mM alanine. (2) Alanine utilisation was also stimulated by cyclic AMP. The rates of transport and metabolism were comparable, both in the presence and absence of cyclic AMP. (3) At concentrations of alanine above 1 mM, addition of ouabain, or the reduction of the Na+ concentration, could partially inhibit transport without affecting the rate of metabolism. (4) At these alanine concentrations, stimulation of metabolism by cyclic AMP was associated with a decrease in the intracellular to extracellular alanine concentration ratio. (5) At alanine concentrations below 0.5 mM, or at higher concentrations when transport was inhibited by reducing the Na+ concentration, cyclic AMP caused an increase in the alanine concentration ratio. (6) It is concluded that at concentrations of alanine above 1 mM, alanine transport is not rate-limiting for alanine metabolism in hepatocytes from fed rats, and cyclic AMP stimulates alanine metabolism primarily by an effect on an intracellular reaction. At physiological concentrations of alanine, however, alanine transport appears to be rate-limiting in agreement with a previous report.

Alanine↗
PubMed1984

Involvement of cellular cyclic AMP in theophylline-induced sugar accumulation in chicken intestinal epithelial cells.

We have studied the possible involvement of cellular cyclic AMP in theophylline-induced sugar gradient enhancement in isolated chicken enterocytes. Theophylline increases 3-O-methylglucose accumulation 3-fold after 30 min incubation. Exogenous cyclic AMP enhances sugar accumulation by 48%. Adenylyl cyclase inhibitor RMI 12 330A reduces theophylline-induced sugar gradients by 22% and theophylline-induced cyclic AMP levels by 24.5%. At the concentration used, RMI 12 330A has no effect on 3-O-methylglucose accumulation or basal cellular cyclic AMP. Since theophylline has a rapid inhibitory effect on Na+-independent sugar permeability, we conclude that the effects of the drug on sugar gradients are the result of its acting by both direct - surface membrane - and indirect - cyclic AMP mediated - mechanisms. The effect of theophylline and exogenous cyclic AMP on sugar accumulation is independent of external chloride.

3-O-Methylglucose↗
PubMed1975

Isozymes of rat AMP deaminase.

Three AMP deaminase isozymes (EC 3.5.4.6 AMP aminohydrolase) were purified from rat heart, kidney and muscle. These enzyme preparations contained only the required isozyme. Antisera to individual isozymes were prepared and immunological relationships were tested. There was no cross-reactivity as tested by precipitation experiments. The antisera precipitated only the corresponding isozyme and there was no effect on other isozymes. These isozymes were also different in Km values for AMP and in substrate specificity. From the present studies, combined with previous results, it seems clear that the heart, kidney and muscle enzymes are different basic types. It is proposed that the muscle enzyme be designated as AMP deaminase A; the enzyme in kidney and liver, AMP deaminase B; the enzyme in heart, AMP deaminase C. Brain extracts contained five isozymes; two parent isozymes (B and C) and presumably their three hybrids.

AMP Deaminase↗
PubMed1978

Effects of various ligands on interaction of AMP deaminase with myosin.

Purified rat muscle AMP deaminase (AMP aminohydrolase, EC 3.5.4.6) binds tightly to rat myosin. The binding is abolished in the presence of low concentrations of various ligands. Pyrophosphate and GTP at concentrations as low as 0.1 micrometer were effective in abolishing the interaction between two proteins. Other nucleoside triphosphates were less effective than GTP and the concentrations required for 50% inhibition were approximately 0.3 to 0.7 micrometer. ADP and AMP are effective in inhibiting the interaction between two proteins, but they are less effective than the nucleoside triphosphates; 50% inhibition occurred at 34 micrometer with ADP and at 1 mM with AMP. Creatine phosphate and inorganic phosphate showed 50% inhibition at 5 to 6 mM. All of the compounds, which affected AMP deaminase activity, were effective in abolishing the interaction of the enzyme with myosin; however, the interaction-abolishing effects of the compounds are not parallel with their inhibitory effects on the deaminase activity. Although there exist three parental isozymes of AMP deaminase in the rat, all three enzymes interacted with myosin.

AMP Deaminase↗
PubMed1979

Cyclic nucleotide binding properties and molecular forms of the cyclic-AMP-dependent protein kinase from bovine eye lens.

The activity of the cyclic-AMP-dependent protein kinase found in the crude extract of bovine eye lens cortical fibers was increased by 10(-6) M cyclic AMP or 10(-5) M cyclic GMP to the same extent, However, the interaction between cyclic AMP and cyclic GMP in the course of binding to the cyclic-AMP-dependent protein kinase did not seem to be competitive. Scatchard analysis of cyclic GMP binding by the crude extract indicated the presence of two type of cyclic GMP binding sites (Kd1 about 2 . (10(-7) M, Kd2 about 5 . 10(-6) M). Different species of cyclic nucleotide binding fractions were separated by Sephadex G-200 gel chromatography of the crude extract. The bulk of the low affinity cyclic GMP binding activity was found in the exclusion volume. The cyclic-AMP-dependent protein kinase eluted in two fraction (apparent molecular weight 300 000 and 150 000) and both protein kinase fractions were accompanied by the high affinity cyclic GMP binding activity. However, the ratios of this activity to the cyclic AMP binding activity were different in the two fraction, suggesting that different molecular weight forms of the holoenzyme had different cyclic nucleotide binding properties.

