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 present study investigated the effects of celiprolol a novel beta 1-antagonist with partial beta 2-agonist activity on the human failing heart. Experiments were performed on isolated electrically driven atrial and ventricular cardiac preparations and in membrane preparations from the left ventricles of nine patients (four with dilated cardiomyopathy; five with ischemic cardiomyopathy) undergoing cardiac transplantation for terminal heart failure. Celiprolol produced a negative inotropic effect in atrial and ventricular heart muscle. However, in the presence of forskolin--which activates the catalyst of the adenylate cyclase-or the cAMP phosphodiesterase inhibitor milrinone, celiprolol produced concentration-dependent positive inotropic effects and positive lusitropic effects. Experiments with the beta 1-and beta 2-selective antagonists CGP 207.12A and ICI 118.551, respectively, suggest that the positive inotropic response is mediated by beta 2-adrenoceptors. In radioligand binding experiments, a selectivity of 15.7 [-Gpp(NH)p] or 23.9 [+Gpp(NH)p] as judged from the Ki values--of binding to beta 2-adrenoceptors was measured in the failing human ventricular myocardium. Competition curves with celiprolol alone and in the presence of the guanine nucleotide Gpp(NH)p revealed no evidence for agonist activity at beta 1- or beta 2-adrenoceptors. It is concluded that amplification of the cAMP response is able to unmask partial agonist activity of celiprolol in the failing human heart at beta 2-adrenoceptors. The inotropic measurements are a more sensitive approach than radioligand binding studies. Whether the pharmacological profile of celiprolol will be useful in conditions like heart failure is questionable with respect to the potential downregulation of beta 2-adrenoceptors by its partial agonist activity.
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PMID:Positive inotropic effects due to partial agonistic activity of the beta-adrenoceptor antagonist celiprolol following amplification of cAMP formation in failing human myocardium. 127 96

In patients with congestive heart failure, down-regulation of beta-adrenoceptors is present, probably as a result of sympathetic overstimulation. In end-stage dilated cardiomyopathy, beta 1-adrenoceptor density is markedly reduced, while beta 2-adrenoceptor density is normal. This latter finding does not necessarily imply normal sensitivity to beta 2-stimulation, due to possible alterations in the beta-adrenoceptor/adenylate cyclase complex beyond the receptor. In some disease states, such as ischemic cardiomyopathy and mitral valve disease, there seems to be a concomitant reduction of the beta 1- and beta 2-adrenoceptor density. The finding of beta-adrenoceptor down-regulation has stimulated the search for novel therapeutic approaches in heart failure patients. Beta-agonists could even further down-regulate beta receptors, and this perhaps explains why they seem not to be useful in long-term use. Agents that directly stimulate adenylate cyclase activity, such as forskolin, or that increase cyclic adenosine monophosphate degradation, such as the phosphodiesterase inhibitors, are being tested. Beta-adrenoceptor blocking agents were used in treatment of heart failure before beta-adrenoceptor down-regulation was recognized in these patients. It is tempting to speculate that the beneficial clinical and hemodynamic effects seen in these patients treated with metoprolol is indeed due to an antagonism of the beta-adrenoceptor down-regulation. Studies testing whether beta-adrenoceptor blocking agents can improve survival in congestive heart failure patients are on-going.
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PMID:Receptor function in heart failure. 164 66

Forskolin, a diterpene derivative of the Indian plant Coleus forskhohlii, proved to be a marked positive inotropic and vasodilatory compound in animal experiments with a mechanism of action distinct from catecholamines, cardiac glycosides, and phosphodiesterase-inhibiting compounds. The cardiovascular effects of forskolin seem to be mediated by a direct stimulatory action at the catalytic unit of sarcolemmal adenylate cyclase. The aim of the present study was to clarify the cardiovascular profile of this compound in 12 patients with stage III (NYHA) congestive cardiomyopathy. The effects of forskolin were investigated by invasive techniques using the thermodilution catheter method and compared to the beta 1-receptor agonist dobutamine and the vasodilator sodium nitroprusside in an intraindividual comparison. Forskolin dose-dependently reduced cardiac pre- and afterload values, and led to a reduction in systolic, diastolic, and mean pulmonary artery pressure as well as pulmonary wedge pressure by greater than 50% concomitant with an increase in cardiac output. There was a slight increase in heart rate. Cardiac stroke volume and stroke volume index was increased by approximately 70%. The cardiovascular effects of dobutamine and nitroprusside were less pronounced; however, it seemed that a similar hemodynamic profile could be achieved by the combination of both dobutamine and sodium nitroprusside. In view of the rapid development of tolerance toward beta 1-receptor stimulation, forskolin, with its receptor-independent mechanism of action, may be advantageous for the treatment of severe heart failure, especially in patients with catecholamine-insensitive heart failure.
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PMID:Cardiovascular effects of forskolin (HL 362) in patients with idiopathic congestive cardiomyopathy--a comparative study with dobutamine and sodium nitroprusside. 169 72

The comparison of two invasive studies using intravenous application of the phosphodiesterase enoximone demonstrated unchanged cardiac output in patients with dilated cardiomyopathy NYHA II-III, and increased cardiac output (from 3.22 +/- 1.15 to 5.04 +/- 2.05 l/min; p less than 0.01) in acute heart failure. This comparison of hemodynamic parameters in addition to studies on myocardial oxygen consumption support the use of intravenous enoximone in acute heart failure, whereas the long-term application of enoximone in chronic heart failure is judged to be critical.
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PMID:[Vasodilatation and positive inotropic effect of the phosphodiesterase inhibitor enoximone]. 183 95

