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

The systems regulating the levels of Ca(2+)-Mg2+, Ca(2+)-ATPase and potential-dependent absorption of Ca2+ as well as content of cyclic nucleotides, beta-adrenoreceptors, activities of adenylate-, guanylate cyclases and phosphodiesterase were studied in the synaptosomes of rat brain cortex in evolving myocardial infarction. In addition, reverse absorption of noradrenaline, dopamine and serotonin was studied. In one of the animal groups myocardial infarction was simulated after stress. The myocardial infarction, affecting the systems of Ca2+ regulation, caused an increase in reverse absorption of dopamine and serotonin simultaneously with accumulation of lactate in the synaptosomes. In myocardial infarction developed after stress adenylate cyclase was activated, reverse absorption of dopamine was decreased and the content of lactate tended to decrease as compared with the infarction formed without stress effects.
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PMID:[Systems for regulating the level of Ca2+, cyclic nucleotides, and reverse absorption of neurotransmitters in isolated nerve endings of the rat brain during development of myocardial infarct]. 809 86

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

The influence of the beta-blocker metoprolol on the capacity either of low-dose dobutamine echocardiography or the recently introduced enoximone echocardiography to detect viable dysfunctioning myocardium after myocardial infarction was investigated. Initial clinical experience would suggest that the phosphodiesterase III inhibitor enoximona could be an alternative pharmacological stimulation, inducing an increase in contractility in the presence or absence of beta-receptor stimulation. Ten patients with a baseline low-dose dobutamine-echocardiographic test (up to 10 micrograms/kg/min) positive for myocardial viability in > or = 1 segment(s), performed 4-5 days after a first acute myocardial infarction treated with rtPA, were randomized after the administration of intravenous metoprolol (15 mg in three 5-mg boluses) either to dobutamine (up to 15 micrograms/kg/min) or to an enoximone intravenous bolus (1 mg/kg over 5 min) under echocardiographic monitoring, in a crossover sequence, with a 24-h interval. The infarct related artery was patent (TIMI grade 2 o 3) in all the patients. Follow-up echocardiograms were performed 5-7 weeks later. Resting asynergy was found in 40 segments; of these, 17 were viable. All the viable segments remained unresponsive during the post-metoprolol dobutamine infusion, while improved their contractility during enoximone echocardiography. Two patients suffering from early post-infarction angina underwent coronary angioplasty successfully. Eight out of ten patients (2 revascularized and 6 not) showed contractile recovery in a total of 14 segments at the follow-up echocardiogram. Sensitivity, specificity and overall accuracy in predicting reversible dysfunction after acute myocardial infarction for enoximone echocardiography were 93, 85, and 88%, respectively. Our results support the value of enoximone echocardiography in the identification of myocardial viability after myocardial infarction, in patients treated with beta-blockers, which interfere heavily with the results of dobutamine echocardiography.
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PMID:Identification of viable myocardium early after acute myocardial infarction under beta-blockade by enoximone echocardiography. 919 52

The present study was conducted to assess the preventive effect of combined treatment with probucol, an antioxidant, and cilostazol, a phosphodiesterase inhibitor, against poststenting restenosis. Study patients were randomized to 4 modality groups 1 week before stenting: control, probucol (500 mg/day), cilostazol (200 mg/day), and probucol plus cilostazol. Treatment on these modalities was conducted from 5 prestent days until the poststenting follow-up evaluation (6 poststenting months). All patients received aspirin (81 mg/day). The efficacy of each modality against restenosis was evaluated in a total 126 patients with 165 coronary arterial lesions, using a quantitative method. The decrease in luminal diameter at the poststenting follow-up was 1.04 +/- 0.57 mm for controls, 0.88 +/- 0.82 mm for those taking probucol, 0.61 +/- 0.59 mm for those taking cilostazol (p <0.05 vs control), and 0.40 +/- 0.52 mm (p <0.01 vs control) for the combined treatment group. Restenosis rate per segment was 31.7% for controls, 16.7% for the probucol group, 12.5% for the cilostazol group (p <0.05 vs control), and 9.5% for the combined treatment group (p <0.05 vs the control). Neither mortality, myocardial infarction, stent thrombosis, or coronary bypass surgery, nor any serious complications were observed in the combined treatment group. Combined treatment with probucol and cilostazol has thus proved safe and effective in preventing acute poststenting complications and suppressing chronic restenosis.
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PMID:Effects of probucol and cilostazol alone and in combination on frequency of poststenting restenosis. 967 82

