Phosphodiesterases, properties

In addition, vinpocetine selectively inhibits a specific calcium, calmodulin-dependent cycHc nucleotide phosphodiesterase (PDF) isozyme (16). As a result of this inhibition, cycHc guanosine 5 -monophosphate (GMP) levels increase. Relaxation of smooth muscle seems to be dependent on the activation of cychc GMP-dependent protein kinase (17), thus this property may account for the vasodilator activity of vinpocetine. A review of the pharmacology of vinpocetine is available (18). 

Theophylline is also considered an alternative to inhaled corticosteroids for the treatment of mild persistent asthma however, limited efficacy compared to inhaled corticosteroids, a narrow therapeutic index with life-threatening toxicity, and multiple clinically important drug interactions have severely limited its use. Theophylline causes bronchodilation through inhibition of phosphodiesterase and antagonism of adenosine and appears to have anti-inflammatory and immunomodulatory properties as well.36... 

TABLE 21-1 Classification and selected properties of cyclic nucleotide phosphodiesterases... 

Swinne, J., Tsikalas, K. E. and Contim, M. Properties and hormonal regulation of two structurally related cAMP phosphodiesterases from the rat Sertoli cell. /. Biol. Chem. 266 18370-18377,1991. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

These compounds competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP (see Box 14.3) and subsequent release of adrenaline. This leads to the major effects a stimulation of the central nervous system (CNS), a relaxation of bronchial smooth muscle, and induction of diuresis. These effects vary in the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine. 

Theophylline, a dimethylxanthine, causes broncho-dilation, possibly by inhibiting the enzyme phosphodiesterase in smooth muscle of the bronchioli. An other proposed mechanism of action is that of adenosine receptor antagonism. It has positive chronotropic and inotropic, CNS stimulant and weak diuretic properties. In obstructive lung disease sustained release tablets are to be preferred. Theophy-line has a narrow therapeutic index. Therapeutic plasma concentrations are between 7-15 mg/1. Theophylline undergoes N-demethylation via CYPl A2 in the liver and is eliminated in the urine as metabolites... 

Digoxin remains the mainstay of treatment for patients with chronic myocardial failure. Other drugs with inotropic and/or vasodilator properties, including the catecholamines and phosphodiesterase III (PDE) inhibitors, are used in the treatment of acute cardiac failure. The inotropic actions of most of these drugs result from a direct or indirect elevation of [Ca2-i-]i (intracellular Ca2+ concentration). This acts as a trigger for a process which leads to increased contractile state and cardiac contraction (Figures 8.3 and 8.4). Myofilament calcium sensitisers increase the sensitivity of contractile proteins to calcium. Some newer drugs, such as vesnarinone, have multiple mechanisms of action. 

Apart from important similarities in the endo- and exonucleolytic properties of staphylococcal nuclease and other well-studied phosphodiesterases (67), those from snake venom and spleen, the basic structural substrate elements for these enzymes appear to be quite different... 

The conclusion of Bernardi and Griffe (3) that the phosphodiesterase activity of acid DNase is an intrinsic property of the enzyme molecule has been recently challenged by Slor (46, 58), Swenson and Hodes (54), and Slor and Hodes (55), who claimed to have obtained a separation of the two activities. In fact, none of the reported results proves an actual separation of the two activities and constitutes an acceptable evidence against the two activities being carried by the same protein molecule. Some data suggest, however, that the phosphodiesterase activity may be inactivated preferentially by some treatments. In connection with the phosphodiesterase activity of acid DNase, see also Tables I and II in reference (56) and the related discussion (56a). 

The second messenger molecules Ca2+ and cyclic AMP (cAMP) provide major routes for controlling cellular functions. In many instances, calcium (Ca2+) achieves its intracellular effects by binding to the receptor protein calmodulin. Calmodulin has the ability to associate with and modulate different proteins in a Ca2+-dependent and reversible manner. Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE, EC 3.1.4.17) is one of the key enzymes involved in the complex interactions that occur between the cyclic-nucleotide and Ca2+ second messenger systems (see Figure 13.2). CaMPDE exists in different isozymic forms, which exhibit distinct molecular and catalytic properties. The differential expression and regulation of individual phosphodiesterase (PDE) isoenzymes in different tissues relates to their function in the body. 

The effect of FTIs on retinal function also needs to be carefully examined. Several proteins involved in retinal signal transduction are farnesylated in vivo, presumably by FTase. These include rod cell cGMP phosphodiesterase a-subunit,108,109 rod cell transducin y-subunit,110,111 and rhodopsin kinase.112 Since the retina consists of terminally differentiated, nondividing cells, the anti-proliferative properties of FTIs should be inconsequential. Visual function could possibly be affected by alterations in the prenylation of proteins involved in retinal signal transduction, although any changes of this sort should be reversible. 

Today 11 members of the human PDE superfamily are known, all of which are class I phosphodiesterases and all of which are intracellular or membrane-bound enzymes. Several of the isoenzymes are encoded by more than one gene which, in combination with the presence of different splice variants, brings the number of different PDE proteins to well over 50. The different isoenzymes are characterized according to their substrate specificity, sequence homology, kinetic properties, and sensitivity to certain known PDE inhibitors. Table 9.1 shows these properties together with the predominant tissue expression of the various PDEs. 

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