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)

During anesthesia and in intensive care, pharmacological support is often required in patients with preexisting myocardial dysfunction as well as in patients with normal preoperative ventricular function. Abnormalities in both systolic and diastolic function may occur in this situation. Standard therapy used in this situation act on alpha-, beta- or dopaminergic-receptors. However, the observation of beta-receptor down-regulation phenomenon has led to the development of substances which act independently of the beta-receptor. The imidazole derivative enoximone belongs to a new class of non-catecholaminergic positive inotropics, which acts by selectively inhibiting phosphodiesterase type-III thus using a mechanism distal of the beta-receptor. Enoximone has been proven to successfully improve hemodynamics by either its positive inotropic and lusitropic or its vasodilating properties. The expected increase in MVO2 secondary to the increase in myocardial contractility appears to be compensated by the decrease in ventricular pre- and afterload. The most obvious positive hemodynamic effects are reported for patients undergoing cardiac surgery. In both adults and pediatric patients hemodynamics were improved significantly in this situation. There is a particular indication for enoximone for patients with severely impaired hemodynamics awaiting heart transplantation ("pharmacological" bridging). The first promising results were documented when PDE-III-inhibitors were given in myocardial infarction and septic shock patients. The most important risk associated with the use of enoximone is the reduction in blood pressure due to its arterial and venous vasodilatory effects. Limitation to a bolus of 0.5 mg/kg or a perfusor controlled therapy help to avoid critical decrease in perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Value of phosphodiesterase inhibitors in anesthesia and intensive care]. 809 29

It has been clearly established that ischemic heart disease, hypertension and ageing affect diastolic function before any change is observed in contractile function. Though an increasingly recognised clinical entity, cardiac failure with normal systolic function still does not have any specific treatment. Phosphodiesterase inhibitors which increase AMPc, in addition to their inotropic and vasodilator effects, accelerate relaxation. Major and isolated abnormalities of relaxation have been demonstrated in vitro in non necrosed tissues of both the dilated and hypertrophic forms of advanced cardiomyopathy. The myocardium seems unable to restore rapidly the low cytosolic calcium concentrations required for the deactivation of the contractile proteins. The underlying mechanisms are probably very complex but a deficit in AMPc production has been demonstrated in very advanced stages of cardiomyopathy. In ischemia, however, the abnormalities of relaxation seem to be directly related to a defect in free energy production inhibiting the sarcoplasmic reticulum calcium pump. If abnormalities of relaxation due to ischemia and those due essentially to a passive mechanism are excluded, phosphodiesterase inhibitors would seem to have pharmacological effects likely to improve diastolic function. Clinical studies confirm the beneficial effects of Milrinone and Enoximone on relaxation and the rapid phase of diastolic filling, both in acute and chronic studies. However, it has not yet been clearly established whether improved diastolic function is due to a direct action on the myocardium or an indirect action due to improved conditions of load. In order to determine the specific effects of phosphodiesterase inhibitors on diastolic function, further research is required.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of phosphodiesterase inhibitors on diastolic function]. 821 93

Mitral valve surgery may be complicated by a post-operative low output state requiring inotropic support, and a wide variety of factors may influence the choice of agents used to treat this condition. The authors have examined and compared the haemodynamic effects of the highly specific phosphodiesterase inhibitor enoximone, and the adrenergic agents dobutamine and dopamine in patients undergoing mitral valve surgery. Enoximone, 0.5 mg kg-1 bolus, followed by a continuous infusion of 5 micrograms kg-1 min-1, was compared against dobutamine, 7 micrograms kg-1 min-1, and dopamine, 5 micrograms kg-1 min-1, with the protocol allowing for an increase in the infusion rate by a factor of two if clinical and haemodynamic measurements indicated. All 25 patients receiving enoximone were successfully weaned from cardiopulmonary bypass at the first attempt, with significant increases in cardiac index and stroke index, combined with little or no change in heart rate or pulmonary artery pressures and a highly significant reduction in systemic vascular resistance, and a reduction in mean arterial pressure. Three of the 25 patients receiving dobutamine were withdrawn from the study because of inadequate haemodynamic response, while the remaining 22 patients demonstrated significant increases in heart rate, cardiac index and stroke index, with a reduction in systemic vascular resistance. Nine of the 25 patients receiving dopamine failed to respond adequately, while the remaining 16 demonstrated an increase in heart rate and cardiac index but with little change in stroke index and a modest reduction in systemic vascular resistance. Enoximone has been shown to be a highly effective first-line inotrope in patients following mitral valve surgery with significant advantages over dobutamine and dopamine.
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PMID:Haemodynamic effects and comparison of enoximone, dobutamine and dopamine following mitral valve surgery. 822 51

