Specific inhibition of a calcium dependent activation of brain cyclic AMP phosphodiesterase activity by vinblastine.

Vinblastine selectively inhibits the activation of brain cyclic AMP phosphodiesterase activity by Ca++-protein activator (50% inhibition by 2 x 10(-5) M). This inhibitory effect was reversed by excessive amounts of the activator, whereas large quantities of Ca++ caused only a slight suppression of the vinblastine effect. This result of vinblastine suggests a new site of its action and also suggests the possible role of protein activator, phosphodiesterase proteins or cyclic nucleotides in the previously known effects of vinblastine in vivo and in vitro.     

Lack of effect of neurotransmitters on cyclic AMP phosphodiesterase activity in an insect CNS

Summary The inhibition of cyclic nucleotide phosphodiesterase from the nerve cord ofManduca sexta was studied using theophylline as a model compound. 11 putative neurotransmitters had no effect on enzyme activity.Supported in part by NIH grant NS-09161-20 to R. W. Newburgh     

Flavonoid compounds are potent inhibitors of cyclic AMP phosphodiesterase

Summary The inhibitory activity of 19 flavonoid molecules on cyclic AMP breakdown by a commercial beef heart phosphodiesterase preparation is reported. 7 compounds are active in the micromolar range, 2 of which have a potency equivalent to that of papaverine. Some structure activity relationships are drawn.This investigation was partially supported by grants from the Centre National de la Recherche Scientifique (ATP 2315) and from the Institut National de la Santé et de la Recherche Médicale (CRL 75.1.188.5).     

Lack of effect of neurotransmitters on cyclic AMP phosphodiesterase activity in an insect CNS.

The inhibition of cyclic nucleotide phosphodiesterase from the nerve cord of Manduca sexta was studied using theophylline as a model compound. 11 putative neurotransmitters had no effect on enzyme activity.     

Possible regulation of membrane-associated cyclic AMP phosphodiesterase in rat cerebral cortex by lipids

Summary Cyclic AMP phosphodiesterase (PDE) in membrane fraction from rat cerebral cortex was activated by Triton X-100, and treatment at alkaline pH and with phospholipase C. These results suggest that membrane PDE exists in a latent form and is influenced by microenvironmental changes within the membrane. Furthermore, the PDE, unlike soluble enzyme, is not influenced by a protein activator and Ca⁺⁺.     

Flavonoid compounds are potent inhibitors of cyclic AMP phosphodiesterase.

The inhibitory activity of 19 flavonoid molecules on cyclic AMP breakdown by a commercial beef heart phosphodiesterase preparation is reported. 7 compounds are active in the micromolar range, 2 of which have a potency equivalent to that of papaverine. Some structure activity relationships are drawn.     

Hyperpolarization by cyclic AMP (activation of diphosphoinositide kinase)

Zusammenfassung In-vitro-und In-vivo-Versuche beweisen, dass ein molekulärer Mechanismus für das Zustandekommen der Membran-Hyperpolarisation verantwortlich ist.

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Presented in part at the Annual Meeting of the Biophysical Society, Toronto, Canada, February 1972.     

Possible regulation of membrane-associated cyclic AMP phosphodiesterase in rat cerebral cortex by lipids.

Cyclic AMP phosphodiesterase (PDE) in membrane fraction from rat cerebral cortex was activated by Triton X-100, and treatment at alkaline pH and with phospholipase C. These results suggest that membrane PDE exists in a latent form and is influenced by microenvironmental changes within the membrane. Furthermore, the PDE, unlike soluble enzyme, is not influenced by a protein activator and Ca++.     

Effects of several preoperative medications on fat cell lipolysis,and activity of adipose tissue cyclic AMP phosphodiesterase

Summary Effects were examined of atropine, diazepam, pethidene, promethazine, scopolamine, omnopon and papaverine on basal and noradrenaline-stimulated lipolysis in rat isolated fat cells and on rat adipose tissue cyclic AMP phosphodiesterase activity. Papaverine at high concentration (1 mM) inhibited both basal and hormone-stimulated lipolysis, whereas diazepam enhanced basal lipolysis. At a clinical dose, omnopon increased both basal and noradrenaline-stimulated lipolysis. Adipose tissue cAMP phosphodiesterase activity was strongly inhibited by 1 mM diazepam, papaverine, promethazine and omnopon (280 g ml^–1). Lack of enhancement of lipolysis by the established cAMP phosphodiesterase antagonist papaverine, is compartible with simultaneous inhibition also of adipose adenyl cyclase. Diazepam-stimulated lipolysis is compatible with its phosphodiesterase inhibitory activity. It is proposed that papaverine-containing omnopon may offer some survival advantages during surgical stress by facilitating a caloric supply.The authours are grateful to Dr D. C. Williams for his continued support and encouragement.     

