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 effect of cAMP phosphodiesterase inhibitor EG626 on the left ventricular function was studied in 23 patients with ischemic heart disease at rest and during the IHG test. Administration of a single dose of the substance produced changes in STIs indicating an increase in cardiac output and a possible enhancement of myocardial contractility during the IHG test. EG626 may have a beneficial effect on impaired left ventricular function in patients with ischemic heart disease.
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PMID:Effect of isometric handgrip on systolic time intervals in patients with ischemic heart disease and cyclic amp phosphodiesterase inhibitor pretreatment. 19 6

The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1-100 microM rolipram when neutrophils were stimulated with a 10(-7) M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 +/- 0.095 micrograms/ml (2.76 +/- 0.34 microM) at the time of reperfusion, and 0.574 +/- 0.098 micrograms/ml (2.08 +/- 0.36 microM) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 +/- 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 +/- 0.07 ml/min/g, n = 6; p = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of granulocyte cAMP-phosphodiesterase by rolipram in vivo is not sufficient to protect the canine myocardium from reperfusion injury. 137 23

Improved contractility after applying piroximone (PIR) a new phosphodiesterase III inhibitor drug, is difficult to prove clinically. However, augmented contractility could increase the risk of myocardial ischemia when used in coronary artery disease (CAD). Analysis of the end-systolic pressure-volume relationship (ESPVR) as a load-independent parameter of the contractile left ventricular (LV) function allows for differentiation of PIR's effects: contractility vs. unloading. We therefore analyzed ESPVR and LV function in 16 CAD patients before and after PIR, 0.75 mg/kg intravenously. Emax increased by 39% (9/16 patients) and loops of the ESPVR (16 patients) moved leftward, indicating improved contractility. The difference in percent change PIR versus control (16 patients) demonstrated augmentation of LV function via unloading: LV volumes decreased (ESV by 37%, EDV by 19%), LV-filling pressure by 34%, and systemic vascular resistance by 19%; dP/dtmax increased by 28%, LV efficiency by 24%, cardiac index by 21%, and ejection fraction by 13%. Pacing-induced anginal threshold increased by 47% after PIR while the ischemic postpacing LV-filling pressure and ST-segment changes tended to normalize under the drug's influence. Thus, PIR improved LV function both by unloading and by positive inotropy. Lack of PIR-induced angina and an increased anginal threshold indicate that the drug can be used safely in CAD patients as well. The analysis of ESPVR proved to be safe and reliable in identifying contractility during the diagnostic cardiac catheterization routine.
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PMID:Proof for piroximone's inotropic influence; can it safely be used in coronary artery disease? Analysis of end-systolic pressure-volume relations (conductance technique). 138 31

Treatment of patients with heart failure due to major ventricular systolic dysfunction should aim not only at symptomatic but also at prognostic improvement. If correction of the underlying problem is not possible, treatment should slow down the progression of cardiac failure and eliminate triggers for sudden cardiac death due to electromechanical dissociation or arrhythmias. In every patient with chronic congestive heart failure screening for myocardial ischemia and complete revascularization is mandatory, if possible. In patients with coronary artery disease and diminished systolic function, beta-blockade may improve prognosis by reducing ischemic events and sudden cardiac death. The incidence of life-threatening arrhythmias in patients with heart failure may be reduced by eliminating facilitating factors like electrolyte disturbances, altered autonomic tone and raised intracardiac pressure rather than by antiarrhythmic medical treatment itself. One of the most important prognostic aspects in treatment is the interference with the development of the cardiomyopathy of overload, uniformly observed in chronic congestive heart failure. Modification of mechanical and neuroendocrine stimuli may postpone myocardial hypertrophy and interstitial hyperplasia as a consequence of altered gene expression. Early treatment with ACE inhibitors and in certain patients with betablockers are the most promising strategies to delay the progression of the disease. In contrast, positive inotropic drugs, including digitalis and phosphodiesterase inhibitors, do not improve prognosis. Calcium antagonists should also be used with restriction, as Verapamil and Diltiazem, but also Nifedipine may adversely affect the outcome in congestive heart failure patients.
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PMID:[Prognostic aspects in the treatment of chronic heart insufficiency]. 173

