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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Phosphodiesterase III (PDEII) inhibitors as so-called inodilators have previously proven a valuable alternative to positive inotropes in patients with cardiac insufficiency. In this study we compared patients receiving piroximone (P, n = 14, 0.5-mg/kg bolus in 30 min and then 3-6 micrograms/kg/min) with enoximone patients (E, n = 13, 1-mg/kg bolus and then 4-20 micrograms/kg/min) and with a third group (D, n = 14) receiving a combination of dopamine (4-10 micrograms/kg/min) and glyceroltrinitrate (0.5-5 micrograms/kg/min) for hemodynamic support. All three groups were comparable in terms of age, body surface area, and preoperative cardiac function [cardiac index (CI) less than or equal to 2.5 L/min/m2, LAP greater than 15 mm Hg]. Hemodynamic measurements (10) and Holter monitoring were performed until 18 h post MVR. In all groups, epinephrine was used for additional inotropic therapy if mean arterial pressure (MAP) was less than 60 mm Hg and/or CI was less than 2.5 L/min/m2. There was no early or late postoperative mortality in either group. Continuous support with epinephrine was necessary in 8 patients in group D, whereas initially 8 patients in group E and 6 patients in group P required epinephrine support. After PDE III inhibitor infusion, 2 patients in group E and 2 patients in group P remained epinephrine dependent (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of enoximone and piroximone in patients after mitral valve operation: a prospective and controlled clinical study. 137 6

In addition to the underlying pathophysiological processes that cause myocarditis and dilated cardiomyopathy, structural, biochemical, neurohormonal and haemodynamic influences and interrelations promote progression of the heart failure syndrome. Independent of their symptomatic benefits, diuretics, digitalis, ACE inhibitors, PDE inhibitors and dopamine agonists exert specific influences on factors that retard or accelerate progression of congestive heart failure (CHF). Important factors that indicate or promote progression of CHF are discussed here, with special emphasis on therapeutic options. Interference with baroreceptor function (digitalis, ACE inhibitors), the RAA system (ACE inhibitors), the sympathetic nerve system (dopamine agonists, ACE inhibitors, digitalis) can potentially retard progression of CHF, while other therapeutic options, such as PDE inhibitors and diuretics, might accelerate progression of left ventricular dysfunction and CHF.
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PMID:Therapeutic alternatives in dilated cardiomyopathy--a review of current options. 168 Jun 88

Potentially malignant ventricular arrhythmias are common in chronic heart failure. The aggravation of such arrhythmias has many causes in these patients and cannot be predicted. Therefore, proarrhythmia due to PDE-inhibitors which increase cytosolic calcium levels by specific inhibition of the degradation of cyclo-AMP may be difficult to recognize. A retrospective analysis of 24-h Holter ECG was performed in 31 patients (NYHA classes III and IV) under long-term enoximone therapy. At baseline, 68% of the patients had ventricular couplets and nonsustained ventricular tachycardia. After a mean treatment period of 7 months, 10% of the patients showed a significant increase, 16% a significant decrease (greater than 90%) of ventricular couplets and salvos, and an additional 32% of the patients showed a significant decrease (greater than 70%) of single PVCs. The change of the arrhythmia profile was not related to the clinical course in these patients. Furthermore, 24-h Holter recordings were analyzed in a randomized long-term trial with captopril and enoximone that included 20 patients of NYHA class II. Despite comparable baseline findings, a reduction of cardiopulmonary exercise capacity was observed in patients treated with enoximone, but not with captopril. However, the arrhythmia profile was similar in both treatment groups. These findings suggest that, in most patients with advanced chronic heart failure, long-term enoximone therapy is not associated with an important increase of ventricular arrhythmias. According to the 24-h Holter findings of the European Enoximone Data Bank, proarrhythmia can be expected in 12% of all patients. Control of the arrhythmia profile, however, is mandatory, because the incidence of proarrhythmia cannot be predicted in the individual patient.
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PMID:[Enoximone and ventricular arrhythmia in chronic heart failure]. 183 3

Since the discovery of cyclic nucleotide phosphodiesterase 30 years ago, there have been major advances in our knowledge of this group of isoenzymes. Five families, each composed of several isoforms and having differing tissue distributions, have been described. David Nicholson and colleagues compare the tissue distribution of phosphodiesterase isoenzymes and discuss the differential effects of inhibition of particular isoenzymes, with differing subcellular localization, on tissue function. They also review the potential use of isoenzyme selective phosphodiesterase inhibitors in a range of clinical disorders such as heart failure, asthma, depression and dementia.
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PMID:Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. 184 33

