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)

The comparison of two invasive studies using intravenous application of the phosphodiesterase enoximone demonstrated unchanged cardiac output in patients with dilated cardiomyopathy NYHA II-III, and increased cardiac output (from 3.22 +/- 1.15 to 5.04 +/- 2.05 l/min; p less than 0.01) in acute heart failure. This comparison of hemodynamic parameters in addition to studies on myocardial oxygen consumption support the use of intravenous enoximone in acute heart failure, whereas the long-term application of enoximone in chronic heart failure is judged to be critical.
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PMID:[Vasodilatation and positive inotropic effect of the phosphodiesterase inhibitor enoximone]. 183 95

The peripheral mechanisms by which ephedrine and caffeine influence thermogenesis were investigated in innervated rat interscapular brown adipose tissue (IBAT) by assessing its rate of oxygen consumption (MO2) in vitro. Dose-response measurements with tissues from intact or sympathectomized (6-OHDA) animals indicate that the thermogenic effects of low concentrations of ephedrine and also of caffeine are entirely dependent upon the presence of intact sympathetic nerve endings, and thus depend on presynaptic mechanisms. Direct postsynaptic stimulation of thermogenesis is only apparent at much higher concentrations, namely greater than 1 microM for ephedrine and greater than 2mM for caffeine. At subminimal concentrations that neither ephedrine nor caffeine influenced basal tissue respiration, they induced a 4-5-fold increase in basal MO2 when administered in combination, a synergistic response prevented by pre-treatment of the rat with 6-OHDA. Synergistic increases in IBAT respiration were also obtained when subminimal concentration of ephedrine was added to 3-propylxanthine (a specific inhibitor of phosphodiesterase), to 8-phenyltheophylline (a potent adenosine receptor antagonist) or to adenosine deaminase (for enzymatic inactivation of endogenous adenosine). Conversely, the marked synergism in thermogenic response with ephedrine + caffeine was reduced in the presence of 2-chloroadenosine (an adenosine analogue). In tissues from fasted rats, the ephedrine + caffeine synergism in thermogenic response, although attenuated, was nevertheless present. These studies therefore demonstrate that ephedrine, at doses comparable with therapeutic use, stimulates thermogenesis in BAT via sympathetically released NA. In addition, a synergistic interaction between caffeine and ephedrine on BAT thermogenesis is explained by ephedrine's enhancement of sympathetic neuronal release of NA, together with caffeine's dual ability to antagonize adenosine and to inhibit cellular phosphodiesterase activity.
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PMID:Peripheral mechanisms of thermogenesis induced by ephedrine and caffeine in brown adipose tissue. 188 57

To assess hemodynamic and energetic effects of different drug interventions on idiopathic dilated cardiomyopathy (IDCM), we determined hemodynamic variables of myocardial oxygen consumption (MVO2) in 37 patients with IDCM. Hemodynamics were measured during routine left and right heart catheterization. MVO2 was analyzed from myocardial blood flow (measured by the argon method) and aortocoronary sinus blood oxygen difference. The hemodynamic variable which correlated best with MVO2 was shown to be the systolic stress time integral (STI). Four different representative compounds were tested with respect to their acute effects on myocardial energetics (MVO2/STI) in patients with IDCM who were in compensated heart failure (NYHA class II-III). The drug interventions were performed at rest. Intravenous injection of the vasodilator nitroprusside yielded a 35% reduction in STI and a 30% reduction in MVO2; in other words, the ratio MVO2/STI was not altered. Injection of the calcium sensitizer and phosphodiesterase inhibitor pimobendan also did not alter this ratio, as both STI (36%) and MVO2 (33%) were lowered. The profound reduction in STI (60%) seen with the phosphodiesterase inhibitor enoximone was accompanied by a much smaller decrease in MVO2 (19%); therefore, the ratio of MVO2/STI increased significantly. An increase of this ratio was also seen with the partial beta-1 receptor agonist xamoterol. However, in this case STI did not change, whereas MVO2 increased by 26%. In summary, vasodilation has energy-saving effects, whereas positive inotropism is an energy-consuming process. We conclude that the overall effect on myocardial energetics of a drug which possesses both positive inotropic and vasodilating properties depends on the balance of the two properties.
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PMID:Myocardial energetics in dilated cardiomyopathy. 197 66

Cardiac muscle cell hypertrophy, hyperplasia of connective tissue, abnormal peripheral circulation and metabolic changes in the cardiac fibre and in the smooth muscle cell as a consequence of mechanic overload are described in variable proportions in heart failure. These changes in turn are essential factors for progression of the disease. Results of early drug intervention in patients with few or no symptoms suggest that decrease of mechanic overload by vasodilator therapy slows down the progression of the disease. In late stages, treatment with diuretics and vasodilators improves the symptoms and the outcome of heart failure. Diuretics alone and inotropic positive substances bring about some improvement of symptoms and maximal oxygen consumption, but they have no favourable effect on the outcome. Positive inotropic substances remain restricted to late forms of heart failure, in which they seem to ameliorate symptoms but have a rather unfavourable effect on the outcome. The role of diuretics, ACE inhibitors and digoxin is well defined. This is not the case for newer calcium-channel blockers from the dihydropyridine group, of beta blockers, of phosphodiesterase inhibitors and of substances with partial beta agonist and partial beta blocking activity. These drugs must still be classified as experimental agents for the treatment of heart failure.
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PMID:[Current problems of pharmacotherapy--heart failure]. 197 5

