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 phosphodiesterase inhibitors have been recognised as potent inotropic and vasodilating drugs. In acute congestive heart failure they increase cardiac output, decrease left pulmonary capillary wedge pressure, and reduce total peripheral resistance with an improvement in loading conditions of the failing heart. Their potency in reversal of symptoms of acute congestive heart failure is quite similar to, or even better than, treatment with intravenous catecholamines and sodium nitroprusside. In chronic congestive heart failure, however, these agents increase mortality and have deleterious effects in the outcome of patients with severe left ventricular dysfunction.
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PMID:Current status of phosphodiesterase inhibitors in the treatment of congestive heart failure. 128 64

The existence of multiple isozymes of cyclic nucleotide phosphodiesterase (PDE) in many tissues including the heart has been demonstrated. Five isozyme families, each composed of several subtypes and having different tissue and subcellular distributions, have been characterized. Selective inhibitors of PDE III (cGMP-inhibited PDE) elevates the cAMP level which mediates positive inotropic actions with compartmentation of cAMP related to cardiac cell particulate structures. Both cardiac cytosolic and particulate PDE III were potently and selectively inhibited by the new cardiotonic agents competitively with respect to cAMP, except for vesnarinone. There might be at least two subtypes of PDE III, and vesnarinone may be a selective subtype inhibitor of PDE III in human heart. It was also reported that vesnarinone was beneficial in treating patients with congestive heart failure. Moreover, selective inhibitors of PDE III with ancillary properties such as calcium sensitization may prove to be more useful drugs for the treatment of heart failure.
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PMID:[Molecular cardiopharmacology of selective inhibitors of cyclic nucleotide phosphodiesterase isozymes]. 132 1

OPC-18790 [(+/-)-6-[3-(3,4-dimethoxybenzylamino)-2-hydroxypropoxy]- 2(1H)-quinolinone], a novel positive inotropic agent, was investigated in several in vitro and in vivo experiments to elucidate its cardiovascular effects and its mechanism of action. In isolated blood-perfused dog heart preparations, OPC-18790 increased contractile force at 10 to 1,000 nmol i.a.; increased coronary arterial blood flow at 30 to 1,000 nmol; and decreased sinus rate slightly at 1,000 nmol. Atrio-ventricular nodal conduction was slightly facilitated with OPC-18790 (10 to 1,000 nmol), whereas ventricular automaticity tended to decrease. OPC-18790 (10(-6) to 10(-4) M) increased contractile force in isolated ventricular muscles of dogs, cats, rabbits and guinea pigs but not rats. OPC-18790 increased left ventricular contractile force dose-dependently in anesthetized open-chest dogs and in conscious dogs with slight or no changes in heart rate and blood pressure. The positive inotropic effect of OPC-18790 was not affected by beta-blockade. OPC-18790 (10(-5) to 10(-4) M) prolonged the duration of action potential in guinea pig papillary muscles. Na+, K(+)-ATPase was not inhibited, but peak-III phosphodiesterase (low Km cyclic AMP specific fraction, inhibited by cyclic GMP) was inhibited by OPC-18790 (IC50 = 0.41 x 10(-6) M) in dog myocardium. However, such an inhibitory action of phosphodiesterase can hardly be reconciled with the lack of a positive chronotropic effect shown by OPC-18790. Thus, these results suggest that OPC-18790 may have an additional mechanism. The cardiovascular effects revealed by this study suggest that OPC-18790 may exert a beneficial effect in the treatment of congestive heart failure.
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PMID:Cardiovascular actions of OPC-18790: a novel positive inotropic agent with little chronotropic action. 132 45

Activation of the adrenergic nervous system appears to play a crucial role in the genesis of fatal arrhythmias associated with the very early stages of acute myocardial infarction. The second messenger of beta-adrenergic catecholamine stimulation, cyclic adenosine monophosphate (AMP), has established arrhythmogenic qualities, acting by an increase in cytosolic calcium, which potentially has three adverse electrophysiologic effects. First, stimulation of the transient inward current by excess oscillations of cytosolic calcium can invoke delayed afterdepolarizations, so that triggered automaticity can develop in otherwise quiescent ventricular muscle. Second, cyclic AMP can evoke calcium-dependent slow responses in depolarized fibers, so that conditions for reentry are favored. Third, excess cytosolic calcium can cause intercellular uncoupling with conduction slowing. Focal changes in cyclic AMP and cytosolic calcium promote the development of ventricular fibrillation. Beta-adrenergic blockade can limit the formation of cyclic AMP in ischemic tissue. Furthermore, by reducing sinus tachycardia it can lessen cytosolic calcium overload. Hence, beta-adrenergic blockade helps to prevent ventricular fibrillation in the early stages of acute myocardial infarction and protects from sudden death in the postinfarction phase. In congestive heart failure, abnormalities of cytosolic calcium patterns exist with cytosolic calcium overload. It is proposed that the adverse effects of phosphodiesterase inhibitors on the mortality rate in patients with congestive heart failure can be explained by increased rates of formation of cyclic AMP and the development of calcium-dependent arrhythmias. Because calcium is the ultimate messenger of cyclic AMP-induced arrhythmias and because cytosolic calcium is increased in heart failure, it will be difficult to develop positive inotropic agents that are free of the risk of sudden death.
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PMID:Potential arrhythmogenic role of cyclic adenosine monophosphate (AMP) and cytosolic calcium overload: implications for prophylactic effects of beta-blockers in myocardial infarction and proarrhythmic effects of phosphodiesterase inhibitors. 135 May 97

