Cyclic nucleotide phosphodiesterase inhibition

The stimulation of the octopaminergic nervous system of invertebrates is a proven strategy for the control of important pest species. This has been achieved in the past by the use of octopamine receptor agonists such as formamidine and imidazoline derivatives. However, other potential strategies to achieve this end include the inhibition of cyclic nucleotide phosphodiesterase, inhibition of the neural reuptake of octopamine, and inhibition of octopamine N-acetyltransferase. Using the American cockroach nervous system, formamidines were found to inhibit both the uptake and acetylation of octopamine, but not with a potency comparable to their effect on octopamine receptors. The tricyclic antidepressant, desipramine, and the benzylamine, xylamine, were the most active inhibitors of these octopamine removal systems. The pharmacological profiles for uptake and N-acetylation appear to be quite similar, but differ from that of the adenylate cyclase-linked octopamine receptor. 

Orallo, F., Camifla, M., Alvarez, E., Basaran, H., and Lugnier, C. 2005. Implication of cyclic nucleotide phosphodiesterase inhibition inthe vasorelaxant activity of the Citrus-fruits flavonoid (-)-naringenin ,7 la/ifaMe[Pg.479]

There are several mechanisms involved in the vasodilator effect of flavonoids. The main mechanism seems to be related to the inhibition of protein kinase C or some of the processes activated by this protein. The inhibition of other protein kinases and cyclic nucleotide phosphodiesterase activity and blockage of calcium entry can also contribute to this effect to a greater or lesser extent (Alvarez Castro and Orallo, 2003 Herrera and others 1996). Certain flavonoids, like the flavonol myricetin, have a two-phase action on blood vessels vasoconstrictor in lowest active concentrations and vasodilator in higher concentrations (Alvarez Castro and Orallo, 2003). 

Because of its ability to bind CaM, tamoxifen can increase cyclic AMP surges by inhibiting cyclic AMP hydrolysis by the Ca2+-calmodulin-dependent cyclic nucleotide phosphodiesterase (Fanidi et al. 1989 Rowlands et al. 1990). In bovine brain preparations, tamoxifen appears to act as a competitive inhibitor of calmodulin-activated phosphodiesterase with an IC50 of 2 p,M, similar to the value reported for trifluoperazine under the same experimental conditions (Lam 1984). 

GTP-bound a-subunit activates a cGMP-specific phosphodiesterase as described briefly earlier. A benzophenone derivative of cGMP was prepared and found to inhibit several types of cyclic nucleotide phosphodiesterases at low concentrations. In rod outer segment preparations, the [a-32P]-tagged probe... 

Inhibition of cyclic nucleotide phosphodiesterases is widely accepted as the predominant mechanism by which theophylline produces bronchodilation. Phosphodiesterases are enzymes that inactivate cAMP and cyclic guanosine monophosphate (GMP), second messengers that mediate bronchial smooth muscle relaxation. 

When the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMP-stimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5 -AMP by several cyclic nucleotide phosphodiesterases (PDE Figure 2-13). Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20). 

Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family (Figure 20-3). Because the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cyclic AMP (cAMP) and, in some tissues, cGMP. CAMP is responsible for a myriad of cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells. 

Picq M, Dubois M, Prigent AF, Nemoz G, Pacheco H. 1989. Inhibition of the different cyclic nucleotide phosphodiesterase isoforms separated from rat brain by flavonoid compounds. Biochem Int 18 47-57. 

Dopamine activates adenylate cyclase and phospholipase C (PLC) via a D, receptor and inhibits through a D2 receptor, thereby regulating the production of intracellular second messengers, cAMP, Ca2+, and 1,2-diacylglycerol. D, and D2 receptors are decreased in the striatum of patients with dementia. There is considerable evidence to suggest that intracellular levels of cAMP have a protective role for dopaminergic neurons. Intracellular concentrations of cyclic nucleotides are regulated by cyclic nucleotide phosphodiesterases and CaMPDE, one of the most intensely studied and best-characterized phosphodiesterases. 