Acute heart failure following cardiac surgery in extracorporeal circulation (EC) still poses a formidable problem requiring intensive pharmacological therapy and, often, also mechanical support. Preoperatively reduced left ventricular (LV) function raises the risk for the development of this complication. In their pilot study, the authors evaluated the haemodynamic effects of enoximone, a selective phosphodiesterase III inhibitor, administered at a dose of 1 mg/kg b.w. to 15 patients with a preoperative LV ejection fraction < or = 35% 15 minutes before weaning from EC after an elective myocardial revascularization procedure. All patients were weaned from EC at first attempt without any problems and left the operating theatre in good condition. Enoximone administration led, in the monitored period (45 minutes after administration), to statistically significant increases in cardiac index (+68%; p < 0.01), oxygen supply (+75%; p < 0.01) and oxygen saturation in mixed venous blood (+10%; p < 0.1) and statistically significant decreases in pulmonary and systemic vascular resistance indexes (-52% and -48%, respectively; p < 0.001) and in oxygen extraction (-31%; p < 0.001). These changes were associated with decreases in central venous, mean pulmonary artery, and pulmonary capillary wedge pressure (n.s.). No serious side effects were seen, and the authors conclude enoximone can be the drug of first choice in high-risk patients following heart surgery in EC and requiring inotropic support.
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PMID:[Hemodynamic effects of enoximone in patients with low left ventricular ejection fraction in surgery for ischemic heart disease]. 825 78

Enoximone is a phosphodiesterase inhibitor that has both positive inotropic and systemic vasorelaxant activities. The latter are mediated by an increase in vascular smooth muscle concentration of cyclic 3'5' guanosine monophosphate. However, the effect of enoximone on pulmonary vasoreactivity is not established. The authors, therefore, have studied its effect on endothelium-dependent relaxation mediated by the endothelium-derived relaxing factor nitric oxide (NO), as well as endothelium-independent relaxation of isolated porcine pulmonary arteries. Enoximone (10(-7) to 10(-4) M) caused a dose-dependent relaxation in all pulmonary arterial rings. This relaxation neither required the presence of the endothelium nor was affected by the addition of the inhibitor of NO synthase omega-nitro-L-arginine methyl ester (10(-4) M). Also, the vasorelaxant response of the rings to the endothelium-dependent vasodilator adenosine diphosphate (10(-10) to 10(-5) M) was not affected by pretreatment with enoximone. The authors conclude that enoximone is a potent vasodilator that relaxes pulmonary vascular rings through mechanisms independent of the endothelium. This endothelium-independent vasodilatory effect of enoximone makes it a potentially valuable drug for the treatment of pulmonary hypertension. This particularly applies to diseases in man where NO production by the endothelial cells is impaired.
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PMID:In vitro pulmonary vasorelaxant effect of the phosphodiesterase inhibitor enoximone. 845 79

We have investigated the circulatory effects of halothane and isoflurane in the presence of the phosphodiesterase inhibitor, enoximone, in 20 patients, ASA class III, aged 40-70 yr, undergoing coronary artery bypass grafting. After induction of anaesthesia (midazolam, fentanyl, etomidate and pancuronium) all patients received enoximone 0.5 mg kg-1, followed, 10 min later, by either halothane 1 MAC (group I; n = 10) or isoflurane 1 MAC (group II; n = 10). Haemodynamic variables were measured and blood samples (arterial and mixed venous) were obtained before (control, t0), 5 (t1) and 10 (t2) min after the injection of enoximone and immediately (t3) and 5 (t4) min after steady state conditions with halothane or isoflurane, as verified by the end-expiratory concentration. Heart rate, mean arterial pressure (MAP), mean pulmonary artery pressure, pulmonary capillary wedge pressure and right atrial pressure were recorded. Cardiac (CI) and stroke volume indices, systemic (SVR) and pulmonary vascular resistance, oxygen availability (QO2), oxygen consumption and oxygen extraction rate were calculated using standard formulae. MAP decreased significantly in both groups after bolus injection of enoximone (group I: 11%; group II: 7%). Under steady state conditions with the volatile anaesthetics, a further significant decrease in MAP was observed (group I: 12%; group II: 12%). Enoximone produced a significant increase in CI (group I: 25%; group II: 27% compared with control). After administration of isoflurane, CI remained essentially unchanged, while halothane decreased CI significantly by 20%. In both groups, SVR decreased significantly after administration of enoximone (group I: 26%; group II: 24%).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Haemodynamic changes produced by inhalation anaesthetics in the presence of phosphodiesterase inhibition. 849 3

