Cyclic adenosine monophosphate phosphodiesterase

O Donnell, J.M. (1993) Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by differential reinforcement of low response rate. / Pharmacol Exp Tfcer 264(3) 1168-1178. 

Pennington (PI) and Uberti (U1) first introduced the technique of liquid chromatographic enzyme assays by using the ion-exchange mode of HPLC in their analyses of 3, 5 -cyclic adenosine monophosphate phosphodiesterase and adenosine deaminase, respectively. Since that time, a number of liquid chromatographic enzyme assays have been developed. 

Brattleboro homozygotes) had intact arginine vasopressin-dependent cyclic adenosine monophosphate generation. The activity of cyclic adenosine monophosphate phosphodiesterase was not affected in lithium-treated rats. Hence, it seems that the main cellular effect of lithium involves impairment of arginine vasopressin-sensitive adenylate cyclase and that this results in impairment of intracellular cyclic adenosine monophosphate formation. 

With the inhibitory activity against cyclic adenosine monophosphate phosphodiesterase as an index, in vitro bioassay of the activity of 21 canthin-6-one alkaloids was carried out. The strongest inhibitory activities were detected with 4, 17, and 27 among the compounds tested. The activities shown by 10, 28, and 34 were the same, twice as strong, and 15 times as strong, respectively, as the activity of papaverine, the control. Acetylation and methylation of the hydroxy derivatives of canthin-6-one decreased activity (108,109). 

Beer, B. et al. Cyclic adenosine monophosphate phosphodiesterase in brain Effect on anxiety. Science 1972, 176, 428-430. 

Nikaido, T., T. Ohrnoto, H. Saitoh, et al. 1982. Inhibitors of cyclic adenosine monophosphate phosphodiesterase in Polygala tenuifolia. Chem. Pharm. Bull. 30(6) 2020-2024. 

Adenylyl Cyclases Guanylyl Cyclases Transmembrane Signalling Cyclic Adenosine Monophosphate Cyclic Guanosine Monophosphate Cyclic Nucleotide-gated Channels Phosphodiesterases... 

Cyclic nucleotide phosphodiesterases (PDEs) are a class of enzymes that catalyze the hydrolysis of 3, 5 -cyclic guanosine monophosphate (cGMP) or 3, 5 -cyclic adenosine monophosphate (cAMP) to 5 -guanosine monophosphate (GMP) or 5 -adenosine monophosphate (AMP), respectively. 

Dipyridamole exerts its effect by inhibition of platelet phosphodiesterase E5, increasing cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). By inhibiting its uptake and metabolism by erythrocytes, dipyridamole also increases the availability of adenosine within blood vessels, promoting inhibition of platelet aggregation and local vasodilatation. " Dipyridamole may also inhibit cAMP phosphodiesterase in platelets, which further increases cAMP levels and may enhance endothelial nitric oxide production, contributing to its antithrombotic effect. Existing trials of dipyridamole in stroke have focused on secondary prevention and will be discussed briefly. 

The effect of receptor stimulation is thus to catalyze a reaction cycle. This leads to considerable amplification of the initial signal. For example, in the process of visual excitation, the photoisomerization of one rhodopsin molecule leads to the activation of approximately 500 to 1000 transdudn (Gt) molecules, each of which in turn catalyzes the hydrolysis of many hundreds of cyclic guanosine monophosphate (cGMP) molecules by phosphodiesterase. Amplification in the adenylate cyclase cascade is less but still substantial each ligand-bound P-adrenoceptor activates approximately 10 to 20 Gs molecules, each of which in turn catalyzes the production of hundreds of cyclic adenosine monophosphate (cAMP) molecules by adenylate cyclase. 

Theophylline and aminophylline may produce bronchodilation by inhibition of phosphodiesterase (thereby increasing cyclic adenosine monophosphate levels), inhibition of calcium ion influx into smooth muscle, prostaglandin antagonism, stimulation of endogenous catecholamines, adenosine receptor antagonism, and inhibition of release of mediators from mast cells and leukocytes. 

Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

The nucleotide cyclic AMP (3, 5 -cyclic adenosine monophosphate, cAMP) is a cyclic phosphate ester of particular biochemical significance. It is formed from the triester ATP by the action of the enzyme adenylate cyclase, via nucleophilic attack of the ribose 3 -hydroxyl onto the nearest P=0 group, displacing diphosphate as leaving group. It is subsequently inactivated by hydrolysis to 5 -AMP through the action of a phosphodiesterase enzyme. 

It is believed that theophylline can inhibit phosphodiesterase, which in turn can lead to elevated levels of cellular cyclic adenosine monophosphate, and subsequently, to the weakening of smooth musculature of the respiratory tract. However, theophylline is not a powerful phosphodiesterase inhibitor, and the necessary concentrations for this cannot be achieved in vivo. 

Action on the CNS depends directly on the dose of administered drug, and can be manifested as fatigue, anxiety, tremors, and even convulsions in relatively high doses. Theophylline acts on the cardiovascular system by displaying positive ionotropic and chronotropic effects on the heart, which, can likely be linked to the elevated influx of calcium ions by modulated cyclic adenosine monophosphate and its action on specific cardiac phosphodiesterases. In the gastrointestinal system, methylxanthines simultaneously stimulate secretion of both gastric juice and digestive enzymes. 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

Mechanism of Action A positive inotropic agent that inhibits myocardial cyclic adenosine monophosphate (cAMP) phosphodiesterase activity and directly stimulates... 

Mectianism of Action A cardiac inotropic agent that inhibits phosphodiesterase, which increases cyclic adenosine monophosphate and potentiates the delivery of calcium to myocardial contractile systems. Therapeutic Effect Relaxes vascular muscle, causing vasodilation. Increases cardiac output decreases pulmonary capillary wedge pressure and vascular resistance. 

A) Inhibition of platelet phosphodiesterases (PDEs) [91]. Quercetin and myricetin potentiated the anti-aggregatory action of prostacyclin (PGI2), a potent stimulator of platelet adenylate cyclase synthesised by the vascular endothelium, on ADP-induced platelet aggregation in washed human platelets, and the elevation of platelet cyclic adenosine monophosphate (cAMP) elicited by PGI2 [89,92,93]. These effects are probably due to an inhibition of PDEs. As suggested by Ferrell and co-workers [92], this inhibition arises from the similarity between the pyranone ring of flavonoids and the pyrimidine ring of adenine. 

A frequently cited mechanism of action for these agents is phosphodiesterase (PDE) inhibition and the associated antiplatelet effects that accompany increases in intracellular cyclic adenosine monophosphate (cAMP). In fact, the effects of these drugs go far beyond their direct effect on PDE inhibition or platelet function. This chapter discusses (/) cyclic nucleotides, PDE, and PDE inhibitors (if) the mechanisms of action of dipyridamole and cilostazol (Hi) drug issues and (iv) current clinical applications for dipyridamole and cilostazol, including recent clinical trials that may have changed our perception of the possible utility of these agents for percutaneous intervention. 

Mechanism of action The methylxanthines may act by several mechanisms, including translocation of extracellular calcium, increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) caused by inhibition of phosphodiesterase, and blockade of adenosine receptors. 

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