Dipyridamole (Persantine) is a vasodilator that, in combination with warfarin, inhibits embolization from prosthetic heart valves and, in combination with aspirin, reduces thrombosis in patients with thrombotic diseases. Dipyridamole by itself has little or no benefit in fact, in trials where a regimen of dipyridamole plus aspirin was compared with aspirin alone, dipyridamole provided no additional beneficial effect. Dipyridamole interferes with platelet function by increasing the cellular concentration of adenosine 3, 5 -monophosphate (cyclic AMP). This effect is mediated by inhibition of cyclic nucleotide phosphodiesterase and by blockade of uptake of adenosine, which acts at A2 receptors for adenosine to stimulate platelet adenylyl cyclase. The only current recommended use of dipyridamole is for primary prophylaxis of thromboemboli in patients with prosthetic heart valves the drug is given in combination with warfarin. 

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

Since cyclic AMP derivatives and inhibitors of cyclic nucleotide phosphodiesterase stimulate prolactin release (17, 37, 38) and dopamine is a potent inhibitor of prolactin secretion (1, ly 39), it is not surprising that the catecholamine does not stimulate the adenylate cyclase system. On the contrary, the data summarized above show that the pituitary DA receptor is negatively coupled to adenylate cyclase. The pituitary DA receptor is thus a typical DA -receptor (40, 41). In view of the multiplicity of factors involved in the control of prolactin secretion, including sex steroids, it is likely that mechanisms other than cyclic AMP are involved (39, 42). It does however appear that inhibition of cyclic AMP formation by dopamine is a key element in a multifactorial control system responsible for the fine tuning of prolactin secretion. 

The above-described data show that CRF added to cells of the rat Intermediate lobe In culture causes a rapid stimulation of oe-MSH release and cyclic AMP accumulation, thus demonstrating a direct action of the peptide on pars intermedia cells (15). It is however difficult, using intact cells, to dissociate between increases in cyclic AMP levels due to stimulation of adenylate cyclase activity or to Inhibition of cyclic nucleotide phosphodiesterase or to a combination of both effects. Definitive proof of the role of adenylate cyclase In the action of CRF In the intermediate lobe of the pituitary gland is provided by the following findings of a CRF-lnduced stimulation of adenylate cyclase activity in homogenate of rat and bovine pars Intermedia cells. 

The regulatory role of calcium ions in intermediary metabolism is well documented. Calcium has been shown to be involved in activation or inhibition of specific enzyme systems [105], For example, it activates cyclic nucleotide phosphodiesterase, phosphofructokinase, fructose 1 6 biphosphatase, glycerol phosphate dehydrogenase, pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase. Calcium ions inhibit pyruvate kinase, pyruvate carboxylase, Na+/K+-AT-Pase and adenylate cyclase. 

Lugnier, C, Schoeffler, P, Bee, AL, Strouthou, E, Stoclet, JC, Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta., Bioc/iem. P/iarmaco/., 1986,35 1743-1751. 

A major factor complicating the quantitative interpretation of most adenylate cyclase measurements is contamination by other enzymes including ATPase, inorganic pyrophosphatase, cyclic nucleotide phosphodiesterase, and various deaminases. Some degree of inhibition of phosphodiesterase is necessary in most preparations, and a methylxan-... 

Theophylline, available under many proprietary names, relaxes bronchial smooth muscles to relieve or prevent asthma. The therapeutic effect of theophyUine is likely due to antagonism of adenosine receptors in smooth muscle, whereas the toxic effects are due to inhibition of cyclic nucleotide phosphodiesterase. With increased use of p-adrenergic agonists, and because of the considerable toxicity associated with it, theophylline is now considered... 

Hagmann, J. Inhibition of calmodulin-stimulated cyclic nucleotide phosphodiesterase by the insecticide... 

Four examples of structurally characterised, vanadate-inhibited phosphorylation enzymes working on the hydrolysis of phospho-ester bonds in nucleotides I, the vanadate-uridine complex of bovine pancreatic ribonuclease-A II, the vanadate complex of ribonuclease-Tj from the fungus Aspergillus oryzae-. III, the vanadate-uridine complex of cyclic nucleotide phosphodiesterase from the cruciferous plant Arabidopsis thaliana-, IV, human tyrosyl-DNA phosphodiesterase (Ur = uridine). 

Podzuweit T, Nennstiel P, Muller A (1995) Isozyme selective inhibition of cGMP-stimulated cyclic nucleotide phosphodiesterases by erythro-9-(2-hydroxy-3-nonyl) adenine. Cell Signal 7 733-738... 

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