Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the use of cardiac glycosides for heart failure therapy is limited by their narrow margin of safety, numerous efforts have been made to find and develop novel cardiotonic agents that are superior to the cardiotonic glycosides. Positive inotropic drugs acting on beta-adrenoceptors and inhibitors of cAMP phosphodiesterase have been extensively studied for the treatment of patients with heart failure. The main mechanism of these agents is elevation of cAMP tissue levels. Furthermore, Ca sensitizers such as sulmazol, pimobendan, MCI-154, END 53998 and DPI 201-106 are of interest, since such a mechanism of action may be beneficial for the failing heart. Recently, cardiotonic substances with a novel mechanism of action such as gingerol and xestoquinone have been isolated from natural sources. Natural products, purealin, goniodomin and okadaic acid, have proven to be valuable pharmacological tools for studies on cardiac muscle contraction.
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PMID:[Novel types of cardiotonic drugs]. 139 36

The inotropic actions of various drugs known to increase force of contraction in isolated mammalian cardiac muscle were investigated in electrically driven (1 Hz) guinea-pig left atria under both normal [K+]o (4.7 mM) and high [K+]o (22 mM). Under normal [K+]o a concentration-dependent increase in force of contraction could be confirmed with the beta-adrenoceptor agonist, isoprenaline, the cyclase activator, forskolin, the inhibitors of the cyclic AMP-phosphodiesterase (PDE), amrinone, IBMX, and OPC 8212, the Na+ channel activators, DPI 201-106, SDZ 210-921, veratridine, and ATX II, the Na(+)-ionophore monensin, the inhibitor of Na+/K(+)-ATPase, ouabain, and the Ca2+ channel activators, Bay K 8644, CGP 28 H 392, and SDZ 202-791. Partial depolarization of the muscle preparations by increasing [K+]o in the organ bath to 22 mM completely abolished the positive inotropic action of the Na+ channel-activating drugs. In contrast, the effects of the other compounds were still present, although changes in the maximal force development were observed. The efficacy of the PDE inhibitors amrinone and IBMX were slightly increased; the maximal effects of isoprenaline, monensin, forskolin, and OPC 8212 were unchanged; the effect of ouabain decreased to about half maximal values; while the efficacy of the Ca2+ channel activators were either unchanged (CGP 28 392) or decreased (Bay K 8644 and SDZ 202-791). The results suggest that inactivation of cardiac fast Na+ channels by partially depolarizing isolated, electrically driven atria is a suitable model to distinguish between cardiotonic agents acting through activation of Na+ channels and those with other mechanisms of action.
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PMID:Identification of cardiotonic sodium channel activators by potassium depolarization in isolated guinea-pig atria. 170 Feb 27

In heart failure, an increase in the activity of the sympathetic nervous system takes place to maintain perfusion pressure to vital organs, resulting in increased levels of noradrenaline in the blood of these patients. This permanent stimulation produces a down-regulation of cardiac beta-adrenoceptors. Since noradrenaline acts primarily on the cardiac beta 1-adrenoceptor subtype, beta 1-adrenoceptors decrease in number, whereas the beta 2-adrenoceptor subpopulation remains unchanged in most instances. Consequently, the positive inotropic response to beta-adrenoceptor agonists is diminished. However, there is also a decrease in the positive inotropic effect of beta 2-adrenoceptor agonists, histamine and cAMP-phosphodiesterase inhibitors such as milrinone, whereas the positive inotropic effect of cAMP-independent Na(+)-channel activators such as DPI 206-106 and the effects of cardiac glycosides are not diminished. These observations suggest a more generalised alteration of the cAMP-adenylate cyclase system in the failing heart. Stimulatory guanine nucleotide-binding protein (Gs) couples receptors to adenylate cyclase that stimulate cAMP formation, such as beta-adrenoceptors, histamine receptors and glucagon receptors. In the failing human heart, Gs content has been reported to remain unchanged as compared with that in non-failing myocardium. However, there is a 35%-40% increase in inhibitory guanine nucleotide-binding proteins (Gi), which are involved in the receptor-mediated inhibition of adenylate cyclase. Taken together, two defects of the cAMP-adenylate cyclase system have been identified: an increase in Gi content and a decrease in the number of beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Alterations of the cAMP-adenylate cyclase system in the failing human heart. Consequences for the therapy with inotropic drugs]. 197 43