1. This study was designed to investigate the role of rat phosphodiesterase 3 (RPDE3) in regulation of liver metabolism in sepsis. We studied the effects of the phosphodiesterase 3 inhibitor (PDI), enoximone, alone and in combination with regulating factors of hepatic carbohydrate metabolism and bile secretion in the perfused liver of rats treated 4 h earlier with endotoxin. In addition, cyclic AMP and cyclic GMP levels were determined in the effluate and bile by radio immunoassay methods. 2. After endotoxin treatment, infusion of enoximone at three concentrations (1 microM, 10 microM) resulted in an increased glucose output from -1.4 +/- 0.9 to 7.8 +/- 2.5 mumol l-1 20 min-1. Bile acid-independent bile flow increased also, in a dose-dependent manner. 3. In untreated livers, cyclic AMP release increased in the effluate from 1000 +/- 73 fmol g-1 min-1 to 1710 +/- 143 fmol g-1 min-1 when enoximone (10 microM) was administered. In bile from untreated livers, the level of cyclic AMP was also significantly increased by enoximone. After endotoxin treatment, the enoximone (10 microM) effect on cyclic AMP levels in effluate and bile was greatly reduced. Levels of cyclic GMP in the effluate and bile appeared unchanged in the presence of enoximone. 4. During co-infusion of glucagon (1 nM) and enoximone (10 microM), cyclic nucleotide levels in the effluate and bile of livers after endotoxin treatment were determined. In the effluate, cyclic AMP release increased from 827 +/- 144 fmol g-1 min-1 to 17802 +/- 2821 fmol g-1 min-1 when glucagon was administered. The presence of enoximone enhanced cyclic AMP further to 41696 +/- 920 fmol g-1 min-1. The same changes in cyclic AMP release were found in bile. Levels of cyclic GMP in the effluate and bile were not significantly affected by the administration of glucagon and the PDI. 5. Glucose release was determined during glucagon, sympathetic nerves stimulation and phenylephrine administration in the presence and absence of enoximone. The addition of enoximone to glucagon increased glucose release by 8.2 +/- 2.8 mumol g-1 20 min-1, without alteration of lactate balance. The PDI enhanced the glycogenolytic effects of nerve stimulation and of phenylephrine, accompanied by a reduction in lactate production. 6. Enoximone significantly enhanced the bile acid independent bile flow after glucagon, nerves stimulation and after administration of phenylephrine. Bile acid secretion was unaffected by the PDI. The vasoconstrictor effect of nerve stimulation was reduced by the PDI. 7. We conclude that endotoxin treatment reduces the ability of the PDI, enoximone, to increase cyclic AMP release in the perfused liver. The significant increase in cyclic AMP release after stimulation with glucagon and enoximone favours the view that RPDE3 is involved in the degradation of cyclic AMP in the liver after exposure to endotoxin. Additionally, the inhibition of the RPDE3 results in glucose release, vasodilatation and choleresis in endotoxin pretreated livers.
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PMID:Effects of selective phosphodiesterase 3 inhibition in the perfused liver of the rat after endotoxin treatment. 876 9

In 1991 and 1992, we introduced the new phosphodiesterase-III-inhibitor, enoximone, in the treatment of cardiac low-output-syndromes in the early phase after valve replacement or coronary bypass grafting. We introduced enoximone in cases which met the following criteria: cardiac index < or = 2.4 l/min/m2; systolic arterial pressure < or = 90 mmHg; left ventricular filling pressure > or = 20 mmHg despite the use of dopamine (> or = 12 micrograms/kg/ min); epinephrine (> or = 0.12 microgram/kg/min) and glyceroltrinitrate (1 microgram/kg/min). After clarification of preoperative risk factors and postoperative complications, retrospective evaluation of complete haemodynamic monitoring in patients after valve replacement (14 out of 86) and patients after coronary bypass grafting (22 out of 228) led to the following conclusions. Enoximone is of essential importance for the treatment of cardiac low-output at the end of extracorporeal circulation, particularly in cases complicated by preoperative myocardial deterioration. The use of enoximone is especially effective combined with beta-sympathomimetics as a result of elevation of cAMP-levels in two ways: by stimulation of beta-adrenoceptors directly and by inhibition of phosphodiesterase. Cardiac indices early after bypass, compared with measurements taken before bypass, reveal a clear rise indeed caused by increase in heart rate. Only in patients who underwent coronary bypass grafting did we observe a moderate increase in stroke volume indices. The therapeutic principle of using vasodilators--to lower peripheral resistance for improving stroke volume --appears to be effective immediately after extracorporeal circulation only in part. The vasodilating effect of enoximone has to be constantly compensated for by volume supplementation and alpha-mimetic stimulation, especially after valve replacement surgery. In contrast to this, we continued the application of glyceroltrinitrate in about 25% of the cases. Coronary surgery patients tolerated the vasodilating action particularly well; consequently, despite inotropic stimulation to a high degree, these patients showed no additional signs of ischaemia. Based on our therapeutic measures, the therapy led to very good short-term results. However, this therapeutic regime failed in patients suffering from extended myocardial infarction or irreversible pulmonary hypertension.
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PMID:[Enoximone--clinical experiences in heart surgery]. 876 97

