Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of this study was to examine the effects of pharmacologic alterations of adrenergic terminating mechanisms by cocaine, tropolone, aminophylline, and ketamine on the ability of epinephrine to induce arrhythmias during halothane-nitrous oxide anesthesia in dogs. Because the first three drugs inhibit intraneuronal uptake of catecholamines, extraneuronal catechol-O-methyl transferase (COMT), and phosphodiesterase, respectively, they might be expected to potentiate epinephrine-induced arrhythmias. To evaluate this possibility, the authors devised a technique for determining the minimal arrhythmic dosage of epinephrine that permitted graded assessment of changes in the sensitivity of the heart to epinephrine-induced arrhythmias. When the first three drugs were administered to the same dog in the order listed at intervals of 60 minutes, they sequentially increased the ability of epinephrine to induce arrhythmias. Ketamine, according to several investigators, also appears to block reuptake of catecholamines, and when studied was also found to enhance the arrhythmogenicity of epinephrine. The extent of enhancement was comparable to that seen with cocaine. These results indicate that drugs like cocaine and ketamine that interfere with intraneuronal uptake can facilitate the development of epinephrine-induced arrhythmias and that the successive pharmacologic interference of intraneuron uptake, COMT, and phosphodiesterase leads to a stepwise increase in the arrhythmogenicity of epinephrine.
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PMID:Effects of pharmacologic alterations of adrenergic mechanisms by cocaine, tropolone, aminophylline, and ketamine on epinephrine-induced arrhythmias during halothane-nitrous oxide anesthesia. 18 37

The methods of synthesis and the pharmacological evaluation of a new non-tricyclic antidepressant drug, N-benzo[b]furan-2-ylcarbonyl-N'-benzylpiperazine (befuraline), are reported. The chemical structure of befuraline is clearly different from that of the tricyclic antidepressant drugs. While the gross behavior in animals remains unaffected, the central nervous system depressed by reserpine, tetrabenazine or perphenazine is activated by even small doses of this novel compound. Exploratory activity is prolonged, and performance in operant behavior tests and in the conditioned avoidance response is improved by befuraline, indicating increased alertness, attentiveness and the capacity to react to environmental stimuli. High doses stimulate the CNS, causing EEG desynchronization. Befuraline displays an aggression-inhibiting activity; without having a sedative effect on the animals' normal behavior, it inhibits fighting behavior. The central anticholinergic effect of befuraline is negligible. No apomorphine or tryptamine potentiation is observed and hexobarbital anesthesia is not influenced. The peripheral autonomic nervous system, with the exception of the nictitating membrane in cats, is not affected by befuraline. It has a biphasic effect on the norepinephrine induced contraction of isolated guinea pig seminal vesicle and of isolated cat spleen slices. Although the mechanism of action is as yet not clear, it is assumed that, in addition to a direct influence on the central adrenergic structures, the inhibition of norepinephrine and serotonin uptake and the inhibition of phosphodiesterase are responsible for the drug's effect. Befuraline has no undesirable effects on either the peripheral autonomic nervous system or the cardiovascular system, and it does not affect the normal gross behavior of animals. Because these favorable therapeutic aspects are coupled with low toxicity, befuraline may provide a new alternative in the treatment of depression.
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PMID:Synthesis and pharmacological activity of befuraline (N-benzo[b]furan-2-ylcarbonyl-N'-benzylpiperazine), a new antidepressant compound. 58 30

The feasibility of using beta,beta'-monochloromethylene diadenosine 5',5"'-P1,P4-tetraphosphate (AppCHCl-ppA) as an antithrombotic agent was studied in a rabbit intracarotid cannula thrombosis model previously shown to be sensitive to antiplatelet agents. This analogue, having a P-C-P bridge in place of a P-O-P internucleoside linkage, has been found resistant to phosphodiesterase activity. Rabbits were infused with the dinucleotide at a dose of 50 mg per kg over a 2-hr period, at a controlled rate by pump. A 1-cm length of polyethylene cannula (1 mm i.d.) was tied into the carotid artery. Animals were stable under general anesthesia during the entire period of the experiment. In the control group, 16 of 20 animals formed clots, an incidence of 80%, whereas in the test animals, 6 of the 20 formed clots (30% incidence, P < 0.05). After preincubation of whole blood with 50 microM AppCHClppA at 37 degrees C for up to 3 hr, a consistent suppression of ADP-induced platelet aggregation was observed. The present study suggests that AppCHClppA may be useful as an antithrombotic agent in certain clinical situations, such as hemodialysis, arteriovenous shunts, and introduction of artificial heart valves. It may also possibly prevent extension of recent clots. The toxicity and metabolism of AppCHClppA have, however, yet to be explored.
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PMID:Antithrombotic effect of beta,beta'-monochloromethylene diadenosine 5',5"'-P1,P4-tetraphosphate. 143 14