Effects of several preoperative medications on fat cell lipolysis, and activity of adipose tissue cyclic AMP phosphodiesterase.

Effects were examined of atropine, diazepam, pethidene, promethazine, scopolamine, omnopon and papaverine on basal and noradrenaline-stimulated lipolysis in rat isolated fat cells and on rat adipose tissue cyclic AMP phosphodiesterase activity. Papaverine at high concentration (1 mM) inhibited both basal and hormone-stimulated lipolysis, whereas diazepam enhanced basal lipolysis. At a 'clinical dose', omnopon increased both basal and noradrenaline-stimulated lipolysis. Adipose tissue cAMP phosphodiesterase activity was strongly inhibited by 1 mM diazepam, papaverine, promethazine and omnopon (280 microgram ml-1). Lack of enhancement of lipolysis by the established cAMP phosphodiesterase antagonist papaverine, is compatible with simultaneous inhibition also of adipose adenyl cyclase. Diazepam-stimulated lipolysis is compatible with its phosphodiesterase inhibitory activity. It is proposed that papaverine-containing omnopon may offer some survival advantages during surgical stress by facilitating a caloric supply.     

Interconvertibility of molecular forms of 3'5' cyclic AMP phosphodiesterase of human platelets]

Three forms of cyclic AMP phosphodiesterase from human platelets are resolved upon sucrose gradient centrifugation : 2.5S (monomer), 4.8S (dimer) and 7S (tetramer). They are interconvertible and form an association-dissociation equilibrium depending on the concentration of enzyme. The dissociated form has a high Km for cyclic AMP (Km : 3-5.10(-4) M) whereas the associated form has a low Km (Km : 3-5.10(-5) M).     

Inhibition of cyclic 3′, 5′-nucleotide phosphodiesterase activity by diuretics and other agents

Résumé Différent composés organo-mercuriels ainsi que l'acide éthacrinique inhibent les phosphodiestérases de l'AMP cyclique, du cur de cobaye, de buf et de rat, des plaquettes de rat et de l'homme ainsi que du cerveau de rat.     

Effect of cyclic AMP and theophylline on phagocytotic activity ofTetrahymena pyriformis

Summary Dibutyril cAMP and the cPDE-inhibitor theophylline both enhance the phagocytotic activity ofTetrahymena. Theophylline and cAMP-activating histamine are synergistic. It follows that the cAMP-adenylcyclase system functions in the unicellular animalTetrahymena.     

Regional cyclic AMP levels in homogenates of rat brain after ketalar and trifluoperazine

Summary There was a significant fall in cAMP levels after administration of TFP or ketalar. Different amounts of cAMP were present in different regions of rat brain. Concentrations of cAMP in different regions of the rat brain were found to decrease in the following order: cerebrum > thalamus with hypothalamus > midbrain > hippocampus > cerebral cortex.Conducted under ocntract No 10.4.2 with the Polish Academy of Science.     

Regional cyclic AMP levels in homogenates of rat brain after ketalar and trifluoperazine

There was a significant fall in cAMP levels after administration of TFP or ketalar. Different amounts of cAMP were present in different regions of rat brain. Concentrations of cAMP in different regions of the rat brain were found to decrease in the following order: cerebrum > thalamus with hypothalamus > midbrain > hippocampus > cerebral cortex.     

Effect of vinblastine on pancreatic enzymes secretion induced by cyclic nucleotide derivatives

Summary Vinblastine did not affect the basal secretion of enzymes from the rat pancreas, but it potentiates the secretory response to dibutyryl cyclic AMP. This potentiation is confirmed by the observation of numerous pictures of exocytosis at the apical part of the acinar cell. Dibutyryl cyclic GMP by itself, or associated with vinblastine, failed to modify the spontaneous release of enzymes or the secretion induced by dibutyryl cyclic AMP.This work was supported by the Institut National de la Santé et de la Recherche Médicale (France).