The benzimidazol analogue BM14.478 is a phosphodiesterase inhibitor with both vasodilator and positive inotropic properties. Hemodynamic parameters and plasma hormone levels of 8 patients (1 female, 7 male) with chronic congestive heart failure NYHA Classes II-IV (1 patient with coronary artery disease, 7 patients with primary dilated cardiomyopathy) were assessed before and until 6 h after the intravenous application of 1.0 mg BM14.478. There was a significant decrease of mean pulmonary artery pressure (28 +/- 11 vs. 23 +/- 11 mmHg; p less than 0.05), mean right atrial pressure (8.6 +/- 5.2 vs. 5.0 +/- 4.7 mmHg; p less than 0.02), and systemic vascular resistance (1651 +/- 484 vs. 1206 +/- 252 dynes.s.cm-5; p less than 0.05) as early as 10 min after injection of BM14.478. Pulmonary vascular resistance also was reduced (128 +/- 86 vs. 61 +/- 39 dynes.s.cm-5, 30 min after injection; p less than 0.02). Simultaneously there was a significant increase of cardiac index (2.3 +/- 0.7 vs. 3.1 +/- 0.8 l.min-1.m-2, 10 min after injection; p less than 0.02), and stroke volume index (28.8 +/- 11.7 vs. 33.9 +/- 8.5 ml.min-1.m-2; 30 min after injection; p less than 0.05). Although mean heart rate did not change significantly, some patients reacted with a transient increase. There was also a slight but insignificant increase of the double product. No serious side effects were observed. The hemodynamic improvement was followed by a delayed reduction of plasma levels of epinephrine (51 +/- 20 vs. 41 +/- 21 pg/ml; p less than 0.02; 30 min after injection) and atrial natriuretic peptide (229 +/- 283 vs. 121 +/- 168 pg/ml; p less than 0.05; 1 h after injection). Mean levels of plasma norepinephrine, however, did not change significantly and individual responses showed large variations, which could not be predicted by the behavior of the hemodynamic parameters. Three of eight patients (2 of these with elevated baseline filling pressures) even showed a marked increase of plasma norepinephrine levels after BM14.478. Response of plasma renin activity and plasma vasopressin levels to BM14.478 also was heterogeneous. According to the results of this study, acute administration of the phosphodiesterase inhibitor BM14.478 has an immediate beneficial hemodynamic effect in patients with severe congestive heart failure by reducing both preload and afterload, and by increasing cardiac index and stroke volume. However, this improvement of hemodynamic parameters is not necessarily accompanied by a favorable short-term response of plasma hormones, and therefore does not allow any conclusions on survival of these patients.
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PMID:Hemodynamic and neuroendocrine response to acute administration of the phosphodiesterase inhibitor BM14.478 in patients with congestive heart failure. 204 89

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

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

Phosphodiesterase inhibition promotes both cellular uptake and release of calcium, which should thus facilitate both myocardial relaxation and myocardial contraction. To test the hypothesis that phosphodiesterase inhibition augments both diastolic and systolic ventricular function, parameters of left ventricular ejection and filling were measured in patients with dilated cardiomyopathy before and after therapy with the phosphodiesterase inhibitor enoximone. Baseline radionuclide ventriculography was performed in all subjects with derivation of left ventricular ejection fraction and peak diastolic filling rate. These parameters were again assessed after 3 months of therapy with either placebo (six patients) or enoximone (seven patients). Ejection fraction increased significantly (p less than 0.05) in the enoximone group (change from baseline = 11 +/- 14 ejection fraction units) but did not change in the placebo group (0.2 +/- 5 ejection fraction units). Enoximone administration was associated with a significant (p less than 0.05) increase in peak filling rate, from 0.9 +/- 0.5 to 1.4 +/- 0.5 end-diastolic volumes per second, which was noted in the placebo group (1.2 +/- 0.6 to 1.4 +/- 0.9 end-diastolic volumes per second; p = not significant). Thus, in comparison with placebo, exoximone augmented both diastolic and systolic function in dilated cardiomyopathy. This identifies an additional influence of this class of inotropic agent on the function of the intact ventricle that is consistent with previously described cellular mechanisms and that may significantly contribute to a restoration of normal hemodynamic status in dilated cardiomyopathy.
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PMID:Augmentation of diastolic function with phosphodiesterase inhibition in congestive heart failure. 252 35

In the first part of this presentation, data is reported on the hemodynamic effects of forskolin given to patients with dilated cardiomyopathy in a concentration of 3 micrograms/kg/min and 4 micrograms/kg/min. At the lower dosage, forskolin had no effect on dP/dtmax, cardiac index, ejection fraction, or myocardial oxygen consumption. With small dosages of dobutamine, however, an increase of all four parameters has been observed in the same group of patients. Systemic vascular resistance and left ventricular enddiastolic pressure fell with forskolin given at the lower concentration. Forskolin administered at a dosage of 4 micrograms/kg/min induced an increase in dP/dtmax by 19% and a 16% rise in heart rate. However, these changes were associated with symptomatic flush syndromes. Therefore, forskolin may serve as a vasodilating substance in lower concentrations, but cannot be used as a positive inotropic compound because of the subjective symptoms. In the second part, a study is reported in which an anti-ischemic effect of the phosphodiesterase inhibitor enoximone was observed in patients with proven significant coronary heart disease. With respect to the hemodynamic parameters, the most striking findings were the decreases in left ventricular enddiastolic pressure and systemic vascular resistance. Furthermore, when left ventricular stroke work index was plotted as a function of the left ventricular enddiastolic pressure, enoximone shifted the left ventricular function curve to the left. Therefore, the anti-ischemic effect of enoximone may not only be due to a reduction in preload and afterload but may rather reflect an effect on diastolic compliance. Studies with intracoronary injections of enoximone and animal experiments support this hypothesis.
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PMID:Cardiovascular effects of forskolin and phosphodiesterase-III inhibitors. 253 Sep 74


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