Intracellular Ca2+ release and reuptake are necessary for normal contraction and relaxation of the human heart. Intracellular Ca2+ transients were recorded with aequorin during isometric contraction of myocardium from patients with end-stage heart failure. In contrast to controls, contractions and Ca2+ transients of muscles from failing hearts were markedly prolonged, and the Ca2+ transients exhibited two distinct components. Muscles from the failing hearts showed a diminished capacity to restore a low resting Ca2+ level during diastole. These data obtained in actively contracting human myocardium suggest that intracellular Ca2+ handling is abnormal and might cause both systolic and diastolic dysfunction in heart failure. The inotropic effectiveness of drugs that act to increase intracellular levels of cyclic adenosine monophosphate (AMP), such as beta-adrenergic agonists and phosphodiesterase inhibitors, was markedly reduced in muscles from patients with heart failure. In contrast, the effectiveness of inotropic stimulation with drugs that act by cyclic AMP-independent mechanisms, such as the cardiotonic steroids and DPI 201-106, were preserved. Stimulation of intracellular cyclic AMP production by the adenylate cyclase activator forskolin restored the inotropic response to phosphodiesterase inhibitors. These studies indicate that an abnormality in cyclic AMP production may be a fundamental defect in patients with end-stage heart failure that may markedly diminish the effectiveness of agents that depend on generation of this nucleotide for a positive inotropic effect. Moreover, deficient production of cyclic AMP seems, at least in part, to account for the reversal of the force-frequency relation that characterizes failing myocardium. Of interest, direct measurement of total cellular cyclic AMP content and protein kinase activity did not reveal significant differences between the control and myopathic tissue, suggesting the presence in human ventricular muscle of physiologically distinct compartmentalized pools of cyclic AMP. Finally, changes in the sensitivity of the contractile apparatus to Ca2+ also seem to play an important role in the differential responsiveness to drugs of myopathic versus normal human myocardium.
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PMID:Abnormal intracellular calcium handling, a major cause of systolic and diastolic dysfunction in ventricular myocardium from patients with heart failure. 215 79

Intense efforts during the last decade to identify a useful positive inotropic agent to replace digitalis for the treatment of congestive heart failure have led to the discovery of several dozen potential substitutes, of which a number are currently undergoing clinical trials. In addition to producing a variety of new therapeutic entities, research in this area has also yielded valuable new information regarding the fundamental events that regulate calcium homeostasis and contractile function in the cardiac cell. For example, several of these new inotropic agents, including the calcium-channel stimulator BAY-k 8644, the sodium-channel stimulator DPI-201-186, and the sodium-calcium exchange inhibitor dichlorobenzamil, have provided considerable insight into the role of sodium and calcium in regulating contractility and the molecular events that mediate potential-dependent ion channels. Likewise, the discovery and development of agents like imazodan, amrinone, enoximone, and other selective type III phosphodiesterase inhibitors have provided new information regarding multiple molecular forms of cyclic nucleotide phosphodiesterase, compartmentation of cyclic AMP, and the importance of soluble vs. membrane-bound phosphodiesterases.
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PMID:New mechanisms for positive inotropic agents: focus on the discovery and development of imazodan. 248 22

This review deals with the principal mechanisms which are known to play a role in positive inotropism: 1) The myoplasmic Ca2+ concentration may be increased by increases in cyclic AMP. Beside receptor-mediated stimulation (isoprenaline) or direct stimulation (forskolin) of the adenylate cyclase, the cyclic AMP may be increased by phosphodiesterase inhibition; 2) Cyclic AMP-independent activation of Ca2+ channels can be brought about by alpha-adrenergic agents (phenylephrine) or so-called calcium agonists; 3) Only a small increase in myoplasmic Na+ concentration can greatly enhance the force of contraction by an increase in the intracellular Ca2+ concentration. This is possible by inhibition of the Na+/K+-ATPase (glycosides) or by prolongation of the open state of Na+ channels (DPI 201-106); 4) A direct inhibition of the Na+/Ca2+ exchange has been discussed for amiloride; 5) A prolongation of the action potential induced by K+ channel-inhibiting agents such as 4-amino-pyridine may increase the myoplasmic Ca2+ concentration by a prolongation of the slow Ca2+ inward current; 6) An increased Ca2+ sensitivity of the contractile proteins has been demonstrated for a number of compounds in vitro; the contribution of such an effect to the overall positive inotropism is unknown because a calcium sensitizer without any effects on calcium or sodium movements is not yet available.
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PMID:Mechanisms of positive inotropic effects. 255 73

Phosphomonoesterase and diesterase that cleave phosphatidylinositol-4-phosphate (diphosphoinositide, DPI) and phosphatidylinositol-4,5-bisphosphate (triphosphoinositide, TPI) were detected in three subfractions of purified rat brain myelin, and some properties of the enzymes were studied. Monoesterase activity was stimulated by KCl, maximally at a concentration of 25 mM, and inhibited at KCl concentrations above 50 mM. Addition of boiled pH 5 supernatant of rat brain homogenate doubled the enzymic activity; EDTA was inhibitory. The specific activities were nearly equal in the "low density", "medium density", and "heavy density" myelin fractions but about 30% lower than in whole brain homogenate. The monophosphatase could be solubilized by extraction with 0.2% Triton X-100. The phosphodiesterase activity was inhibited by EDTA and EGTA and not stimulated by KCl or pH 5 supernatant. Specific activities were nearly equal in whole brain and myelin but were by about 60 percent elevated in the "heavy density" over the "low density" myelin fractions. These results show that hydrolases operative in the fast turnover of the inositide phosphate groups are distributed over the entire myelin structure.
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PMID:Polyphosphoinositide mono- and diphosphoesterases of three subfractions of rat brain myelin. 628 49