Animals↗
PubMed1981

Interaction of AMP deaminase with RNA.

tRNA, 18 S and 28 S ribosomal RNAs were found to activate muscle AMP deaminase (AMP aminohydrolase, EC 3.5.4.6) but inhibit liver and heart AMP deaminases. The macromolecular structures are essential for modulation of enzyme activity, since the effects of RNA disappeared after RNAase treatment. Sucrose density centrifugation experiments clearly demonstrated the binding of purified muscle AMP deaminase to tRNA, 18 S and 28 S RNAs. The binding is reversible and responsive to alterations of pH and KCl concentration. The binding was stable at pH 5.1-7.0 in 0.1 M KCl, but most of the enzyme dissociated at pH 7.5. KCl below 0.1 M concentration had no effect on dissociation of enzyme-RNA complex, but in 0.15 M KCl the complex was partially dissociated and in 0.2 M KCl most of the enzyme was released. Various nucleotides were also effective in dissociation of the enzyme from complex. The binding is saturable and the maximum number of muscle AMP deaminase molecules bound per mol 28 S RNA was calculated to be approx. 30. Liver and heart AMP deaminases were also found to interact with RNA.

AMP Deaminase↗
PubMed1984

Opposing actions of methylxanthines and dibutyryl cyclic AMP on 1,25 dihydroxyvitamin D3 production and calcium fluxes in isolated chick renal tubules.

In contrast to dibutyryl cyclic AMP, the methylxanthine phosphodiesterase inhibitors theophylline and caffeine were found to inhibit the conversion of 25 hydroxyvitamin D3 to 1,25 dihydroxyvitamin D3 in isolated renal tubules from vitamin D deficient chicks. This inhibition occurred at concentrations of methylxanthines which were shown to increase renal tubule cyclic AMP levels. No effect of theophylline or caffeine on 25 hydroxyvitamin D3 metabolism in isolated chick renal mitochondria was detected. Because of a demonstrated inhibitory action of calcium (10 and 20 mumol/l) on renal mitochondrial conversion of 25 hydroxyvitamin D3 to 1,25 dihydroxyvitamin D3, the effect of theophylline and dibutyryl cyclic AMP on cellular calcium-45 efflux and total renal tubule calcium content was estimated. Theophylline 10 mmol/l was found to inhibit renal tubular calcium efflux and to increase total cellular calcium content, while dibutyryl cyclic AMP 1 mmol/l had the reverse effect on both parameters. Divergent actions of the methylxanthines and dibutyryl cyclic AMP on the formation of 1,25 dihydroxyvitamin D3 and renal tubule calcium efflux and content support the hypothesis that intracellular calcium is an important regulator of renal vitamin D metabolism. The results indicate that observed actions of methylxanthines cannot always be ascribed to cyclic AMP accumulation.

Animals↗
PubMed1984

Modulation of renal ATPase activities by cyclic AMP.

A possible link between cellular cyclic AMP content and Na+K+ATPase activity was investigated in homogenates of rat kidney. Enzyme kinetics of Mg2+ and Na+K+ATPase were run in the presence of cyclic AMP, dibutyryl cAMP and compounds expected to elevate cyclic AMP levels such as forskolin, a potent adenylate cyclase activator, IBMX, an inhibitor of phosphodiesterases, and the beta-agonist isoproterenol. Medullary Na+K+ATPase is strongly inhibited by cyclic AMP whereas cortical Na+K+ATPase was stimulated in the same conditions. The correlation between ATPase activity and cellular cyclic AMP content supports the concept of a possible regulation of the enzyme by cyclic AMP.

1-Methyl-3-isobutylxanthine↗
PubMed1987

Direct evidence for the modulation of human platelet cytosolic free Ca2+ by intracellular cyclic AMP produced with a photoactivatable derivative.