The available literature on the evaluation of diastolic function, the importance of diastolic dysfunction in congestive heart failure (CHF), and the effects of therapeutic agents on diastolic dysfunction are summarized. The normal cardiac cycle consists of two components: systole (contraction; ventricular emptying) and diastole (dilation; ventricular filling). Recent studies have shown that 30-40% of patients with CHF have normal systolic function; the majority of these patients have diastolic dysfunction as the underlying disorder. As a result, the role of diastolic dysfunction in CHF is currently an area of interest for researchers. The two primary causes of diastolic dysfunction are left ventricular hypertrophy and ischemic heart disease. Patients with CHF caused by diastolic dysfunction and patients with CHF caused by systolic dysfunction have nearly identical clinical presentations. Therapy with diuretics, vasodilators, angiotensin-converting-enzyme inhibitors, beta-agonists, the partial beta-agonist xamoterol, phosphodiesterase III inhibitors, or calcium-channel blockers may be beneficial in patients with diastolic dysfunction. Therapy with digitalis glycosides would be of no benefit, and could theoretically be detrimental, in patients with predominant diastolic dysfunction. Available data indicate that beta blockers have neither an important beneficial effect nor an important detrimental effect on diastolic function. Continued studies into diastolic dysfunction and the diastolic properties of agents that are used in the treatment of CHF should enhance the understanding of this clinical syndrome and the drugs used to treat it.
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PMID:Diastolic dysfunction in congestive heart failure. 179 21

Enoximone, a phosphodiesterase inhibitor, is a positive inotropic agent with direct vasodilator properties. Its acute effects after I.V. administration and the possibility of oral relay were studied in 14 patients (13 men and 1 woman), 40 to 78 years of age (mean 61 years) with Stage IV cardiac failure (NYHA Classification). Eleven patients had dilated cardiomyopathy, 2 had ischemic heart disease and 1 a dilated hypertrophic cardiomyopathy. The haemodynamic inclusion criteria were: cardiac index less than or equal to 2.2 l/mn/m2 and pulmonary capillary pressure greater than or equal to 18 mmHg. Patients with cardiogenic shock and severe renal or hepatic failure were excluded. The drug was administered as a bolus of 1 mg/kg followed by a continuous infusion of 5 to 15 g/kg/mn (average 8.9 +/- 2.6 for 7 to 72 hours; average 27 +/- 16 hours). Haemodynamic effects of I.V. administration: no change in heart rate, slight lowering of blood pressure, very significant reduction in right atrial and pulmonary capillary pressures, of pulmonary artery pressures, of arteriolo-capillary and systemic resistances and marked increase in cardiac output. General tolerance was excellent with no clinical secondary effects and no signs of hepatic, renal or haematological (platelets) toxicity. Cardiac tolerance was also excellent, no aggravation of preexisting arrhythmias. There was no immediate mortality. Oral relay was undertaken in 14 patients with a daily dose of 300 mg in 12 cases, 400 mg in 1 case and 500 mg in 1 case. Six patients underwent control haemodynamic evaluation on the 8th day: there were no signs of the haemodynamic improvement obtained by I.V. administration.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Enoximone: hemodynamic effect in patients with cardiac insufficiency]. 214 30

Mechanical ventilation is a valuable therapeutic option in left ventricular failure because of its effect on ventricular load. However, weaning cardiac patients form mechanical ventilation may result in severe pulmonary oedema, especially if it is not properly prepared. Some of the factors which contribute to pulmonary oedema are: 1) increased venous return due to the inversion ot the regime of inthrathoracic pressures and the release of catecholamines commonly observed during weaning, 2) reduction of left ventricular compliance due to myocardial ischemia, compression of the cardiac chambers by the lungs, ventricular interdependence in some cases and left ventricular dilatation in others, 3) increased left ventricular afterload due to negative intrathoracic pressures and increased systolic blood pressure. Of all the causes of unsuccessful weaning, left ventricular dysfunction should be carefully considered because its treatment alone may enable the patients to be taken off the ventilator. The authors report six cases of pulmonary oedema in coronary patients after discontinuing mechanical ventilation. The administration I.V. enoximone, a phosphodiesterase inhibitor, prevented acute left ventricular dysfunction in 5 of the 6 cases and enabled successful and definitive weaning from mechanical ventilation.
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PMID:[Left ventricular dysfunction while weaning from mechanical ventilation. Contribution of enoximone]. 214 40