1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life-threatening toxicity while beta-adrenoceptor agonists become less effective inotropic compounds as heart failure progresses. A new approach to positive inotropy is ion channel modulation. 2. An increased influx of Na+ during the cardiac action potential, as measured with DPI 201-106 and BDF 9148 which increase the probability of the open state of the Na+ channel, will increase force of contraction. 3. Activation of L-type Ca2+ channels with Bay K 8644 will increase influx of Ca2+ and increase the force of contraction. However the Ca2+ channel activators developed to date have little potential for the treatment of heart failure as they are vasoconstrictors. 4. Blocking cardiac K+ channels is a possible mechanism of positive inotropy. Terikalant inhibits the inward rectifying K+ channel, tedisamil inhibits the transient outward K+ channel and dofetilide is one of the newly developed inhibitors of the slow delayed outward rectifying K+ channel. All these drugs prolong the cardiac action potential to increase Ca2+ entry and force of contraction. 5. Thus drugs which increase Na+ influx or block K+ channels represent exciting possibilities for positive inotropy and the potential of these compounds for the treatment of heart failure needs to be fully evaluated.
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PMID:Ion channel modulators as potential positive inotropic compound for treatment of heart failure. 788 74

Inodilation, i.e., the combination of positive inotropic and vasodilating therapy, conceptually should be an ideal form of heart failure treatment. However, available orally active inodilator drugs, such as beta-agonists, dopaminergic compounds, and agents with phosphodiesterase (PDE)-inhibiting properties, have not been generally accepted for the treatment of heart failure. In contrast, there is serious concern that agents that act predominantly through PDE inhibition and thereby increase cellular cyclic AMP (cAMP) content, e.g., amrinone, milrinone, and enoximone, not only are ineffective in heart failure but also may lead to serious adverse events, i.e., arrhythmogenicity, and may increase mortality rate in advanced heart failure. Similarly, combined beta 1- and beta 2-agonists do not afford long-term clinical efficacy and also may lead to serious ventricular arrhythmias. Moreover, dopaminergic compounds that, besides dopamine-1 and dopamine-2 activation, act through beta-receptor stimulation do not consistently improve the patient's clinical condition. Thus, inodilation by way of increasing cAMP may not be the right approach, at least not in advanced heart failure, in which cAMP-dependent inotropic activity is significantly diminished. In contrast, clinical efficacy may be present when partial PDE inhibitors that also act through calcium sensitization, such as pimobendan, are administered to patients with mild to moderate or moderately severe heart failure. Moreover, adverse events may be less at the lower dose level at which, consequently, the degree of PDE inhibition is reduced. Calcium-sensitizing properties may afford an alternative, more economical way to improve contractile force in failing hearts. Hence, agents that combine calcium sensitization with a relatively low degree of PDE inhibition may well be the inodilators of choice, in particular in mild to moderate failure. Whether they improve the condition of such patients without affecting relaxation and whether they do not lead to adverse events and an increase in mortality rate have as yet to be evaluated. Furthermore, the potential beneficial effect of additional neurohumoral modulation by dopaminergic inodilator compounds and of heart rate-reducing properties of inodilators, such as OPC-8212 and DPI 201-106, needs to be clarified to assess the place, if any, of inodilator therapy in heart failure.
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PMID:Inodilator therapy for heart failure. Early, late, or not at all? 809 71

A number of new positive inotropic agents with diverse mechanisms of action have been discovered over the past 20 years. Most of these cardiotonic drugs exhibit characteristic electrophysiologic profiles. This prompted us to propose a classification scheme based on electrophysiologic principles, modifying the categories recently suggested by another author. Class I actions designate positive inotropic mechanisms that enhance the transmembrane calcium current by various means, such as beta-receptor stimulation (dobutamine, class I/A), phosphodiesterase inhibition (milrinone, class I/B), direct stimulation of adenylate cyclase (forskolin, class I/C), or direct modulation of calcium channel gating (BAY K 8644, class I/D). Class II action includes mechanisms that lead to elevation of intracellular sodium activity either by inhibiting the Na,K pump (digitalis, class II/A) or by increasing transmembrane sodium influx (DPI 201-106, class II/B). Class III action involves a mechanism by which sensitivity of the myofilaments to calcium increases (EMD 53998, levosimendan). This mechanism is not associated with apparent electrophysiologic manifestations. Positive inotropism due to lengthening of the cardiac repolarization (almokalant) is considered as class IV action. The possible clinical implications of the various positive inotropic mechanisms are also discussed.
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PMID:Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed? 890 29


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