Beta-adrenergic stimulants (Dobutamine and Dopamine) and recently introduced phosphodiesterase inhibitors (PDI) such as Amrinone, Milrinone, Enoximone and Piroximone are the principal inotropic agents for the treatment of acute cardiac failure. Most of the hemodynamic effects of these drugs are comparable, but peripheral vasodilatation is more marked with PDI. A potential advantage of the latter group is the lack of development tolerance, which occurs within 48 to 72 hours after beta-stimulants. On simultaneous administration, additive effects can be observed. Short term clinical results with PDI are good, especially in patients with postoperative cardiocirculatory failure, including cardiogenic shock. In contrast, long-term oral treatment with Amrinone, Milrinone and Enoximone in recent studies was disappointing. Efficacy was not superior to Digoxin, and unwanted side effects were frequent. Intermittent instead of continuous administration of positive inotropic agents should be evaluated in patients with severe congestive heart failure not responding to vasodilators and diuretics.
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PMID:[New positive inotropic drugs in acute and chronic heart failure]. 135 9

The phosphodiesterase inhibitor UK 61260 exhibits positive inotropic activity in animal studies and is under clinical investigation for treatment of congestive heart failure (CHF). We examined the lusitropic and inotropic responses to UK 61260 in electrically driven (1 Hz, 37 degrees C) human auricular trabeculae (AUT, aortocoronary bypass operation, nonfailing hearts, n = 13) and in papillary muscle strips (PAP) from moderately (New York Heart Association, NYHA II-III, mitral valve replacement, n = 6) and terminally (NYHA IV, heart transplantation, n = 7) failing human hearts. For comparison, we studied the effects of UK 61260 after prestimulation with forskolin (FOR 0.03 microM) and isoprenaline (ISO 0.03 microM), as well as the effects of milrinone (MIL 1-1,000 microM), ISO (0.01-10 microM), ouabain (OUA, 0.1 microM), and Ca2+ (1.8-15 mM) in failing human myocardium alone. UK 61260 increased force of contraction (FOC), peak rate of tension increase (+T) and decay (-T) significantly (p less than 0.01) in AUT but not in PAP of NYHA II-III and NYHA IV. Only after prestimulation (FOR and ISO), was UK 61260 effective in stimulating FOC in NYHA II-III and NYHA IV. UK 61260 increased (p less than 0.01) +T and -T, resulting in a shortening of twitch time. As judged from the EC50 values, UK 61260 increased FOC more potently than MIL. The effectiveness of OUA and Ca2+ in increasing developed tension in human failing myocardium was significantly higher as compared with UK 61260. We conclude that during stimulation of the cardiac beta-adrenoceptor-adenylate-cyclase system, UK 61260 increases myocardial systolic and diastolic function in failing human myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of the phosphodiesterase inhibitor UK 61260 on human myocardial inotropy and diastolic relaxation. 137 20

1. SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 microM. The IC50 values were greater than 100 microM for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 microM) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 microM). 2. In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3. Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dp/dtmax in the range 10-50 micrograms kg-1. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtmax were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4. SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5. The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets. 6. Collagen-induced aggregation of rat PRP was also inhibited by SK&F 95654 (ICso = 65 nM). The effects of SK&F 95654, administered intravenously, on ex vivo platelet aggregation were studied in the conscious rat. At 1 mg kg-', SK&F 95654 inhibited aggregation for at least 4 h post dose and was more potent than the two other cGI-PDE inhibitors studied (siguazodan and SK&F 94120).7. In contrast to its potent effects on heart and platelets, SK&F 95654 caused only a modest relaxation of histamine- or U46619-induced bronchoconstriction in the anaesthetized, ventilated guinea-pig.8. Taken together, these results indicate that SK&F 95654 may be a suitable agent for the treatment of congestive heart failure.
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PMID:The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function. 142 92

Pimobendan is a positive inotropic agent with additional calcium-sensitizing effects of the phosphodiesterase III-inhibitor group. In short-term studies, beneficial hemodynamic effects have been demonstrated in patients with congestive heart failure. The aim of this prospective study was to examine the long-term effect of pimobendan (during at least 6 months) on subjective state, hemodynamic parameters, and arrhythmias in patients with congestive heart failure NYHA classes II and III. After double-blind randomization, 24 patients received pimobendan 5 mg bid or placebo orally in addition to a basic therapy (diuretics, digitalis). After 3 months, pimobendan-treated patients showed a significant clinical improvement (p < 0.03). In the placebo group, one patient underwent acute cardiac transplantation due to rapid clinical deterioration; another patient died suddenly after 5 months. No cardiac events occurred in the pimobendan group. In comparison to placebo, no proarrhythmogenic effect of pimobendan was detected. Clinical stabilization of patients in the pimobendan group was not paralleled by improvement of the hemodynamic parameters of left-ventricular performance.
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PMID:[Pimobendan (UDCG 115 BS) in long-term therapy of chronic heart failure]. 144 95

