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)

Low heart stroke volume syndrome is clinically manifested with hypoperfusion of all body systems. Inotropic or mechanical support is applied. Acute heart failure is one of the most important complications after open heart surgery. Catecholamines have been up to non considered as a therapy of choice for the acute heart failure. Effectiveness of catecholamines could be limited with some side effects. Phosphodiesterase inhibitors promise a new therapeutic approach. PDE III primary act through phosphodiesterase inhibition which leads to a rise of aAPM levels. Thus they show positive inotropic and lusitropic effects, which could be monitored by occlusive pulmonary capillary pressure values. Amrinone is obviously superior to inotropic catecholamines.
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PMID:[Hemodynamic effects of amrinone, dobutamine and dopamine in the cardiac low output syndrome following open-heart surgery]. 864 47

Amrinone, a selective phosphodiesterase III inhibitor, has been developed as a nonglycoside, noncatecholamine agent with positive inotropic effect. In this study, we examined the effect of amrinone on human pulmonary arterial strips in vitro to understand its action on human pulmonary circulation. Amrinone (10(-5)-10(-3) g/ml) caused dose-dependent relaxation of human pulmonary arterial strips precontracted with 60 mM KCl. Preincubation with either meclofenamate (3.1 microM), a cyclooxygenase inhibitor, or L-N(G)-nitroarginine (100 microM), a competitive inhibitor of EDRF/NO, failed to inhibit amrinone-induced pulmonary vasodilation. The cyclic AMP (cAMP) levels in the supernatant of the lung vessel homogenates increased after incubation with amrinone (10(-3) g/ml). These findings indicate that amrinone causes vasodilation of human pulmonary artery in vitro, and suggest a possible role for cAMP in the mechanisms of amrinone-induced pulmonary vasodilation. Because it is suggested that amrinone has not only positive inotropic effect but also pulmonary vasodilative effect in human in this study, we speculate that amrinone could be an useful agent for the treatment of an increase in right heart afterload and consequent pulmonary hypertension and right heart failure after lung resection in human.
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PMID:Relaxation of human isolated pulmonary arteries by amrinone. 867 27

We studied the effects of various phosphodiesterase (PDE) III inhibitors: amrinone, pimobendan and vesnarinone: a PDE IV inhibitor (Ro 20-1724) and a PDE V inhibitor (E-4021) on the production of cytokines which have been shown to depress myocardial function. Recently developed inotropic agents which inhibit PDE III activity have produced short-term hemodynamic benefits in patients with advanced heart failure, but long-term treatment with these agents has an adverse effect on survival. However, vesnarinone, which has been shown to improve survival dramatically, has an immunomodulating effect and inhibits the production of cytokines. Peripheral blood mononuclear cells obtained from healthy human subjects were stimulated with lipopolysaccharide and each PDE inhibitor was added. After 24 h of incubation, tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta) and IL-6 in the culture supernatants were measured by an enzyme-linked immunosorbent assay. All three PDE III inhibitors, amrinone, pimobendan and vesnarinone, inhibited TNF-alpha production, but vesnarinone's inhibitory effect was the most prominent. Amrinone and pimobendan enhanced IL-1 beta production, whereas vesnarinone had no effect. Vesnarinone inhibited IL-6 production and pimobendan slightly decreased IL-6 production, whereas amrinone had no significant effect on IL-6 production. The PDE IV inhibitor, Ro 20-1724, decreased the production of IL-1 beta and TNF-alpha and also tended to inhibit IL-6 production; its modulation of cytokine production was similar to the effects of vesnarinone. Because 8Br-cAMP or 8Br-cGMP did not suppress cytokine production, the modulating effects were not considered to result from an increase in cAMP or cGMP. Differential modulation of cytokine production may play a role in the therapeutic effect in heart failure patients who are treated with drugs that have PDE-inhibitory actions. It may be important to study whether the use of dual inhibitors of PDE III and PDE IV is therapeutically more useful for the treatment of heart failure due to their immunomodulating properties.
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PMID:Differential modulation of cytokine production by drugs: implications for therapy in heart failure. 900 65

