PDEs

Reoxidation occurs when the metallic iron in hot DRI reacts with oxygen in the air to form either Ee O or Ee202. The reaction continues as long as the DRI remains hot and sufficient oxygen is avadable. Because reoxidation reactions are exothermic and DRI is a good insulator, it is possible that once reoxidation begins inside a pde, the DRI temperature increases and accelerates the reoxidation rate. Although the inner core of the pde may reach temperatures up to the fusion point of iron, the maximum temperature of the outer parts of the pde will be much lower because of heat dissipation. 

Allowing DRI to become wet does not necessatily cause it to overheat. When large pdes of DRI are wetted with rain, the corrosion reactions are limited to the outer surface area of the pde and the resultant heat from the corrosion reactions is dissipated into the atmosphere. However, if water penetrates into the pde from the bottom, or if wet DRI is covered with dry DRI, the heat from corrosion reactions can budd up inside the pde to the point where rapid reoxidation begins. Corrosion occurs significantly faster with salt water than with fresh water. DRI saturated with water can cause steam explosions if it is batch charged into an electric arc furnace. 

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

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... 

CDP840 is a selective inhibitor of the PDE-IV isoenzyme and interest in the compound arises from its potential application as an antiasthmatic agent. Chemists at Merck Co. used the asymmetric epoxidation reaction to set the stereochemistry of the carbon framework and subsequently removed the newly established C-O bonds." Epoxidation of the trisubstituted olefin 51 provided the desired epoxide in 89% ee and in 58% yield. Reduction of both C-O bonds was then accomplished to provide CDP840. 

Arylimino-2,3,6,7-tetrahydro- (00MIP19) and 2-aryloxy-6,7-dihydro-4//-pyrimido[6,1-a]isoquinolin-4-ones (00MIP20) were patented as PDE inhibitors and as useful agents for treatment of respiratory disorders, respectively. 

Other methods for solving PDE s include Monte Carlo, spectral, and variational. Spectral methods in particular converge more rapidly than finite difference methods, but do not handle problems involving irregular geometries or discontinuities well. 

LGs can also serve as powerful alternatives to PDEs themselves in modeling physical systems. The distinction is an important one. It must be remembered, however, that not all PDEs (and perhaps not all physical systems see chapter 12) are amenable to a LG simulation. Moreover, even if a candidate PDE is selected for simulation by a LG. there is no currently known cookbook recipe allowing a researcher to go from the PDE to a LG description (or vice versa). Nonetheless, by their very nature, LGs lend themselves to modeling any partial differential equation (PDE) for which the underlying physical basis for its construction involves a large number of particles with local interactions [wolf86c]. 

FIGURE 9.13 Cardiovascular responses to the PDE inhibitor fenoximone in different contexts, (a) In vivo effects of fenoximone in anesthetized dogs. Ordinates reflect positive inotropy. Redrawn from [47]. (b) In vitro effects of fenoximone in guinea pig untreated isolated left atria (filled circles) and atria in the presence of sub threshold P-adrenoceptor stimulation with prenalterol (open circles). Redrawn from [48]. 

The tethering of PKA through AKAPs by itself is not sufficient to compartmentalize and control a cAMP/ PKA-dependent pathway. Cyclic AMP readily diffuses throughout the cell. Therefore, discrete cAMP/PKA signalling compartments are only conceivable if this diffusion is limited. Phosphodiesterases (PDE) establish gradients of cAMP by local hydrolysis of the... 

Inhaled NO has been used for treatment of persistent pulmonary hypertension of newborn infants, critical respiratory failure of preterm infants, and acute hypertension of adult cardiac surgery patients. PDE-5 inhibitors such as sildenafil are also effective for treatment of pulmonary hypertension. The combination of PDE-5 and NO inhalation yields additive beneficial effects on pulmonary hemodynamics. On the other hand, measurement of exhaled NO is a noninvasive and reproducible test that is a surrogate measure of airway inflammation in patients with bronchial asthma. 

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. 

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

PDE Family Genes Probable splice variants Regulatory domains/role Phosphorylation Substrate (s) Commonly used inhibitors... 

PDE 10 10A 2 GAF/activation Unknown cAMP, cGMP None identified... 

PDE1C2 and PDE4A are expressed. PDE1C2 is found in the cilia of the epithelium, where it colocalizes with adenylyl cyclase. PDE4A is found throughout the epithelial layer, but not in cilia. Therefore, as in the kidney mesangial cells, different PDEs must be working on different cyclic nucleotide pools. More recently, substantial data has been developed for compartmenta-tion of cAMP and PDEs in cardiac myocytes. 

Beyond Viagra, there are a number of other PDE inhibitors that are used clinically. In fact, the classic drugs papaverine and dipyridamole were used clinically before their effects on PDEs were known. Caffeine and theophylline (a compound found in tea) are also PDE inhibitors. However, all of these drugs most likely have multiple targets, making conclusions regarding the roles of PDEs in processes that are sensitive to these agents difficult to interpret. Certainly, some of their effects are due to their actions on adenosine receptors. 

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