The myocardial effects of milrinone are mediated through inhibition of myocardial phosphodiesterase III. This inhibition results in accumulation of cyclic adenosine monophosphate and consequently increased calcium influx through voltage-dependent channels. The vascular effects also result from increased cyclic adenosine monophosphate. Direct coronary artery infusion of milrinone causes a concentration-related increase in left ventricular +dP/dt and substantial improvement in pump function as indicated by increased stroke work at lower left ventricular end-diastolic pressures. Subsequent intravenous administration of milrinone produces additional hemodynamic improvement, which is associated with a further reduction in systemic vascular resistance and left and right heart filling pressures. There is also a downward displacement of the left ventricular pressure-volume curve and acceleration of isovolumic relaxation, findings which indicate improved diastolic filling and accelerated isovolumic myocardial relaxation, respectively. The former action may reflect unloading of the right ventricle, whereas the latter may be due to improved calcium reuptake in the myocardium. Myocardial oxygen demand is unaltered because peripheral vasodilatation reduces wall stress and counteracts the increased oxygen requirement necessary to support enhanced contractility. This therapeutic profile differs from that of inotropic agents such as dobutamine and vasodilators such as nitroprusside, and contributes significantly to the usefulness of phosphodiesterase III inhibitors such as milrinone in the short-term management of patients with heart failure.
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PMID:Cardiovascular effects of milrinone. 203 24

The calcium channel-blocking activity and associated cardiovascular effects of diproteverine, a novel compound derived from papaverine, were investigated. Electrophysiological measurements in sheep Purkinje fibres showed diproteverine to reduce the amplitude of the slow action potential (IC30 = 2 microM) and to shorten the duration of the fast action potential at 50% repolarisation (IC30 = 2.5 microM). Higher concentrations (4-5 times) were required to block block the sodium channel, as assessed by a reduction in Vmax of the fast action potential. Papaverine was found to possess marginal membrane channel-blocking activity and to be much more potent than diproteverine as a cAMP-phosphodiesterase inhibitor. The most significant haemodynamic property of diproteverine, seen in anaesthetised dogs and conscious dogs pretreated with atropine, was to cause a reduction in heart rate. This appeared to be a particular feature of diproteverine as the other calcium antagonists studied produced either a smaller decrease in heart rate or tachycardia as a reflex response to hypotension. In a chronic myocardial infarct model in dogs, diproteverine caused a redistribution of the available coronary blood flow, to the benefit of an ischaemic area of the myocardium. Diproteverine resembled diltiazem in its effects on coronary blood flow, with both these agents being preferable to nifedipine and verapamil, which caused coronary steal in this model. The combination of the reduction in heart rate, to lower cardiac oxygen demand, with the beneficial action on coronary blood flow should result in diproteverine being particularly beneficial for the treatment of angina pectoris.
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PMID:Diproteverine (BRL 40015): a new type of calcium antagonist with potential antianginal properties. 205 33

A multicenter double-blind, randomized, placebo-controlled trial of oral enoximone, a phosphodiesterase inhibitor, was conducted in 102 outpatients (50 receiving enoximone and 52 receiving placebo) with moderate to moderately severe congestive heart failure. All were on a long-term regimen of digoxin and diuretics without vasodilators and converting enzyme inhibitors. Symptom score was obtained, and exercise testing was performed monthly for 4 months. There were no differences between groups in symptoms or exercise duration at the end of 4 months. A subgroup undergoing analysis of oxygen consumption with measurement of anaerobic threshold during exercise showed an increase (p less than 0.05) in anaerobic threshold at 1 month with enoximone. (2.7 +/- 0.8 ml O2/kg/min) compared with placebo (-0.8 +/- 1.2 ml O2/kg/min). This improvement was not sustained at 4 months (0.5 +/- 1.7 ml O2/kg/min with enoximone and 0.2 +/- 1.5 ml O2/kg/min with placebo). The dropout rate was significantly higher (p less than 0.02) with enoximone (46%) than with placebo (25%). Adverse effects other than death were slightly, but not significantly, higher with enoximone (32%) than with placebo (22%). During therapy, five deaths occurred in the enoximone group, and none occurred in the placebo group (p less than 0.05). Two deaths were sudden, two were from progressive congestive heart failure, and one was from acute myocardial infarction. With intention-to-treat analysis and inclusion of patients who were removed from therapy because of lack of study drug effect, 10 deaths occurred in the enoximone group, and three occurred in the placebo group (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group. 214 15

