Phosphodiesterases cyclic nucleotide PDEs

Phosphodiesterases. Table 1 Characteristics of the individual Class 1 cyclic nucleotide PDE families... 

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. 

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. 

Indolidan has been shown to be a potent highly selective inhibitor of cyclic nucleotide phosphodiesterase (PDE) located in the sarcoplasmic reticulum [80], being bound more avidly by PDE III than cAMP (Ai = 80 nM)... 

The actions of cAMP are terminated by phosphodiesterases (PDEs) that catalyze the breakdown of cAMP to 5 -AMP (Diunan and Nestler 1999). There are at least 11 different forms of PDEs that are characterized based on their affinity and selectivity for cAMP, as well as cGMP. In addition, the PDEs are differentially regulated by the cyclic nucleotides themselves, by phosphorylation, and by increased expression of certain splice variants (e.g., some isoforms are... 

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. 

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. 

PKG and cyclic nucleotide phosphodiesterases (PDEs) (reviewed by Baxter37). A rapid release of natriuretic peptides and induction of their de novo synthesis occurs in myocardial ischemia. Natriuretic peptides may have a cardioprotective role. BNP-32 administration in perfused rat hearts prior to left main coronary artery occlusion and until 30 min of reperfusion resulted in limitation of infarct size in a concentration dependent manner. Furthermore, this effect was abolished by 5-hydroxydecanoate (presumed to be a selective blocker of mitochondrial KATp channels), L-NAME, an inhibitor of NOS and ODQ, a specific soluble guanyl cyclase inhibitor.38 Similarly, human recombinant ANP limited infarct size and reperfusion arrhythmias in a canine model of coronary occlusion and reperfusion.39... 

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