Amrinone, a selective phosphodiesterase III inhibitor, is a positive inotropic agent with vasodilating effect which is attributable to an increase in cyclic AMP in vascular smooth muscle. Little is known about the effect of amrinone on airway mechanics. The purpose of this study was to clarify the bronchodilating effect of amrinone in dogs, when bronchoconstriction was induced by methacholine infusion. We also evaluated the effect of amrinone on bronchoconstriction in vagotomized dogs. To evaluate the effect of amrinone on respiratory function, the total respiratory system impedance was measured using forced oscillation method by imposing a random noise. The analysis was performed by dynamic models and a second-order system curve fitting. From the study, we conclude that amrinone 0.5 mg.kg-1.1.0 mg.kg-1 or 2.0 mg.kg-1 attenuates methacholine-induced bronchoconstriction in a dose-related manner. In vagotomized dogs, amrinone also had the same effect on methacholine induced bronchoconstriction.
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PMID:[Effect of amrinone and vagotomy on airway constriction in dogs: analysis by respiratory system impedance method]. 902 82

Systemic hypertension is a constant feature of chronic renal failure, mediated by renin and exacerbated by salt and fluid loading. Vascular atherosclerosis appears to accelerate in patients on long-term dialysis. Therefore, it is important to control hypertension and keep appropriate renal blood flow during living renal transplantation surgery. Amrinone, a phosphodiesterase inhibitor, produces vasodilation in arterial smooth muscle as well as venodilation in the capacitance bed. By increasing myocardial contractility it increases inotropic effect. Amrinone has potent inodilator effects because of its dual mechanism of action. The current study is aimed to compare hemodynamic effects between amrinone (3-5 mg.kg-1.min-1) (AMR group, n = 4) and nitroglycerin (0.3-1.0 mg.kg-1.min-1) (NTG group, n = 5), combined with dopamine (3-5 mg.kg-1.min-1) in nine patients undergoing living renal transplantation. Increase in cardiac index in AMR group was significantly larger than that in NTG group. Values of systemic and pulmonary vascular resistance in AMR group were significantly smaller than those in NTG group. No significant difference was found in renal function in the post-operative period.
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PMID:[Hemodynamic effects of amrinone combined with dopamine in patients undergoing living renal transplantation]. 902 89

Management of acute viral myocarditis is still controversial. Amrinone, a noncatecholamine nonglycoside bipyridine agent, produces sustained improvement of cardiac function and symptomatology in congestive heart failure (CHF). Amrinone demonstrates phosphodiesterase inhibitory activity that is relatively selective for the major phosphodiesterase isozyme in cardiac muscles, PDE III, which specifically hydrolyzes cyclic 3'5' adenosine monophosphate (cAMP). We investigated the effects of amrinone in an animal model of acute CHF related to myocarditis caused by the encephalomyocarditis virus (EMCV). Female C3H mice were inoculated intraperitoneally (i.p.) with 500 plaque-forming units of EMCV in 0.1 ml of saline. A total of 96 mice were randomly assigned to four groups. Each animal was administered 0.2 ml of phosphate-buffered saline (PBS) containing amrinone at a concentration of 1, 10, or 50 mg/kg, or PBS as an infected control, injected i.p. once daily for 21 days, starting on day 1 after viral inoculation. Each group contains 20 to 30 mice. Infected untreated mice survived at 80% (n = 16), however, only 13% (n = 16) of mice treated with amrinone (50 mg/kg) survived (p < 0.01). Downregulation of cardiac cAMP occurred 1 day after the viral infection. Although amrinone (10 and 50 mg/kg) treatment significantly (p < 0.05) increased the cardiac cAMP content and the dose of 10 mg/kg could potentially retard death from CHF due to viral myocarditis. The higher (50 mg/kg) doses of amrinone may produce unfavorable effects when used to treat mammals with viral myocarditis and CHF.
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PMID:Effect of amrinone on murine viral myocarditis. 905 49