Theoretically, there are two reasons for using the association of dobutamine and enoximone in patients with acute cardiac failure; the powerful vasodilator effect of enoximone and the different biochemical actions of the two drugs on the myocardial fibre affecting the production (dobutamine) or the degradation (enoximone) of cyclic AMP. The combined effects of beta adrenergic agonists and phosphodiesterase III inhibitors in vitro and in vivo have been previously reported. An increased contractile response to dobutamine has been demonstrated with enoximone on isolated human ventricle obtained during cardiac transplantation. We confirmed the additive effect of dobutamine (5 to 10 micrograms/kg/min) and enoximone (1 mg/kg/bolus IV) in 8 patients with acute cardiac failure with each molecule used alone. Mild changes in heart rate (+19 bpm) and in systolic blood pressure (-3 mmHg) were observed simultaneously. The absence of an increase in SvO2 compared to the use of each molecule in monotherapy is probably related to a tendency to increase myocardial oxygen consumption which may be potentially deleterious in terms of gas exchange. Having demonstrated the additive effects of the association of dobutamine and enoximone, there is probably a place for this therapeutic association in the management of acute cardiac failure. However, the potential risk of inducing an atrial and/or ventricular tachyarrhythmia and the consequences of lowering ventricular filling pressures and systemic vascular resistances should be born in mind; when using this therapeutic association, the authors suggest starting treatment with low doses of dobutamine (5/kg/min) and enoximone (0.5 - 1 mg/kg) with haemodynamic control and steadily increasing the doses, depending on the results obtained.
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PMID:[Role of the enoximone-dobutamine combination in the treatment of congestive cardiac insufficiency]. 214 32

An unusual compound, cyclic-bis(3'----5') diguanylic acid (c-di-GMP or cGpGp), is involved in the regulation of cellulose synthesis in the bacterium Acetobacter xylinum. This cyclic dinucleotide acts as an allosteric, positive effector of cellulose synthase activity in vitro (Ka = 0.31 microM) and is inactivated via degradation by a Ca2(+)-sensitive phosphodiesterase, PDE-A (Km = 0.25 microM). A series of 13 analogs cyclic dimer and trimer nucleotides were synthesized, employing a phosphotriester approach, and tested for the ability to mimick c-di-GMP as activators of cellulose synthase and as substrates for PDE-A. Seven of the synthetic compounds stimulate cellulose synthase activity and all of these activators undergo the Ca2(+)-inhibited degradation reaction. The order of affinities for synthase activators is cGpGp approximately cdGpGp approximately cGp(S)Gp (S-diastereomer) greater than cIpGp greater than cdGpdGp greater than cXpGp greater than cIpIp greater than cGp(S)Gp (R-diastereomer). Three cyclic dinucleotides of negligible affinity for either enzyme are cApAp, cUpUp, and cCpCp. This same order of affinities essentially pertains to the analogs as inhibitors of PDE-A activity, but at least one cyclic dinucleotide, cXpXp, which does not bind to cellulose synthase, is also a substrate for the degradation reaction, demonstrating that although the two enzymes share a similar, high degree of specificity for c-di-GMP, their cyclic dinucleotide binding sites are not identical. Phosphodiester bonds of activators in which an exocyclic oxygen is replaced with an atom of sulfur (cGp(S)Gp isomers) resist the action of PDE-A, and such derivatives may be prototypes for synthetic non-hydrolyzable c-di-GMP analogs.
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PMID:The cyclic diguanylic acid regulatory system of cellulose synthesis in Acetobacter xylinum. Chemical synthesis and biological activity of cyclic nucleotide dimer, trimer, and phosphothioate derivatives. 217 38

Low cardiac output in acute heart failure can result in a functional impairment of organs, when tissue hypoxia occurs and cardiogenic shock develops. To restore cardiac output, various forms of therapy can be considered. Fluid replacement is sometimes beneficial in acute situations where oedema can reduce effective plasma volume. Vasodilators are often contra-indicated in shock, when arterial pressure is usually low. Inotropic therapy consists primarily of the administration of adrenergic agents. Dopamine and noradrenaline can be indicated in severe hypotension, to maintain coronary perfusion. Dobutamine is the catecholamine of choice to increase myocardial contractility. However, decreased responsiveness of the myocardial receptors to adrenergic stimulation rapidly becomes an important limitation. Phosphodiesterase inhibitors represent an interesting option to increase contractility, also by increasing cyclic AMP levels in the myocardium. In this respect, the combination of phosphodiesterase inhibitors with adrenergic agents is attractive. The additional vasodilatory properties of these agents can contribute to the increase in cardiac output with limited risk of further reduction in arterial pressure. In 13 patients with cardiogenic shock persisting despite the use of adrenergic agents, the addition of enoximone, 0.5 mg/kg, resulted in significant increases in cardiac index and stroke volume index and a significant decrease in pulmonary artery balloon occlusion pressure without consistent change in mean arterial pressure. In 8 patients, a second infusion of 0.5 g/kg amplified these effects. All but one of these patients survived the episode of cardiogenic shock, and 5 patients were discharged alive. In some cases, even lower doses of enoximone resulted in dramatic increases in cardiac output and oxygen transport in patients already treated with dobutamine with limited success.
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PMID:The role of enoximone in the treatment of cardiogenic shock. 217 30


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