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)

A patient with end-stage congestive cardiomyopathy had progressive hemodynamic deterioration while awaiting orthotopic heart transplantation. Attempts to support cardiovascular function by high-dose dobutamine infusions were complicated by life-threatening cardiac arrhythmias. The addition of the noncatecholamine inotropic agent, amrinone, improved ventricular performance, enabling reduction of the dose of dobutamine and resolution of the cardiac arrhythmias. Beta receptor stimulation by dobutamine combined with phosphodiesterase inhibition by amrinone may additively or synergistically augment cardiac function despite severe congestive heart failure and also have an adrenergic "sparing effect."
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PMID:Augmentation of cardiac function in end-stage heart failure by combined use of dobutamine and amrinone. 373 11

The analysis of currently used therapeutic targets provides considerable input in the choice of current and future therapies for dilated cardiomyopathy and congestive heart failure. Of the ion flux agents, a definitive answer concerning digoxin will soon be available. Currently, digoxin is likely of benefit to patients with persistent heart failure and significantly enlarged hearts despite therapy with preload and afterload reducing agents. Most currently available calcium channel blocking agents do not appear to be effective, although newer agents such as amlodipine and felodipine have yet to be adequately tested. Vesnarinone, which operates through the sodium and potassium rectifying channels and has limited phosphodiesterase inhibition, appears to provide a significant improvement in mortality and in symptoms. Part of the latter effect may be due to its anticytokine properties, which are currently being investigated. Analysis of vascular endothelial agents indicate that not all of the vasoactive agents improve survival, as demonstrated with prazosin and flosequinan. The dose of agents may be important, again demonstrating that less is better. Finally, those with additional effects, such as inositol triphosphate stimulation, may offer additional unique properties that may, in the future, provide benefit. Phosphodiesterase inhibitors are potentially beneficial in the short term but clearly should be avoided for long-term use. Lower doses of these agents are now being investigated, but the weight of evidence is against agents that operate primarily through phosphodiesterase inhibition. Renin angiotensin agents are the most efficacious of therapies available at this time. New angiotensin converting enzyme inhibitors are likely to add little to what is already known.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New medical therapies for advanced left ventricular dysfunction. 779 29

M-mode echocardiography and Doppler were used to assess the effects of phosphodiesterase inhibition on subendocardial function in dilated cardiomyopathy, and in particular, to study interactions with both systolic and diastolic left ventricular function. Twelve adult patients with dilated cardiomyopathy were studied (6 ischemic in origin and 6 idiopathic), 7 of whom were being considered for cardiac transplantation. Cardiac index increased without significant change in heart rate or blood pressure. Longitudinal mitral ring motion, which had been uniformly reduced, increased markedly after intravenous milrinone. Left ventricular cavity size decreased, and shortening fraction, posterior wall thickness, and rates of posterior wall thickening and thinning increased markedly. Left atrial pressure decreased, and isovolumic relaxation time increased. However, the peak velocity and duration of the transmitral E wave increased, with no change in the A wave. Improved longitudinal (subendocardial) function was reflected by improved posterior wall dynamics, and early filling, possibly by augmentation of restoring forces. Thus, severely reduced subendocardial function in dilated cardiomyopathy is potentially reversible, with marked effects on systolic and diastolic function. These previously unrecognized actions of milrinone provide further evidence to justify its short-term use in supporting the severely depressed myocardium.
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PMID:Effects of intravenous milrinone on left ventricular function in ischemic and idiopathic dilated cardiomyopathy. 842 84

We studied the interaction of phosphodiesterase inhibitor and isoproterenol in human and guinea-pig ventricular muscle fibers and guinea-pig ventricular myocytes. In ventricular trabeculae obtained from the explanted hearts of 5 patients with dilated cardiomyopathy, isoproterenol (Iso, 10(-8)-10(-6)M) increased twitch force in a concentration-dependent manner. Isobutylmethyl-xanthine (IBMX, 3 x 10(-6)M) alone did not change significantly the twitch force but potentiated the effect of Iso and reduced the concentration for half maximal effect (EC50) of Iso from 140 to 18 x 10(-9)M. As compared to the diseased human heart tissues, papillary muscles obtained from 6 healthy guinea-pigs were much more sensitive to the positive inotropic action of Iso but less reactive to the potentiative effect of IBMX on Iso. The EC50 for the inotropic action of Iso (10(-9) approximately 10(-7)M) in the absence and presence of 3 x 10(-6)M IBMX were 28 and 15 x 10(-9)M, respectively. In 16 guinea-pig ventricular myocytes isolated enzymatically, L-type Ca currents (ICa,L) were recorded in K-free superfusate with whole-cell voltage-clamp technique. The increase in ICa,L induced by the lowest concentration (10(-9)M) of Iso was not significant. Those induced by 10(-8)M and 10(-7)M Iso were about the same (+108 +/- 29% and +75 +/- 20%, respectively). IBMX potentiated the effect of Iso. It is concluded that indeed the ventricular muscles obtained from the failing hearts are poorly responsive to the beta-adrenoceptor agonist. This defect could be corrected at least partially by the PDE inhibitor IBMX. However, the concentration-dependent inotropic and arrhythmogenic effects in guinea-pig ventricular muscle were not accompanied by a parallel increase in iCaL at high concentration of Iso(10(-7)M), suggesting involvement of other mechanisms such as actions on intracellular Ca2+ regulation induced by Iso.
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PMID:Interaction of phosphodiesterase inhibitor and isoproterenol in human and guinea-pig ventricular tissues and myocytes. 884 28