1. Cardiac fibroblasts play an important role in the pathophysiology of cardiac remodelling induced by hypertension and myocardial infarction by undergoing proliferation and depositing extracellular matrix proteins such as collagen. We have examined the effects of atrial natriuretic peptide (ANP) on proliferation and collagen synthesis by adult rat and human cardiac fibroblasts in culture. 2. In cells from both species radioligand studies using 125I-ANP suggested that the majority of binding sites (> 85%) were non-guanylyl cyclase-linked (NPR-C subtype). Nonetheless ANP (10(-9) to 10(-6) M), in the presence of zaprinast, an inhibitor of phosphodiesterase 5 (PDE5), increased fibroblast cyclic GMP levels 3-5 fold in a concentration-dependent manner (P < 0.05). 3. ANP (10(-11) to 10(-6) M), a NPR-C ligand, C-ANF4-23 (10(-11) to 10(-6) M) and zaprinast alone had no significant effect on either basal or serum-stimulated DNA synthesis or fibroblast number. In combination with zaprinast (10(-5) M), however, ANP (10(-9) to 10(-6) M) but not C-ANF4-23 (10(-7) M) inhibited markedly both basal and stimulated fibroblast mitogenesis, an effect reproduced by 8-bromo-cyclic GMP (10(-5) to 10(-3) M). 4. Collagen synthesis, determined by measuring hydroxyproline levels, was stimulated with transforming growth factor-beta1 (40 pM), angiotensin II (10(-7) M) or 2% foetal bovine serum. The increase in collagen production, normalised by cell number, was reduced dramatically (to at or near basal production) by ANP (10(-9) to 10(-7) M) but not C-ANF4-23 (10(-7) M) in the presence of zaprinast. Again 8-bromo-cyclic GMP (10(-5) to 10(-3) M) reproduced the effect. 5. ANP is capable of inhibiting collagen synthesis in adult rat and human cardiac fibroblasts via cyclic GMP, a property unmasked and enhanced by inhibition of PDE5.
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PMID:Effect of atrial natriuretic peptide and cyclic GMP phosphodiesterase inhibition on collagen synthesis by adult cardiac fibroblasts. 972 58

Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), is the first in a new class of orally effective treatments for erectile dysfunction. During sexual stimulation, the cavernous nerves release nitric oxide (NO), which induces cyclic guanosine monophosphate (cGMP) formation and smooth muscle relaxation in the corpus cavernosum. Sildenafil facilitates the erectile process during sexual stimulation by inhibiting PDE5 and thus blocking the breakdown of cGMP. Sildenafil alone can cause mean peak reductions in systolic/diastolic blood pressure of 10/7 mm Hg that are not dose related, whereas the heart rate is unchanged. Sildenafil and nitrates both increase cGMP levels in the systemic circulation but at different points along the NO-cGMP pathway. The combination is contraindicated because they synergistically potentiate vasodilation and may cause excessive reductions in blood pressure. Erectile dysfunction is a significant medical condition that shares numerous risk factors with ischemic heart disease, and hence a substantial overlap exists between these patient groups. From extensive clinical trials, the most commonly reported cardiovascular adverse events in patients treated with sildenafil were headache (16%), flushing (10%), and dizziness (2%). The incidences of hypotension, orthostatic hypotension, and syncope and the rate of discontinuation of treatment due to adverse events were <2% and were the same in patients taking sildenafil and those taking placebo. Retrospective analysis of the concomitant use of antihypertensive medications (beta blockers, alpha blockers, diuretics, angiotensin-converting enzyme inhibitors, and calcium antagonists) in patients taking sildenafil did not indicate an increase in the reports of adverse events or significant episodes of hypotension compared with patients treated with sildenafil alone. In clinical trials, the incidence of serious cardiovascular adverse events, including stroke and myocardial infarction, was the same for patients treated with sildenafil or placebo. Concurrent disease states, such as renal or hepatic impairment, or concomitant use of inhibitors of the cytochrome P450 isozyme CYP3A4 could increase systemic exposure to sildenafil. Since the US market launch in April 1998, monitoring of spontaneous adverse event reports in association with sildenafil has demonstrated a pattern that is generally consistent with the experience observed during clinical development, with the exception of infrequent reports of priapism. In conclusion, extensive clinical testing has shown that overall treatment with sildenafil for up to 1 year is well tolerated and is associated with a low incidence of adverse events that result in discontinuation of treatment in <3% of patients.
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PMID:Overall cardiovascular profile of sildenafil citrate. 1007 41