We have previously reported that intraplatelet "cyclic AMP jumps" produced with newly synthesized photoactivatable cyclic AMP analogue, inhibited washed rat platelet aggregation and serotonin release as induced by thrombin. Using the same approach on human platelets, thrombin-induced platelet aggregation was dose-dependently inhibited only when a flash was delivered. The mechanism of action of intraplatelet cyclic AMP as resulting from photolysis could be by controlling the level of cytosolic Ca2+. In order to test this hypothesis, the same protocol was used on human platelets preloaded with the internal Ca2+ fluorescent indicator, Quin 2, we found that the extent and the rate of the rise of the cytosolic Ca2+ induced by thrombin were dramatically decreased, in the presence of the photoactivatable cyclic AMP, only following photoirradiation. In addition, the flashes were produced, in the presence of photoactivatable cyclic AMP, after the thrombin-induced rise of internal Ca2+ had reached its peak. In these conditions, photoirradiation caused a rapid fall in fluorescence. These experiments provide the first direct evidence that intracellular cyclic AMP is involved in the control of platelet cytosolic Ca2+ by inhibition of its mobilization and by stimulation of its sequestration.

Aminoquinolines↗
PubMed1988

Regulation of lactate/pyruvate ratios by cyclic AMP in Neurospora crassa.

Cyclic AMP is thought to have a general role in stimulating the breakdown of carbohydrate reserves and subsequent glycolytic activity. This would be expected to increase the availability of reducing equivalents in the form of cytoplasmic NADH. The current study examines another potential reaction controlling cytoplasmic NADH in the fungus Neurospora crassa, that of lactate dehydrogenase, to determine whether it is also regulated by cyclic AMP. The cr-1, adenylate cyclase and cyclic AMP-deficient mutant, grown with and without exogenous cyclic AMP was compared with an isogenic wild type. The results show that cyclic AMP raises pyruvic acid pools and lowers both lactic acid pools and lactate/pyruvate ratios. It does that, in part or in whole, by lowering lactate dehydrogenase activity. The possibility that cytoplasmic NAD+/NADH is a major target of cyclic AMP control is discussed. The high performance liquid chromatography procedures used in these studies are applicable to the measurement of intracellular pools of tricarboxylic acid cycle and other organic acids.

Adenylyl Cyclases↗
PubMed1983

Differential role of microtubules in the control of prostaglandin E2 and beta-adrenergic stimulation of cyclic AMP accumulation in the rat myometrium.

A possible modulatory role of microtubules was investigated for the beta-adrenergic and prostaglandin E2 (PGE2)-induced cyclic AMP accumulation in the estrogen-treated rat myometrium. Colchicine, vinblastine and nocodazole, three different antitubulin drugs, enhanced cyclic AMP accumulation caused by PGE2. The effect of inhibitors was dose-(0.1-5 microM) and time-dependent, increased maximal responses without changing EC50 for PGE2, did not occur with trimethyl-colchicinic acid, which does not bind to tubulin, and was totally prevented in tissues pretreated with taxol, an agent that enhances polymerization and stabilization of microtubules. Concomitantly, colchicine reduced the rate and extent of PGE2-induced refractoriness in terms of cyclic AMP. In contrast, the antitubulin drugs failed to affect the rise in cyclic AMP evoked by isoproterenol and cholera toxin but enhanced the response to prostacyclin (PGI2), which is assumed to share common receptors with PGE2. Colchicine and vinblastine also failed to alter the ability of the beta-adrenergic agonist to provoke a cyclic AMP refractory state. Stimulations induced by all effectors were totally insensitive to cytochalasin B. The data suggest a relation between the constraints associated with the microtubules and/or membrane tubulin of the myometrium and the efficacy of PGE2 and PGI2 (but not the beta-adrenergic agonist or cholera toxin) to interact with the cyclic AMP forming system.

1-Methyl-3-isobutylxanthine↗
PubMed1983

Effects of forskolin on bone. Stimulation of cyclic AMP accumulation and calcium efflux from chick embryo tibiae in organ culture.

Forskolin (FSK), an activator of adenylate cyclase in many tissues, was investigated to determine its potential for studying cyclic AMP-mediated, physiological events in bone. Tibiae from 14-day chick embryos were cultured in modified Eagle's medium for up to 8 hr, and the cyclic AMP and Ca2+ efflux responses to parathyroid hormone (PTH) and FSK were observed. FSK caused a concentration-related increase in tissue cyclic AMP, with 10(-6) M FSK producing a cyclic AMP response of similar magnitude to that elicited by 10(-6) M PTH (1-34). However, while 10(-6) M PTH was the maximally-activating PTH concentration, a further elevation was produced by 10(-5) M FSK. Chick embryo tibiae cultured for 8 hr in the presence of PTH exhibited a concentration-related stimulation of Ca2+ efflux up to 10(-6) M PTH. When this physiological effect was examined in bones cultured in the presence of FSK, a biphasic response to increasing FSK concentrations was found; Ca2+ efflux was stimulated by 10(-6) M and 3 X 10(-6) M FSK, but not by 10(-7) M or 10(-5) M FSK. In summary, concentrations of FSK, which produced tissue cyclic AMP accumulation similar to that produced by physiologically effective PTH concentrations, also resulted in net Ca2+ efflux from bone. These results indicate that FSK may be a useful agent for studying the role of cyclic AMP in the response of bone to hormones.

Animals↗