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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscarinic cholinergic agonists such as acetylcholine attenuate phosphorylation of phospholamban induced by agents that activate cAMP-dependent protein kinase. However, cAMP accumulation is variably affected or only slightly reduced; thus, the choline ester might produce effects in addition to inhibition of adenylate cyclase. We hypothesized that acetylcholine might regulate a phosphatase in mammalina myocardium. Exposure of Langendoff-perfused guinea pig ventricles to isoproterenol (10 nM) for 45 s increased phosphatase inhibitor-1 activity 2-fold. Co-administration of acetylcholine (100 nM) antagonized the effect of isoproterenol, and atropine (1 microM) blocked the effect of acetylcholine. Forskolin (1 microM) caused a 3-fold increase in inhibitor-1 activity, and acetylcholine markedly attenuated the effect of forskolin. However, acetylcholine did not lower cAMP levels in the same tissues. Both isoproterenol and forskolin reduced the type 1 phosphatase activity intrinsic to sarcoplasmic reticulum by 25-50%, using [32P]phosphorylase a or 32P-labeled membrane vesicles as a substrate for the phosphatase. Co-administration of acetylcholine markedly attenuated these effects of isoproterenol and forskolin. Acetylcholine alone caused a 50% increase in type 1 phosphatase activity. We concluded that inhibitor-1 and type 1 phosphatase can be regulated in intact cardiac muscle by agents that increase intracellular cAMP and by acetylcholine.
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PMID:Autonomic regulation of type 1 protein phosphatase in cardiac muscle. 253 94

Reversible congestive heart failure can accompany cardiac allograft rejection and inflammatory myocarditis, conditions associated with an immune cell infiltrate of the myocardium. To determine whether immune cell secretory products alter cardiac muscle metabolism without cytotoxicity, we cultured cardiac myocytes in the presence of culture supernatants from activated immune cells. We observed that these culture supernatants inhibit beta-adrenergic agonist-mediated increases in cultured cardiac myocyte contractility and intracellular cAMP accumulation. The myocyte contractile response to increased extracellular Ca2+ concentration is unaltered by prior exposure to these culture supernatants, as is the increase in myocyte intracellular cAMP concentration in response to stimulation with forskolin, a direct adenyl cyclase activator. Inhibition occurs in the absence of alteration in beta-adrenergic receptor density or ligand binding affinity. Suppressive activity is attributable to the macrophage-derived cytokines interleukin 1 and tumor necrosis factor. Thus, these observations describe a role for defined cytokines in regulating the hormonal responsiveness and function of contractile cells. The effects of interleukin 1 and tumor necrosis factor on intracellular cAMP accumulation may be a model for immune modulation of other cellular functions dependent upon cyclic nucleotide metabolism. The uncoupling of agonist-occupied receptors from adenyl cyclase suggests that beta-receptor or guanine nucleotide binding protein function is altered by the direct or indirect action of cytokines on cardiac muscle cells.
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PMID:Interleukin 1 and tumor necrosis factor inhibit cardiac myocyte beta-adrenergic responsiveness. 254 46

Acute fluoride intoxication increases intracellular calcium (Cai), manifested by increased twitch tension in cardiac muscle, and by potassium efflux (mediated by Ca2+-dependent K+ channels) in fluoridated erythrocytes. Fluoride, like isoproterenol, stimulates adenylate cyclase, and could increase Cai via the effects of cAMP on Ca2+ channels. However, while the inotropic effects of fluoride mimicked isoproterenol in rat atria, their effects on the time course of isometric contraction were quite different. In addition, acetylcholine negated isoproterenol's effect on twitch tension but did not modulate the effects of fluoride. Further, the Ca2+ channel antagonist verapamil had no effect on fluoride-stimulated K+ efflux from erythrocytes. Fluoride also inhibits Na+-K+ ATPase, and increases intracellular Na+, so could increase Cai via Na+-Ca2+ exchange. Lanthanum, which blocks Na+-Ca2+ exchange, blocks fluoride-induced K+ efflux in erythrocytes. We conclude that the effects of fluoride on adenylate cyclase are not important in intact tissue, and that inhibition of Na+-K+ ATPase and subsequent Na2+-Ca2+ exchange may be the mechanism of increased Cai in acute fluoride toxicity.
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PMID:Sodium fluoride produces a K+ efflux by increasing intracellular Ca2+ through Na+-Ca2+ exchange. 282 87