We investigated the acute effects of the positive inotropic agents (dobutamine and a novel phosphodiesterase inhibitor OPC-18790) on left ventricular diastolic chamber stiffness in patients with idiopathic dilated cardiomyopathy (DCM). We obtained pressure-volume (PV) data before and after drug administration in 17 patients with DCM by using a conductance catheter with a micromanometer tip. Patients were randomly assigned to receive intravenous infusions of dobutamine (2.5-7.5 micrograms/kg body weight per min, n = 8) or OPC-18790 (5-10 micrograms/kg body weight per min, n = 9). The dynamic diastolic chamber stiffness constant was calculated from a steady-state beat. The passive diastolic chamber stiffness constant was determined from the end-diastolic PV relation determined during transient inferior vena caval occlusion. Dobutamine and OPC-18790 similarly improved left ventricular end-systolic elastance (Ees) and left ventricular isovolumic relaxation time constants. The dynamic diastolic chamber stiffness constant decreased significantly in both the dobutamine (0.0934 +/- 0.0271 to 0.0685 +/- 0.0248; p < 0.01) and OPC-18790 (0.0843 +/- 0.0477 to 0.0569 +/- 0.0246; p < 0.05) groups. The passive diastolic chamber stiffness constant decreased significantly in the OPC-18790-treated group (0.0211 +/- 0.0114 to 0.0144 +/- 0.0117; p < 0.005) but not in the dobutamine-treated group (0.0197 +/- 0.0130 to 0.010186 +/- 0.0102; p > 0.05). Thus both dobutamine and OPC-18790 reduced the dynamic diastolic chamber stiffness constant, but only OPC-18790 reduced the passive diastolic chamber stiffness constant. OPC-18790 had a favorable effect on diastolic function in patients with DCM, compared with that of dobutamine. The passive diastolic chamber stiffness obtained from the end-diastolic PV relations represents more likely passive chamber properties than the dynamic diastolic chamber stiffness obtained from traditional single-beat analysis.
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PMID:Effect of dobutamine and OPC-18790 on diastolic chamber stiffness in patients with idiopathic dilated cardiomyopathy. 905 77

A 51-year-old man with dilated cardiomyopathy, who had been treated with medication for five years, was scheduled for abdomioperineal resection of the rectum. Preoperative echocardiography demonstrated left ventricular dilation and hypertrophy, with an ejection fraction of 0.34. Anesthesia was induced with ketamine 40 mg and fentanyl 0.5 mg intravenously. Endotracheal intubation was facilitated by administration of vecuronium 10 mg. Anesthesia was maintained with nitrous oxide-oxygen-sevoflurane and fentanyl. In order to regulate myocardial contractility and after-load, use of a phosphodiesterase III inhibitor was considered, although phosphodiesterase III inhibitors are known to induce arrhythmias, which should be avoided in dilated cardiomyopathy patients. We chose olprinone, because its inotropic action is not associated with arrhythmogenecity. Before infusing olprinone, cardiac output was 4.5 l.min-1 and systemic vascular resistance was 1306 dynes.sec.cm-5. When olprinone was continuously infused for one hour, cardiac output increased to 5.2 l.min-1 and systemic vascular resistance decreased to 958 dynes.sec.cm-5. Some premature ventricular contractions occurred, but they were easily controlled by administration of 50 mg lidocaine. These clinical data demonstrate that olprinone enhanced myocardial contractility, and decreased after-load and arrhythmogenecity in a dilated cardiomyopathy patients. In conclusion, olprinone is useful in the perioperative cardiovascular management of surgical patients with dilated cardiomyopathy.
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PMID:[Anesthetic management of a patient with dilated cardiomyopathy using olprinone]. 951 40