The actions of SK&F 94120, a selective phosphodiesterase (PDE III) inhibitor, have been characterised on human ventricular myocardium obtained from heart failure patients. Some actions have been compared directly with those of the drug on guinea pig and cat ventricular myocardium. SK&F 94120 caused positive inotropic responses in preparations from all three species. In the human preparations, there was no evidence of differential activity in ventricles obtained from patients with heart failure associated with ischaemic heart disease, congestive cardiomyopathy, or mitral valve disease. The mechanism of positive inotropic activity of SK&F 94120 demonstrated characteristics of PDE III inhibition--e.g., potentiation of isoprenaline responses and reversal by carbachol. In addition, in human tissue a highly significant correlation between positive inotropic activity and increases in intracellular cAMP was demonstrated. Electrophysiological studies in human and guinea pig myocardium demonstrated that SK&F 94120 enhanced the second inward Ca2+ current over the same concentration range as that needed for positive inotropic activity. This was demonstrated in preparations incubated in Krebs bicarbonate solution and, more clearly, in solutions with raised K+ concentration. The data described in this report establish that inhibition of PDE III is an effective positive inotropic mechanism in human ventricular myocardium. Comparison of the responses in human, guinea pig, and cat myocardium shows clear similarities of responses with only small quantitative differences.
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PMID:Analysis of responses to a selective phosphodiesterase III inhibitor, SK&F 94120, on isolated myocardium, including human ventricular myocardium from "end-stage" failure patients. 244 40

The number of cardiac beta-adrenoceptors and the positive inotropic effect of isoprenaline and milrinone were measured in cardiac membranes and isolated, electrically driven muscle strips from nonfailing donor hearts and from patients with mitral valve disease (NYHA II-III), ischemic heart disease, and dilated cardiomyopathy (NYHA IV). In nonfailing hearts, the number of beta-adrenoceptors were 41.5 fmol/mg protein (mean, n = 3). In ischemic heart disease and NYHA II-III, there was a loss of cardiac beta-adrenoceptors (22.1 fmol/mg protein, mean, n = 3; 23.2 +/- 2.7 fmol/mg protein, n = 30), respectively. In NYHA IV, there was a pronounced reduction of the number of cardiac beta-adrenoceptors to 12.1 +/- 1.5 fmol/mg protein (n = 15). The Kd value did not differ in either group. Correspondingly, the positive inotropic effect of isoprenaline was more pronounced in nonfailing myocardium, reduced in NYHA II-III and ischemic heart disease and almost blunted in NYHA IV. Similar results were observed with the phosphodiesterase inhibitor milrinone. A good correlation of the beta-adrenoceptor density to the maximal positive inotropic effect of isoprenaline and milrinone was observed. Neither the number of cardiac beta-adrenoceptors nor the positive inotropic effect of isoprenaline correlated with the age of the patients. We conclude that the number of cardiac beta-adrenoceptors and the positive inotropic effect of beta-adrenoceptor agonists are reduced in the failing human heart depending on the severity of heart failure. Furthermore, the positive inotropic effect of milrinone is also reduced and related to the reduction of beta-adrenoceptors. The lack of correlation with the age of the patients provides evidence for a predominant role of heart disease rather than aging in the reduction of beta-adrenoceptors and subsensitivity to cyclic AMP-increasing positive inotropic agents in the failing human heart.
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PMID:Subsensitivity of the failing human heart to isoprenaline and milrinone is related to beta-adrenoceptor downregulation. 246 92

Conventional pharmacologic therapy for the management of congestive heart failure includes inotropic, vasodilator, and diuretic agents. Phosphodiesterase inhibitors are a new class of inotropic agent that possesses both inotropic and vasodilating capability. Currently, only one of these agents, amrinone (Inocor), has been approved for clinical use in the United States. Nursing management of the patient receiving amrinone requires knowledge of the appropriate vehicle for administration, the recommended dose, and adverse reactions. A thorough understanding of the hemodynamic alterations in CHF, as well as the effect of amrinone on these hemodynamic parameters, is an essential component of nursing care. Amrinone is only available for intravenous administration. Clinical trials, involving several investigational phosphodiesterase inhibitors, are being conducted. These drugs are being administered orally and intravenously. The goal of research is to develop a potent positive inotrope that will be available for both oral and intravenous administration. The focus of current research involving phosphodiesterase inhibitors includes studying the effect of these agents on myocardial ischemia as well as the mortality and morbidity of CHF. Additional knowledge regarding these and other issues is needed before the new inotropes can become a routine component of the pharmacological armamentarium for treatment of CHF.
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PMID:Cardiac drugs: new inotropes. 281 83


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