PDEs, phosphodiesterases methylxanthines

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. 

Theophylline, a methylxanthine, relaxes bronchial muscle, although its precise mode of action is still debated. Inhibition of phosphodiesterase (PDE), especially its type 4 isoform now seems the most likely explanation for its bronchodilator and more recently reported anti-inflammatory effects. Blockade of adenosine receptors is probably unimportant. Other actions of theophylline include chronotropic and inotropic effects on the heart and a direct effect on the rate of urine production (diuresis). 

The enzyme phosphodiesterase (PDE) (Chapter 5), degrades c-AMP to inactive AMP (Eq. 9.6B). Inhibitors of this enzyme also have the effect of raising c-AMP levels and therefore should act synergistically with p-agonists and other hormones utilizing this secondary messenger. Methylxanthines such as theophylline and caffeine are weak PDE inhibitors. Theophylline is orally effective in relieving bronchoconstriction and is frequently used in the treatment of asthma and emphysema. 

B. Mechanism of Action The methylxanthines inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP (Figure 20-3), and thus increase cAMP. This anti-PDF effect, however, requires high concentrations of the drug. Methylxanthines also block adenosine receptors in the CNS and elsewhere, but a relationship between this action and the bronchodilat-ing effect has not been clearly established. It is possible that bronchodilation is caused by a third tis yet unrecognized action. 

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