The acute hemodynamic effects of the phosphodiesterase (PDE) III inhibitor saterinone were compared with dobutamine and sodium nitroprusside in 12 patients with idiopathic congestive cardiomyopathy (NYHA III). Hemodynamic measurements were obtained with a Swan-Ganz thermodilution catheter. At the peak of its dose-response curve, saterinone induced an increase in cardiac index (+102%), stroke volume (+97%), and heart rate (+6%), paralleled by a decrease in pulmonary capillary wedge pressure (-46%), right atrial pressure (-51%), pulmonary arterial pressure (systolic -32%, diastolic -45%, mean -38%), systemic blood pressure (systolic -3%, diastolic -13%, mean -9%), systemic vascular resistance (-54%), and pulmonary vascular resistance (-58%). Dobutamine had similar effects on cardiac index (+106%) and stroke volume (+87%) but lacked vasodilatory characteristics. In contrast to dobutamine, both nitroprusside and saterinone demonstrated more pronounced vasodilatory effects. Nitroprusside was less effective on cardiac index (+66%) and stroke volume (+56%) than was saterinone. The double product was markedly increased by dobutamine (+28%), did not change with saterinone treatment (+2%), and decreased with nitroprusside (-10%). This indicates that according to double product, only the application of dobutamine caused a relevant increase in myocardial oxygen consumption. Saterinone was demonstrated to be a safe and potent drug on short-term application; it combines the vasodilating properties of sodium nitroprusside with the positive inotropic effects of dobutamine without major changes in myocardial oxygen consumption.
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PMID:Saterinone, dobutamine, and sodium nitroprusside: comparison of cardiovascular profiles in patients with congestive heart failure. 978 32

We experienced anesthetic management of left ventricular reduction surgery (Batista procedure) which is a newly developed procedure for treating end-stage dilated cardiomyopathy. The patient was a 41-year-old man who had been suffering from cardiac failure and refractory ventricular tachycardia. The anesthesia was induced and maintained with meticulous administration of fentanyl. After resection of the left ventricular free-wall, the left ventricular diastolic diameter decreased to 46 mm, from 79 mm of preoperative measurement. Weaning from cardiopulmonary bypass was successful with the use of catecholamines and intra-aortic balloon pumping. Administration of both vasodilators and phosphodiesterase inhibitors such as milrinone also contributed to reducing afterload and maintaining cardiac output. In addition to standard hemodynamic monitoring, transesophageal echocardiography provided invaluable information on determining cardiac dimensions and evaluating left ventricular wall motion.
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PMID:[Anesthetic management of left ventricular reduction surgery (Batista procedure)]. 1033 39

Overexpression of cardiac calsequestrin (CSQ) impairs Ca2+ signalling in murine myocytes, leading to marked cardiac hypertrophy. Here we report on contractile, histological and electrophysiological changes accompanying the development of cardiac hypertrophy and failure in CSQ-overexpressing mice. CSQ mice developed contractile dysfunction after 60 days of age, with only 40% survival at 6 months. Four- to 6-month-old CSQ mice revealed biventricular dilatation, cardiomyocyte hypertrophy, patchy interstitial fibrosis and tissue calcifications. Cardiac hypertrophy of CSQ mice was accompanied by progressive P-R and Q-T interval prolongation, conduction blocks, 2-fold prolongation of the ventricular action potential and increased cellular membrane capacitance. Remodelling of ionic currents included marked reduction of both density and absolute magnitude of transient outward (Ito) and inward rectifying (IK1) K+ currents. The density, but not the absolute magnitude, of basal and isoproterenol (isoprenaline)-stimulated Ca2+ current (ICa) was decreased by 42% and the inactivation kinetics of ICa were significantly slowed. Na+ current density was suppressed by 50%, but its steady-state activation and inactivation were shifted to more positive potentials. The density of Na+-Ca2+ exchange current was increased by 35%. In CSQ but not in control myocytes dialysed with cAMP, isoproterenol continued to enhance ICa. This apparent lower responsiveness of ICa to cAMP could be reversed by the non-hydrolysable cAMP analogue 8-Br-cAMP or the phosphodiesterase inhibitor IBMX, suggesting high phosphodiesterase activity of CSQ myocytes. In young CSQ mice (< 60 days) with compensated cardiac hypertrophy, only Ito was significantly suppressed. All other currents remained relatively intact. An increase in cardiac Ca2+-storage capability by overexpression of CSQ results in a dilated cardiomyopathy with tissue fibrosis, calcifications, impaired beta-adrenergic signalling and progressive remodelling of ionic currents. The extent of the changes in ionic currents was age dependent.
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PMID:Remodelling of ionic currents in hypertrophied and failing hearts of transgenic mice overexpressing calsequestrin. 1083 49

A 16-year-old Japanese male diagnosed with congestive heart failure (CHF) due to dilated cardiomyopathy was treated by conventional intensive treatment such as intravenous infusion of diuretics, catecholamines, and phosphodiesterase inhibitors with vasodilators. However, he developed a low output syndrome with appearances of hyponatremia and hypochloremia. As a consequence, intravenous infusion of carperitide (synthetic atrial natriuretic peptide) was added to the therapy. Thereafter his symptoms and hemodynamic parameters promptly and dramatically improved without significant diuresis, and this amelioration persisted for more than 20 days without drug intolerance. This outcome suggests that use of carperitide may be a safe and efficacious means to reduce cardiac preload without hypotension and tachycardia in patients with refractory CHF in whom intensive treatment has already been performed.
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PMID:Marked and prompt hemodynamic improvement by carperitide in refractory congestive heart failure due to dilated cardiomyopathy. 1104 Nov 4


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