CAMP phosphodiesterase inhibition

Most of the isoquinoline quinones described above have antibacterial activity (Table 3) and moderate levels of cytotoxicity (Table 1) have been reported. Other bioactivity reported for mimosamycin and 7-amino-7-demethoxymimosamycin (89) are aldose reductase inhibition, 34.6% at 10 pmol dm 3, and cAMP phosphodiesterase inhibition, 26.3% at 100 pmol dm 3, respectively (71). 

Inhibition of rat ADP-induced platelet aggregation. It might be through cAMP-phosphodiesterase inhibition. ... 

The 0-sulfate of minoxidil has been proposed as an important active metabolite. Unlike minoxidil, 3 is active in vitro and is more potent with a faster onset of action vivo. Evidence suggests the dlhydro-pyrano and dihydrofuranocoumarin vasodilators (e.g. 34) exert their effect by cAMP phosphodiesterase inhibition. Finally, the plvalic acid ester of isoxsuprine has a slower onset and longer duration of action than the parent phenol. ... 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Methylxanthines have relaxing and anti-inflammatory effects. Accumulation of intracellular cAMP by inhibition of PDE3 (phosphodiesterase-3) relaxes airway... 

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. 

Intracellular messengers A biphasic effect of ginkgo extract is seen on cAMP phosphodiesterase under in vitro and ex vivo conditions (Saponara and Bosisio 1998 Macovschi et al. 1987). Whereas low concentrations (0.25-4.0 mg/L) activate the enzyme, higher concentrations (5-250 mg/L), dose-dependently inhibit it. However, tolerance develops to this effect because it is undetectable after daily administration for 4 days. Thus, ginkgo may initially produce effects by inhibiting enzymatic breakdown of cAMP. This mechanism is similar to the stimulant caffeine, but it is not likely to explain any long-term effects of ginkgo because it disappears after chronic daily treatment. The responsible constituent for this effect has not been identified. 

Saponara R, Bosisio E. (1998). Inhibition of cAMP-phosphodiesterase by biflavones of Ginkgo biloba in rat adipose tissue. J Nat Prod. 61(11) 1386-87. 

The inotropic effects of these agents are not mediated via direct stimulation of -adrenergic receptors or indirectly by release of catecholamines, but by selective inhibition of cardiac cAMP phosphodiesterase (PDE) type III [25,35-40]. Recently, it has been demonstrated that the imidazole core is primarily responsible for PDE isozyme specificity, whereas the dihydropyri-dazinone moiety is responsible for inhibitory potency the phenylene moiety obviously acts mainly as a spacer [26]. A five-point model for positive inotropic activity of PDE III inhibitors has been elaborated [41]. 

In contrast to glucagon, the peptide hormone insulin (see p. 76) increases glycogen synthesis and inhibits glycogen breakdown. Via several intermediates, it inhibits protein kinase GSK-3 (bottom right for details, see p. 388) and thereby prevents inactivation of glycogen synthase. In addition, insulin reduces the cAMP level by activating cAMP phosphodiesterase (PDE). 

Cilostazol is a selective cAMP phosphodiesterase inhibitor. It inhibits platelet aggregation and is a direct arterial vasodilator. It is used for the symptoms of intermittent claudication in individuals with peripheral vascular disease. Side-effects of cilostazol include headache, diarrhea, increased heart rate, and palpitations. Drugs similar to cilostazol have increased the risk of death in patients with congestive heart failure. 

A) Inhibition of cAMP phosphodiesterase in monocytic lineage leukocytes... 

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

Hydrolysis of cAMP cAMP is rapidly hydrolyzed to 5-AMP by cAMP phosphodiesterase, one of a family of enzymes that cleave the cyclic 3 5 -phosphodiester bond. 5-AMP is not an intracellular signalling molecule. Thus, the effects of neurotransmitter- or hormone-mediated increases of cAMP are rapidly terminated if the extracellular signal is removed. [Note Phosphodiesterase is inhibited by methylxanthine derivatives, such as theophylline and caffeine.3]... 

Theophylline is found in coffee and in tea in very small amounts, but it has a stronger effect on the heart and breathing than does CF. Along with CF, TP is used as a medicine to treat emphysema and bronchitis (254,255). Caffeine and TP inhibit cAMP phosphodiesterase. In their presence the effects of cAMP, and thus the stimulatory effects of the hormones that lead to its production, are prolonged and intensified. 

Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cyclic adenosine monophos-phate (cAMP) phosphodiesterases (12CE421)... 

Carboline-l-propionic acid Inhibition of cAMP phosphodiesterase 357... 

Forskolin stimulates die catalytic subunit of adenylyl cyclase directly, bypassing the G proteins, which makes forskolin a much used substance in experiments with elevated platelet cAMP-levels. A number of agents has been demonstrated to inhibit the cAMP phosphodiesterases in platelets, e.g. papaverine, dipyridamole and the methylxantines... 

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