Three weeks after myocardial infarction (MI) in the rat, remodeled hypertrophy of noninfarcted myocardium is at its maximum and the heart is in a compensated stage with no evidence of heart failure. Our hemodynamic measurements at this stage showed a slight but insignificant decrease of +dP/dt but a significantly higher left ventricular end-diastolic pressure. To investigate the basis of the diastolic dysfunction, we explored possible defects in the beta-adrenergic receptor-G(s/i) protein-adenylyl cyclase-cAMP-protein kinase A-phosphatase pathway, as well as molecular or functional alterations of sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban (PLB). We found no significant difference in both mRNA and protein levels of sarcoplasmic reticulum Ca(2+)-ATPase and PLB in post-MI left ventricle compared with control. However, the basal levels of both the protein kinase A-phosphorylated site (Ser16) of PLB (p16-PLB) and the calcium/calmodulin-dependent protein kinase-phosphorylated site (Thr17) of PLB (p17-PLB) were decreased by 76% and 51% in post-MI myocytes (P<0.05), respectively. No change was found in the beta-adrenoceptor density, G(salpha) protein level, or adenylyl cyclase activity. Inhibition of phosphodiesterase and G(i) protein by Ro-20-1724 and pertussis toxin, respectively, did not correct the decreased p16-PLB or p17-PLB levels. Stimulation of beta-adrenoceptor or adenylyl cyclase increased both p16-PLB and p17-PLB in post-MI myocytes to the same levels as in sham myocytes, suggesting that decreased p16-PLB and p17-PLB in post-MI myocytes is not due to a decrease in the generation of p16-PLB or p17-PLB. We found that type 1 phosphatase activity was increased by 32% (P<0.05) with no change in phosphatase 2A activity. Okadaic acid, a protein phosphatase inhibitor, significantly increased p16-PLB and p17-PLB levels in post-MI myocytes and partially corrected the prolonged relaxation of the [Ca(2+)](i) transient. In summary, prolonged relaxation of post-MI remodeled myocardium could be explained, in part, by altered basal levels of p16-PLB and p17-PLB caused by increased protein phosphatase 1 activity.
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PMID:Diminished basal phosphorylation level of phospholamban in the postinfarction remodeled rat ventricle: role of beta-adrenergic pathway, G(i) protein, phosphodiesterase, and phosphatases. 1053 53

Sildenafil (Viagra), an inhibitor of phosphodiesterase 5, has a powerful vasodilatory effect on the corpus cavernosa. An evaluation of coronary risk is necessary before its prescription in order to answer two questions: does taking this drug expose the patient to any special risk? Does the return to sexual activity itself carry any risk? Sildenafil is associated with a slight decrease in systolic (10 mmHg) and diastolic (7 mmHg) blood pressure which does not seem to be accentuated by the concommittant use of antihypertensive drugs. The co-administration of nitrate derivatives (before or after taking sildenafil) causes potentially dangerous falls in blood pressure (on average 40 mmHg for the systolic blood pressure). Co-administration of sildenafil and NO-donors is formally contra-indicated. The safety of sildenafil has been shown to be satisfactory in clinical trials: in particular, the risk of myocardial infarction is no greater in treated patients. Sexual activity is a generally moderately intense physical exercise and only rarely causes myocardial infarction. In practice, in patients without known coronary artery disease, the clinical history should be sufficient to determine whether the return of sexual relations is possible without risk. In known cardiac patients, sildenafil is contra-indicated in unstable situations; in stable coronary disease, it would seem wise to take advantage of the annual exercise stress testing to make sure of the absence of ischaemia on effort. In all cases, the patient must be warned that co-administration of nitrate derivatives is an absolure contra-indication to sildenafil treatment.
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PMID:[Sildenafil, the heart patient and the cardiologist]. 1056 4

A combination of ticlopidine and aspirin has been accepted as the standard antithrombotic regimen after coronary stenting. However, ticlopidine poses serious side effects such as neutropenia or thrombocytopenia. Cilostazol, a cyclic adenosine monophosphate phosphodiesterase inhibitor, is a novel antiplatelet agent with vasodilatory properties. We compared the efficacy and safety of cilostazol plus aspirin (C+A) with ticlopidine plus aspirin (T+A) in elective coronary stenting. Three hundred patients were randomly assigned to receive C+A or T+A 2 days before stenting. The primary end point was a composite of angiographic stent thrombosis, or major cardiac events (death, myocardial infarction, bypass surgery, repeat intervention) at 30 days. The secondary end points were bleeding vascular complications, neutropenia, thrombocytopenia, or side effects requiring discontinuation of the drugs at 30 days. The primary end point was reached in 1.4% in the C+A group and 2.0% in the T+A group (p = 1.0). The rate of bleeding vascular complications was 1.4% in the C+A group and 2.0% in the T+A group (p = 1.0). The rate of drug-related side effects was not statistically different between the 2 groups but slightly higher in the T+A group than in the C+A group (2.7% vs 0.7%, p = 0.37). However, neutropenia was seen in 2 patients only in the T+A group. As a poststenting antithrombotic, C+A is as effective as T+A in preventing major cardiac events including stent thrombosis, and safer in that it does not cause neutropenia despite the fact that there is no statistical difference in the incidence of adverse effects and complications.
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PMID:Usefulness of cilostazol versus ticlopidine in coronary artery stenting. 1060 7


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