In mammalian cardiac muscle, muscarinic and adenosine receptors serve as inhibitory physiological modulators of myocardial functions. Dual inhibitory regulation of myocardial function via stimulation of these receptors is established through cyclic AMP-dependent and cyclic AMP-independent subcellular processes. The inhibitory signals triggered by agonist binding to the respective receptors are transmitted to the subsequent biochemical, electrophysiological and functional changes through activation of the GTP-binding proteins, Ni and/or N0, which couple the signal at binding sites to the catalytic subunit of adenylate cyclase in the actions mediated through the cyclic AMP-dependent mechanism, or to potassium channels in those mediated by cyclic AMP-independent processes preferentially exerted in atrial and SA nodal cells. The functional role of polyphosphoinositide breakdown promoted by muscarinic receptor activation in myocardium has not been elucidated. IAP (islet-activating protein, pertussis toxin) is capable of uncoupling the receptor stimulation to activation of Ni and/or N0, thus resulting in the inhibition of negative inotropic and chronotropic responses to muscarinic receptor agonists, and to adenosine and its derivatives such as N6-phenylisopropyladenosine and N6-methyladenosine. Both the cyclic AMP-dependent and cyclic AMP-independent inhibitory mechanisms are susceptible to IAP.
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PMID:[Adenosine and muscarinic receptors in regulation of myocardial contractility: dual mechanism of inhibitory action]. 289 52

Ventricular and atrial cardiac muscle cells isolated from the adult rat have been cultured and characterized. Once established in culture these myocytes resemble morphologically their in vivo counterparts except that they are flattened on the surface of the culture flask. These cultured cells possess differentiated ultrastructural characteristics including sarcomerically arranged myofilaments, appropriately organized sarcoplasmic reticulum, intercalated discs and a highly organized transverse tubular system. These cells regain the capacity to carry out semiconservative DNA replication; this capacity had previously been thought to have permanently been lost during early neonatal development. Other studies have shown that cultured ventricular myocytes resemble metabolically the in vivo and isolated perfused rat heart and that they possess an adenylate cyclase system which responds appropriately to adrenergic stimulation. These cells also appear electrophysiologically to resemble the intact adult heart. Long-term culture of adult cardiac muscle cells provides a new and unique system which can be used to study the structure and function of the adult mammalian ventricular and atrial cardiac myocyte.
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PMID:Long-term culture and characterization of the adult ventricular and atrial cardiac muscle cell. 299 30

A cardiac muscle sarcolemmal preparation, enriched in adenylate cyclase, Na+, K+ -ATPase, beta, muscarinic and ouabain receptors, also contained endogenous protein kinase activity. Phosphorylation of sarcolemmal membrane proteins by the endogenous protein kinase occurred mainly on 22 000 and 12 000 Mr proteins. To determine the effect of this phosphorylation on sarcolemmal properties, sarcolemmal vesicles were preincubated under conditions for optimal phosphorylation while control vesicles were preincubated under identical conditions but in the absence of ATP to avoid phosphorylation. Both control and phosphorylated vesicles were centrifuged, resuspended in 10 mM Tris-Cl (pH 7.4) and subsequently assayed for ATPase activities and for binding of ouabain, dihydroalprenolol and quinuclidinyl benzilate to the membranes. Sarcolemmal phosphorylation was associated with an increase in Ca2+ -ATPase activity but had no effect on Mg2+ ATPase or Na+, K+ -ATPase activity or on ouabain binding. Muscarinic receptor and beta-adrenoreceptor binding also appeared to be unaffected.
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PMID:Influence of protein kinase phosphorylation on isolated sarcolemmal membranes. 300 20

CI-914 is a novel positive inotropic agent whose cardiotonic activity is not due to inhibition of Na+, K+-ATPase or to stimulation of cardiac beta-receptors. CI-914 also has no direct effect on sarcoplasmic reticulum, mitochondria or adenylate cyclase activity. CI-914 does, however, exert a potent inhibitory effect on cardiac phosphodiesterase activity. In evaluating the effect of this agent on the different molecular forms of phosphodiesterase present in cardiac muscle, CI-914 was found to selectively inhibit PDE III, which is a low Km, cAMP-specific form of the enzyme (IC50 = 6.1 microM). This inhibitory effect was found to be competitive with respect to the substrate. Papaverine and theophylline on the other hand were found to inhibit all three forms of phosphodiesterase present in cardiac muscle. The role of phosphodiesterase inhibition in mediating the positive inotropic response to CI-914 is supported by the finding that this agent: (i) significantly elevates cyclic AMP levels in ventricular tissue; (ii) shifts the normal concentration-response to the beta-receptor stimulant isoproterenol to the left: and (iii) restores contractility to K+-depolarized papillary muscles.
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PMID:Studies aimed at elucidating the mechanism of action of CI-914, a new cardiotonic agent. 300 93