In this study we investigated the effects of isoproterenol and enoximone on protamine cardiotoxicity because administration of protamine for heparin reversal during open heart surgery depresses left ventricular function. Eighteen mongrel dogs were entered into this study. After induction of general anesthesia and a stabilization period, a thermodilution catheter was inserted via the jugular vein. Another 2 catheters were inserted into the left ventricle and femoral artery. Heparin and protamine were used in all animals. Heparin dosage was 300 U/kg, and protamine dosage was 4.5 mg/kg. The animals were divided into 3 groups. Six animals received enoximone (5 micrograms/kg per min), 6 animals received isoproterenol (0.05 microgram/kg per min), and 6 animals received no inotropic agent. Measurements were performed before treatment, 5 min after protamine administration, and at 15-min intervals for 1 h. Cardiac output (CO), mean arterial pressure, pulmonary capillary wedge pressure, first derivative of left ventricular pressure (1 +/-) left ventricular systolic pressure, and heart rate were measured. CO was 1582 +/- 34 ml/min in the isoproterenol group (I + P), 1684 +/- 61 ml/min in the enoximone group (E + P), and 1471 +/- 37 ml/min in the protamine group (P) (p < 0.05 E + P vs I + P and P) 60 min after protamine administration. The first derivative of left ventricular pressure (dP/dt) was 1995 +/- 61 mmHg/sec in the I + P group, 2320 +/- 85 mmHg/sec in the E + P group, and 1816 +/- 48 mmHg/sec in the P group (p < 0.05 E + P vs I + P and P). In our experimental study, the isoproterenol and protamine combination did not increase hemodynamic activity. However, isoproterenol alone significantly increased hemodynamic activity as determined by dP/dt values. Protamine administration impairs the effects of beta agonists on the myocardium. In the protamine group, CO and pressure-dependent values were significantly reduced. Isoproterenol administration did not reverse this deterioration because of the loss of the beta-receptor activity. Inotropic agents acting through the beta-adrenergic system have partial effects on myocardium. Enoximone, a phosphodiesterase inhibitor, reverses deterioration of cardiac function after protamine administration because it increases myocardial function via the phosphodiesterase system.
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PMID:Comparison of the effects of enoximone and isoproterenol on protamine cardiotoxicity in anesthetized dogs. 955 31

Biopharmacological evaluations of the protective effects of L-carnitine (a naturally occurring quaternary ammonium compound) against doxorubicin-induced metabolic damage were carried out in isolated cardiac myocytes and in isolated rat heart mitochondria. Perfusion of the heart with DOX (0.5 mM) caused a significant 70% inhibition of palmitate oxidation in cardiac myocytes, while L-carnitine (5 mM) perfusion caused stimulation which accounted for 37%. Perfusion of the heart with L-carnitine after 10-min perfusion with DOX (0.5 mM) caused 88% reversal of DOX-induced inhibition of palmitate oxidation in cardiac cells. In rat heart mitochondria, DOX has no effect on either palmitate oxidation or acyl-CoA synthetase activity, whereas Enoximone (c-AMP-dependent phosphodiesterase inhibitor), caused a significant inhibition of palmitate oxidation and acyl-CoA activity (40 and 27%, respectively). The oxidation of palmitoyl-CoA, an index of carnitine palmitoyltransferse reaction was significantly inhibited by DOX as a function of DOX concentration. Preincubation of mitochondria with L-carnitine caused reversal of DOX-induced inhibition of palmitoyl-CoA oxidation depending on the concentration of L-carnitine. Moreover, L-carnitine treatment did not interfere with the cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. The findings of this study may suggest that inhibition of fatty acid oxidation in the heart is at least a part of doxorubicin cardiotoxicity and that L-carnitine can be used to prevent the doxorubcin-induced cardiac metabolic damage without interfering with its antitumour activities.
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PMID:Reversal of doxorubicin-induced cardiac metabolic damage by L-carnitine. 1020 59


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