Inhibition of phosphodiesterases

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... 

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... 

Three major mechanisms of action have dominated as possible explanations for the ergogenic potential of caffeine in the enhancement of exercise performance. These three mechanisms involve (1) the mobilization of intracellular calcium from the sarcoplasmic reticulum of skeletal muscle, (2) the increase of cyclic-3 ,5 -adenosine monophosphate (cAMP) by the inhibition of phosphodiesterases in muscles and adipocytes, and (3) the competitive antagonism of adenosine receptors, primarily in the central nervous system (CNS).8 9... 

Theophylline and aminophylline may produce bronchodilation by inhibition of phosphodiesterase (thereby increasing cyclic adenosine monophosphate levels), inhibition of calcium ion influx into smooth muscle, prostaglandin antagonism, stimulation of endogenous catecholamines, adenosine receptor antagonism, and inhibition of release of mediators from mast cells and leukocytes. 

Other mechanisms A few other effects of hypericin, and a crude hypericum extract have been found, including affinity for NMDA, inositol triphosphate, and adenosine receptors. However, these are not likely to be significant to its therapeutic effects because concentrations required for these interactions are not likely to be achieved by oral administration (Cott 1997). Vasoactive effects are possible because hypericum extracts blocked the vasoconstricting effects of histamine and prostaglandin F2o in porcine coronary arteries, and some vasorelaxation occurs in one particular fraction. These effects are hypothesized to be mediated by inhibition of phosphodiesterase (Melzer et al. 1991). 

From this series, compound MCI-154 (CAS 98326-33-1) (30) has been investigated in detail [95,96]. In vivo studies (anaesthetized dogs) revealed that doses of 0.3-100 tg/kg (i.v. administration) of MCI-154 produce dose-dependent increases in dF/dtmax and cardiac output, and decreases in arterial blood pressure and total peripheral resistance. The positive inotropic effect of (30) has been found to be superior to that exhibited by amrinone and milrinone [97,98]. It has been stated that MCI-154 exerts its activity probably by increasing the calcium-ion sensitivity of the contractile protein system of the cardiac skinned fibres [99,100]. A recent investigation suggests that inhibition of phosphodiesterase III is an important component of its cardiotonic activity [101]. 

Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum. They also have an important vasodilating effect. Inhibition of phosphodiesterase results in an increase in cAMP and the increase in contractility and vasodilation. 

The methylxanthines have positive chronotropic and inotropic effects. At low concentrations, these effects appear to result from inhibition of presynaptic adenosine receptors in sympathetic nerves increasing catecholamine release at nerve endings. The higher concentrations (more than 10 i mol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (more than 100 mol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired. 

In horizontal cells of turtle and fish retinae, a dopamine-induced increase in intracellular cAMP levels is associated with cellular uncoupling [DeVries and Schwartz, 1989 McMahon et al., 1989] (the connexin isoform involved is not identified). Inhibition of phosphodiesterase with IBMX after stimulation of adenylate cyclase using forskolin resulted in an increase in intracellular... 

Similar to a P-adrenoceptor stimulation intracellular cAMP can be increased by inhibition of phosphodiesterase. Thus, in turtle retina cells, cAMP leads to uncoupling and this can be mimicked by stimulation of adenylate cyclase with forskolin and concomitant inhibition of phosphodiesterase by IBMX [Piccolino et al., 1984]. In cardiac cells inhibition of phosphodiesterase has been investigated using methylxanthine derivates [De Mello, 1989], resulting in an enhancement of intercellular coupling. 

The approved drugs for erectile dysfunction (ED) all share the same mode of action, which is inhibition of phosphodiesterase type 5 (PDE5). PDE5 hydrolyzes the phosphodi-ester of cyclic GMP (cGMP). Elevated levels of cGMP relax the muscle tissue that lines the blood vessels of the corpus cavernosum in the penis. Blood freely enters the tissue,... 

Dipyridamole exerts its antiplatelet action by several mechanisms [7]. One of these is through the inhibition of phosphodiesterase enzyme in platelets, resulting in an increase in intraplatelet cyclic AMP and the consequent potentiation of the platelet inhibiting actions of prostacyclin. Another is the direct stimulation of the release of this eicosanoid by vascular endothelium, and the third is the inhibition of cellular uptake and metabolism of adenosine (thereby increasing its concentration at the platelet vascular interface). 

Mechanism of action The methylxanthines may act by several mechanisms, including translocation of extracellular calcium, increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) caused by inhibition of phosphodiesterase, and blockade of adenosine receptors. 

Calcium, via calmodulin, also activates cyclic AMP phosphodiesterases which inactivate cyclic AMP by metabolism to AMP. Inhibition of phosphodiesterase yields a small increase in ACTH-stimulated steroidogenesis [2], This is relatively slight in the adrenocortical zona fasciculata-reticularis cell, which has a low phosphodiesterase level the zona glomerulosa cell has a higher activity [60,61], which may result from higher level of activation of the calcium/calmodulin intracellular messenger system in the zona glomerulosa. 

Inhibition of phosphodiesterase, causing elevation of intracellular platelet cyclicAMP and a consequent reduction in calcium inhibitions this platelet activation and granule releases... 

THEOPHYLLINE PHOSPHODIESTERASE INHIBITORS-ENOXIMONE Theophylline may i efficacy of enoximone Possibly competitive inhibition of phosphodiesterases Be aware watch for poor response to enoximone... 

Figure 11.14. Stracture of sildenafil (Viagra ), and sketch of its mechanism of action Inhibition of phosphodiesterase increases cGMP levels.

Like other G-proteins, transducin has innate GTPase activity, and over a time course of seconds or less is autocatalytically converted to transducin-GDP, which does not interact with phosphodiesterase. This restores the normal inhibition of phosphodiesterase, permitting cGMP concentrations to rise again, reopening the sodium channels and restoring the dark current. 

Methylxanthines inhibit phosphodiesterase in many tissues, and theophylline is about six times as potent as caffeine [6]. The potentiation of drug effects by methylxanthines has often been interpreted as accumulation of cyclic AMP, but methylxanthines also promote the accumulation of cyclic GMP [37]. Methylxanthines also inhibit adenylate cyclase activity in some tissues, as, for example, the noradrenaline-stimulated adenylate cyclase activity in rat erythrocyte ghosts [38], the vasopressin-stimulated adenylate cyclase activity in toad bladder epithelium [39], the increase in cyclic AMP produced in brain slices by depolarising stimuli and by adenosine [40], and the adenylate cyclase activity in guinea-pig lung particles [41]. Both basal and glucagon-stimulated phosphorylase activity in rat liver slices are inhibited by theophylline [42]. However, methylxanthines also have pharmacological effects which are not related to inhibition of phosphodiesterase [43]. 

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-... 

Mode of action. Caffeine and theophylline have complex and incompletely elucidated actions, which include inhibition of phosphodiesterase (the enzyme that breaks down cyclic AMP, see p. 191), effects on intracellular calcium distribution, and noradrenergic function. When theophylline (as aminophylline) is used alongside salbutamol in asthma its action adds up to increased benefit to the bronchi, but increased risk to the heart. 

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