Berberine has been shown to increase developed tension in cardiac muscle but its derivatives have been reported to inhibit the catalytic subunit of adenylate cyclase. In the present study, the cardiac actions of the most potent derivative, 13-propylberberine, were examined. It produced a transient increase followed by a sustained decrease in developed tension in paced left atrial muscle preparations isolated from guinea-pig heart. In the presence of 13-propylberberine, isoproterenol caused only a transient increase in developed tension; marked desensitization to the positive inotropic effect of isoproterenol occurred within 20 min. After washout of isoproterenol and an additional 15-min incubation in the presence of 13-propylberberine, the muscle lost its sensitivity to isoproterenol. Moreover, the positive inotropic effect of ouabain or effects of decrease or increase in extracellular Ca2+ concentration on the force of muscle contraction were markedly attenuated. Isoproterenol-induced elevation of tissue cyclic AMP concentration was inhibited by 13-propylberberine; however, 13-propylberberine did not alter the basal cyclic AMP concentration and its effects on inotropic actions of ouabain or extracellular Ca2+ appear unrelated to tissue cyclic AMP concentration.
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PMID:13-Propylberberine reduces response of guinea-pig myocardium to inotropic interventions including changes in extracellular Ca2+. 302 86

Effects of the new selectively beta 1-adrenergic cardiotonic drug denopamine (TA-064), (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, on the adenylate cyclase-adenosine-3',5'-monophosphate (c-AMP) system of various tissues and cells in rats and guinea pigs were investigated in comparison with those of isoproterenol. Denopamine at concentrations above 10(-6) M stimulated lipolysis in vitro, and, above 10(-5) M, elevated the c-AMP level in isolated rat fat cells. The c-AMP level of guinea-pig heart ventricular muscle was also elevated when the heart was perfused with 3 X 10(-6) M denopamine or when slices of ventricular muscle were incubated with 10(-6) M denopamine. These changes were abolished in the presence of beta-adrenergic antagonists. Incubation with denopamine did not cause substantial elevation of c-AMP levels in rat reticulocytes and diaphragm. Denopamine activated adenylate cyclase of the rat cell membranes in a concentration-dependent manner. Although dose dependence was less apparent, denopamine also activated adenylate cyclase of the membrane fraction from guinea pig cardiac muscle, but it hardly activated the same enzyme from rat reticulocytes. Isoproterenol, on the other hand, showed marked concentration-dependent activation of adenylate cyclase in all these preparations. Denopamine did not inhibit c-AMP phosphodiesterase of both particulate and supernatant fractions of guinea-pig cardiac muscle. The stimulation of lipolysis by denopamine was observed even when elevation of the c-AMP level was not detected, while the stimulation of lipolysis by isoproterenol was always accompanied with an elevation of c-AMP. When guinea-pig hearts were perfused with 3 X 10(-6) M denopamine or 10(-7) M isoproterenol, their cardiotonic effects were of the same magnitude whereas the degree of c-AMP elevation in the ventricular tissue by denopamine was significantly less than that by isoproterenol. It was concluded that stimulation of the adenylate cyclase-c-AMP system by denopamine was restricted to the tissues whose receptors were predominantly of the beta 1-type, and that the elevation of c-AMP levels in these tissues by denopamine was less marked than by isoproterenol, suggesting that the stimulation of lipolysis and heart by denopamine may be mediated by a special pool of c-AMP or some other unknown factor(s).
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PMID:Beta 1-adrenergic selectivity of the new cardiotonic agent denopamine in its stimulating effects on adenylate cyclase. 303 56

Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na+ conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C.
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PMID:Pertussis toxin-insensitive phosphoinositide hydrolysis, membrane depolarization, and positive inotropic effect of carbachol in chick atria. 304 Feb 95


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