A chronic animal experiment was designed to examine the changes in blood components induced by the use of a centrifugal pump (CP). In the pump, an impeller spins in a blood chamber by magnetic coupling with a rotating magnet outside the blood chamber. A pulsatile ventricular assist device was implanted between the left atrium and the descending aorta in four goats weighing from 63 to 75 kg; the CP was installed to replace the assist device, without surgery and anesthesia, more than 2 weeks later when the influences of implantation surgery were diminished. Antithrombotic therapy was performed with oral administration of an antiplatelet agent, cilostazol, a cyclic adenosine monophosphate phosphodiesterase at a dose of 30 mg/kg/day. No significant differences were observed in any of the following parameters: 1) hematocrit, 2) plasma free hemoglobin, 3) lactic acid dehydrogenase, 4) adenosine diphosphate, 5) platelet count, 6) fibrinogen, and 7) antithrombin III, between the data before and after the use of the CP, nor were deformation or pseudopods of platelets seen. The CP developed in the authors' institute and evaluated in this study did not damage blood components, and it proved to be a promising device for long-term use.
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PMID:Influence of an impeller centrifugal pump on blood components in chronic animal experiments. 145 25

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

Interactive effects of the phosphodiesterase-III inhibitor amrinone and isoflurane were investigated in cats. Cardiac output (thermodilution method), and intestinal (IBF) and renal (RBF) blood flows (optical flowmetry) were measured. Intestinal (IVR) and renal (RVR) vascular resistances were derived. To discriminate between pressure-related local myogenic vascular responses and primary vascular drug effects, intestinal and renal perfusion pressures (50 mmHg; 6.7 kPa) were controlled. The protocol included steady-state recordings with and without isoflurane in a randomized order, both before and after the administration of amrinone (2 mg.kg-1 i.v. + 2 mg.kg-1.h-1 i.v.. Amrinone induced no significant changes in IVR or RVR during basal chloralose anesthesia. During administration of 0.8% isoflurane, amrinone produced decreases in IVR and RVR, which were more pronounced than the vasodilator responses induced by this dose of isoflurane alone. On the other hand, with 1.6% isoflurane, amrinone did not add to the vasodilation. The cardiac effects of isoflurane and amrinone were small. Our data indicate that the vascular tone before administration of amrinone could be crucial for the vascular response of the drug and that isoflurane can significantly influence the regional circulatory effects of amrinone.
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PMID:Interactive effects of isoflurane and amrinone in the feline intestinal and renal circulation. 203 24

This case report describes the use of enoximone, a potent phosphodiesterase F-IV inhibitor with inotropic and vasodilator actions, to treat low output syndrome after cardiac surgery. The reduced cardiac output was unresponsive to a combination of inotropic drugs and intra-aortic balloon counterpulsation was contraindicated. Cardiac output was increased dramatically by enoximone, but systemic vascular resistance and perfusion pressure remained low until the addition of metaraminol.
Anaesthesia 1990 May
PMID:Management of low cardiac output syndrome after cardiac surgery using enoximone. 214 44