Positive inotropy requires a rise in myocardial oxygen consumption (MVO2); as far as PDE-III-inhibitors' beneficial hemodynamic effects, increases in contractility are controversial, in part probably because accurate proving is rather tedious. The clinician, however, requires a clear concept of whether or not enoximone (EN), for example, carries the risk of myocardial ischemia when used in patients with coronary artery disease. Using the analysis of pressure-volume relations, we recently established contractility-increasing as a partial effect of EN. There are indications suggesting that the inotropy-induced added increase in MVO2 of the PDE-III-inhibitor drugs could be compensated for by the simultaneous vasodilation and changes in compliance, so that as a net effect an unchanged MVO2 might result. Since, on the other hand, PDE-III-inhibitor drugs have been said to generate antiischemic properties, further clinical investigations with EN clearly seemed indicated and they are the subject of the present report: In five patient groups with stabile angina (AP) studied the following parameters and methods, respectively, were used for the evaluation of EN-induced changes of the anginal threshold: exercise, using pacing and ergometry; PA- and PC-pressure measurements; MVO2, indirectly assessed; hemodynamic profile and regional wall motion as assessed in the immediate post pacing phase; ST- T-segment evaluation; thalium-201 perfusion scintigraphy; myocardial perfusion, indirectly assessed. Lack of EN-induced AP (ischemia) and an increased AP threshold indicated that the drug can be used safety in patients with heart failure, including that due to coronary artery disease.
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PMID:[Effects of the phosphodiesterase III inhibitor in ischemic heart disease]. 192 97

Phosphodiesterase inhibitors that are selective for cAMP-specific cardiac and vascular PDE III comprise a new group of agents for the treatment of heart failure, which at present are limited to clinical shortterm intravenous use and research uses only. Although both intravenous amrinone and milrinone are FDA approved, only amrinone is available for general clinical use. Selective phosphodiesterase inhibition produces beneficial actions of positive inotropy and peripheral vasodilation that result from increased cardiac and vascular muscle concentrations of intracellular cAMP and ionic calcium. In addition, a positive lusitropic action (enhancement of cardiac relaxation) has been observed. Neither beta-adrenergic agonist activity nor inhibition of the sodium-potassium ATPase is produced by these agents. The magnitude of hemodynamic improvement generally exceeds that of the cardiac glycosides and is comparable with that of intravenous catecholamines such as dobutamine. The different pharmacodynamic profile of the PDE inhibitors is additive to the effects of cardiac glycosides, complementary and synergistic to the actions of catecholamines, and has been shown to have favorable effects on coronary hemodynamics. As a result there is continued enthusiasm for the short-term intravenous use of amrinone and potentially milrinone in the setting of acute heart failure resulting from systolic dysfunction (after myocardial infarction, open heart surgery, or infectious or toxic myocarditis), heart failure resulting from right ventricular systolic dysfunction, and when patients with severe heart failure await cardiac transplantation. Initiation of treatment with an intravenous bolus followed by a maintenance infusion provides prompt increases in stroke volume and cardiac output and simultaneous reductions in right and left ventricular filling pressures and systemic vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute positive inotropic intervention: the phosphodiesterase inhibitors. 203 20

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

Many newly developed positive inotropic agents are phosphodiesterase inhibitors. In the heart at least four phosphodiesterases (PDE I-IV) have been isolated. Depending on the species investigated, the positive inotropic effects of the PDE inhibitors appear to be correlated to the inhibition of a soluble or particulate PDE III or to a particulate PDE bound to the sarcoplasmic reticulum. In human ventricular tissue isolated from hearts with end-stage heart failure due to idiopathic dilated cardiomyopathy the positive inotropic effect of phosphodiesterase inhibitors is greatly reduced compared to healthy controls. This cannot be explained by an impaired sensitivity of the PDEs because the PDEs were similarly inhibited by PDE inhibitors in both healthy and diseased hearts. However, because the reduced positive inotropic effect is accompanied by a reduced increase in cellular cAMP concentration, an impaired formation of cAMP by the adenylate cyclase is probably involved. The impaired adenylate cyclase activity can result from an increased inhibitory GTP-binding protein (Gi-protein) recently observed in failing hearts.
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PMID:Phosphodiesterase inhibition and positive inotropic effects. 247 97

Cardiac failure is treated with increasing success by phosphodiesterase-III (PDE-III) inhibitors such as amrinone, milrinone, and enoximone. While relatively pure positive inotropic substances (e.g., dopamine and dobutamine) are limited by tolerance development and MVO2 increase, the efficacy of PDE inhibitors is maintained by avoiding catecholamine and beta-receptors. They have positive inotropic, positive lusitropic, and vasodilatatory properties; myocardial oxygen consumption remains unaltered. PDE-III inhibitors act by selectively inhibiting PDE-III, leading to an increased cAMP concentration in myocardial and smooth muscle cells. In contrast, forskolin increases intracellular cAMP by activation of adenylate cyclase. It could be shown that parenteral administration of the PDE inhibitors sulmazole, amrinone, and enoximone resulted in preload and afterload reduction due to vasodilation with concomitant decrease of peripheral and pulmonary vascular resistance; they also led to elevated cardiac output and ejection fraction as well as a significant increase in dp/dtmax, while left ventricular filling pressures were markedly lowered. Pulmonary pressure values fell significantly, whereas heart rate and myocardial oxygen consumption showed no clinically relevant alterations. In patients with angiographically documented coronary artery disease, the anti-ischemic efficacy of enoximone could be proven both during exercise and stress pacing. The decrease of the pathologically elevated pulmonary pressures during ischemia was accompanied by reduced ST-segment depression following enoximone without changing MVO2 significantly. First tests after intracoronary application of enoximone confirmed its direct myocardial efficacy, indicating its positive inotropic and lusitropic properties. Thus, patients in cardiac failure have useful therapeutic alternatives at their disposal when taking PDE inhibitors. The anti-ischemic properties of these drugs need further evaluation.
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PMID:Present use of positive inotropic drugs in heart failure. 248 Apr 92


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