Indolidan (IN) experimentally inhibits type IV phosphodiesterase. It was administered to twelve patients (age 64 +/- 15 years) with New York Heart Association (NYHA) class 2-3 congestive heart failure in which digoxin and diuretic therapy were continued. IN was administered i.v. at 1,180 +/- 340 micrograms (15 micrograms/kg) over two hours. After 24 hours, IN was given p.o. at 231 +/- 44 micrograms. The time course effect of IN i.v. revealed an increase in cardiac index and a decrease in pulmonary capillary wedge pressure and blood pressure. Daily oral administration of IN or placebo was carried out for up to 3 months. There were no significant hemodynamic changes of chronically administered IN. The maximum oxygen uptake increased in placebo relative to IN therapy. IN tended to be arrhythmogenic as evidenced by a general increased frequency of ventricular premature contractions of both single and paired type. Therefore, IN had some hemodynamic efficacy on acute i.v. and p.o. administration but not during chronic therapy, and there was negative safety features of arrhythmias.
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PMID:Clinical effect of indolidan in congestive heart failure. 144 58

Phosphodiesterase III inhibitors have been established in recent years in the therapy of congestive heart failure. Many disadvantages, such as extensive vasodilation and the lack of proven positive inotropic properties combined with thrombepenia and elevation of transaminases, have complicated the handling of the drug in clinical practice. Enoximone, an imidazole derivative, has been demonstrated to be more cardioselective and vasodilation has been found to be less pronounced than with amrinone. As a consequence, research was performed to enhance the cardioselectivity of phosphodiesterase III inhibitors by reduction of non-specific cross-reactivity with other phosphodiesterases, and R80122 (Janssen Pharmaceutics, Belgium) was introduced into clinical practice. R80122 ((E)-Ncyclohexal-N-methyl-2[[[phenyl (1,2,3,5-tetrahydro-2 oxoimidazo [2,1b]-quinazolin-7-yl)methylene] amino] oxy] acetamide) is a selective inhibitor of phosphodiesterase (PDE) IIIc, which is localized in the myocardium. Thus, its inhibition leads to a positive inotropic effect, whereas phosphodiesterase IIIRo is found in the vessel wall and causes vasodilation. This study was performed to investigate the hemodynamic profile of R80122 under clinical conditions. Additionally, the intestinal hemodynamics were recorded and changes in intestinal perfusion compared with changes in global hemodynamics. METHODS. The study was thoroughly discussed and approved by the local ethics committee; all patients gave written informed consent. The investigation was performed on ten male patients who were about to undergo elective coronary artery bypass surgery. History, physical examination and laboratory results were within the normal limits and revealed no evidence of liver disease. The usual medication was continued until the day before the operation. Premedication consisted of 2 mg flunitrazepam p.o. in the evening before the operation and 1.5 h before induction of anaesthesia. The determination of hepatic plasma flow was performed by the indocyanine green (ICG) infusion extraction technique using liver vein catheterization. After induction of anaesthesia (MP1), after application of a bolus dose of R80122 (0.3 mg/kg BW) (MP2) and at sternotomy (MP3), hemodynamic data (heart rate, arterial pressure, cardiac output) were recorded and blood samples for the determination of hepatic plasma flow by the concentration of ICG were collected. Anaesthesia was induced with a bolus dose of 0.2 mg/kg BW etomidate, 7 micrograms/kgBW fentanyl and 0.1 mg/kgBW pancuronium and maintained with a continuous infusion of 20 micrograms/min fentanyl, 300 micrograms/min midazolam and mechanical ventilation with O2/N2O at an FiO2 of 0.5. Statistical analysis was performed using the Wilcoxon-Mann-Whitney U test comparing the results after induction of anesthesia (MPI) with those after application of R80122 (MPII) and the results of MPII with those at sternotomy (MPIII). Statistical significance was assumed at P less than 0.05. RESULTS. After the induction of anaesthesia, the median heart rate (HR) was 56/min and did not change after administration of R80122. During sternotomy there was a significant increase in the HR from 64 to 78/min (P less than 0.05). Median arterial blood pressure (MAP) tended to decreased from 91 mm Hg after induction of 77 mm Hg after administration of R80122, although there was no statistical significance because of interindividual differences in the tendencies. At sternotomy, MAP remained unchanged. Cardiac output (CO) increased by 60% after administration of R80122 (P less than 0.01) and did not change during sternotomy. As a consequence of the changes in HR and CO, stroke volume (SV) increased by 22% after administration of R80122 (P less than 0.025) and decreased to control values during sternotomy.
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PMID:[Effects of R80122. The influence of a new phosphodiesterase inhibitor on global and intestinal hemodynamics in coronary surgery patients]. 152 59


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