Enoximone belongs to a new class of noncatecholamine-positive inotropes, which selectively inhibit phosphodiesterase type III and increase cyclic AMP (cAMP). This study was performed in 30 coronary artery surgery patients with impaired myocardial function (ejection fraction [EF] less than 50%). The study's two purposes were to investigate the hemodynamic effects of enoximone, 0.5 mg/kg, administered following induction of anesthesia (phase I), and to assess whether enoximone can potentiate the actions of sympathomimetic agents during weaning from cardiopulmonary bypass (CPB) (phase II). Starting with already reduced hemodynamics, induction of anesthesia led to a further deterioration of blood pressure and cardiac output (CO). Administration of enoximone produced a significant increase in cardiac index (CI) (+47%), whereas pulmonary capillary wedge pressure (PCWP) (-37%), pulmonary artery pressure (PAP) (-17%), and systemic vascular resistance (SVR) (-17%) were significantly reduced. Heart rate (HR) was not increased, and no dysrhythmias occurred during the investigation. The hemodynamic effects were maintained for 30 minutes until the start of the operation. In phase II, where weaning from CPB was not possible without pharmacological support, either enoximone (0.5 mg/kg) + epinephrine (0.1 micrograms/kg/min) or only epinephrine (same dosage) was randomly selected. Weaning was successful in both groups, but the combined therapy produced a larger increase in cl and a more pronounced decrease of the elevated filling pressure (PCWP). PAP was not changed in the combined therapy group, but increased in the patients receiving epinephrine alone. It is concluded that enoximone has beneficial hemodynamic effects in the perioperative period, and that potentiation of the effects of epinephrine in severe heart failure may be one of the drug's most useful features.
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PMID:Enoximone treatment of impaired myocardial function during cardiac surgery: combined effects with epinephrine. 215 89

Enoximone belongs to a new class of inotropic drugs that are not related either to digitalis or to catecholamines. It acts primarily through selective inhibition of phosphodiesterase III (PDE-III) and has additional vasodilating properties. Hemodynamic effects of intravenously administered enoximone (0.5 mg/kg) were investigated in patients undergoing aortocoronary bypass grafting before and during anesthesia as well as during extracorporeal circulation (ECC). Patients who were impossible to be weaned off ECC without pharmacological support were investigated also. A significant increase in cardiac index and dp/dtmax, a decrease in pulmonary capillary pressure, and a small decrease in mean arterial pressure were the major hemodynamic effects. Heart rate was not changed and no signs of arrhythmia were seen during the entire investigation period. Interactions with the anesthetics used could not be observed in this study. In patients with impaired myocardial performance during weaning from ECC, enoximone seems to be helpful in stabilizing cardiac output and decreasing filling pressure. The mechanism for improvement appears to be enhanced contractility due to its positive inotropic effects, as well as a decrease in left ventricular outflow resistance resulting from peripheral vasodilation.
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PMID:Hemodynamic effects of enoximone in cardiac surgery patients. 248 Apr 86

The new phosphodiesterase-III inhibitor (PDI) enoximone is a non-catecholamine, non-glycoside cardiotonic agent with concomitant vasodilating properties. It has proved beneficial in patients with severe chronic heart failure. The influence of enoximone i.v. on hemodynamics was investigated during cardiac surgery under various conditions. METHODS. A randomized series of 60 patients undergoing elective aorto-coronary bypass grafting were studied. The hemodynamic effects of 0.5 mg/kg enoximone given i.v. as a bolus (30 s) were investigated before anesthesia (n = 10), during anesthesia (n = 10), and during extracorporeal circulation (ECC, n = 10) and compared with those observed in corresponding control groups (n = 10 in each control) of patients who had received saline solution as placebo. Anesthesia was maintained with weight-dependent dosages of fentanyl, midazolam and pancuronium bromide. All patients were invasively monitored by means of a pulmonary artery catheter. Additionally, left ventricular pressure (LVP), left ventricular end-diastolic pressure (LVEDP) and dp/dtmax were measured before the initiation of ECC. During ECC direct vascular effects were investigated with measurement of perfusion pressure and the volume of the oxygenator. RESULTS. Before the induction of anesthesia no significant change in MAP and HR could be observed, whereas CI increased (+20%) and TSR decreased (-24%) significantly. During anesthesia, the injection of enoximone was followed by a significant decrease in MAP only in the 1st min (-17%); baseline level was reached again after 6 min; and HR was slightly increased (+8%). TSR (-31%) and LVEDP (-38%) decreased, whereas CI (+17%) and dp/dtmax (+45%) were increased significantly. During ECC perfusion pressure (-37%) and the volume of the oxygenator (-17%) were significantly decreased, demonstrating direct vasodilating effects on both the arteries and the vein. CONCLUSION. Arterial and venous vasodilation with an increase in myocardial performance (dp/dtmax) resulting in an increase in CI were the predominant hemodynamic effects of enoximone i.v. No arrhythmogenic effects or interactions with the anesthetics used were observed in this study.
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PMID:[Hemodynamic effects of the new phosphodiesterase inhibitor enoximone in heart surgery patients]. 252 51


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