We compared the effects of pimobendan (0.25 mg/kg i.v.), a Ca++ sensitizer, with some phosphodiesterase-III inhibition effects, and amrinone (1 mg/kg plus 10 microg/kg/min i.v.), a PDE-III inhibitor, on left ventricular (LV) systolic and diastolic performance, both at rest and during exercise, in seven conscious dogs before and after pacing-induced congestive heart failure (CHF). Before CHF, under resting conditions, both pimobendan and amrinone caused a similar significant decrease in left ventricle size and end-systolic pressure, arterial elastance, and the time constant of LV relaxation. Similar results were obtained during exercise. Both agents also produced a similar increase in E(ES), the slope of the LV end-systolic pressure-volume relation (3.4 +/- 1.5 vs. 4.2 +/- 1.1 mm Hg/ml; amrinone vs. pimobendan). After CHF, the vasodilatory effects of amrinone and pimobendan were preserved both at rest and during exercise; however, the inotropic actions were different. After CHF, pimobendan increased E(ES) (3.9 +/- 0.5 vs. 5.7 +/- 0.4 mm Hg/ml, P < .05), decreased the time constant of LV relaxation, increased the maximum rate of LV filling (37 +/- 19 ml/sec) (P < .05) and produced a downward shift of the early diastolic portion of LV pressure-volume loop. Pimobendan also augmented LV contractile performance during CHF exercise. In contrast, after CHF, amrinone no longer produced a positive inotropic effect. Amrinone improved LV relaxation and filling, both at rest and during exercise after CHF, but significantly less than pimobendan. We conclude that after CHF, the cardiac response to a PDE-III inhibitor is attenuated, but the response to Ca++ sensitizer is preserved. Thus, after CHF, pimobendan is more effective than amrinone in enhancing LV contractile state, LV relaxation and LV filling both at rest and during exercise.
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PMID:The cardiac effects of pimobendan (but not amrinone) are preserved at rest and during exercise in conscious dogs with pacing-induced heart failure. 922 36

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. We have recently compared the effects on cytokine production of drugs for therapy of heart failure that have different effects on survival. Amrinone, pimobendan and vesnarinone, phosphodiesterase III inhibitors that have been shown to have short term haemodynamic benefits, inhibited TNF-alpha production. Differential modulation of the production of IL-1beta and IL-6 was observed; amrinone and pimobendan enhanced the production of IL-1beta, whereas vesnarinone did not. As inotropic agents differentially modulate cytokine production, these agents may interfere with induction of inducible nitric oxide (NO) synthase through an inhibition of cytokine formation. Although differential modulation of the production of NO by inotropic agents may explain their different effect in patients with heart failure, further study is necessary to reach this conclusion. We have shown that amlodipine increases the survival of mice with viral myocarditis and inhibits expression of inducible NO synthase and production of NO in vivo and in vitro. The therapeutic effect of amlodipine may in part result from inhibition of overproduction of NO. As we learn more about the pathophysiological and pathogenetic role of cytokines in heart failure, it should be possible to design better and more targeted pharmacological agents. Furthermore, the investigation of inotropic agents that are effective against the production of cytokines may help in the classification of these agents.
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PMID:The use of cytokine inhibitors. A new therapeutic insight into heart failure. 946 76

The level of intracellular cyclic nucleotides is a regulatory factor in a variety of immune processes. Increases in intracellular cyclic AMP (cAMP) and/or cyclic GMP (cGMP) concentration by the inhibition of phosphodiesterase have been shown to modulate the inflammatory response. Amrinone is a clinically used positive inotropic agent which elevates intracellular cAMP and cGMP levels by selective inhibition of the phosphodiesterase III isoenzyme. In the current study, we investigated the effect of various concentrations (1-300 microM) of amrinone on lipopolysaccharide-induced production of pro- and anti-inflammatory cytokines and of nitric oxide (NO) in vitro. In cultured murine J774.1 macrophages, 1 ng/ml-10 microg/ml of lipopolysaccharide from Escherichia coli O55:B5 induced production of tumor necrosis factor-alpha (TNF-alpha), interleukin-10, and nitrite (breakdown product of NO). Pretreatment of cells with amrinone caused a dose-dependent suppression of TNF-alpha production in the concentration range of 1-100 microM. Furthermore, this drug suppressed NO production in the range of 30-300 microM. Similarly to the results in the J774.1 cells, amrinone also inhibited TNF-alpha and NO production in the range of 10-100 microM in primary rat peritoneal macrophages. At 300 microM, but not at lower concentrations, amrinone inhibited interleukin-10 production in lipopolysaccharide-treated J774.1 macrophages. Pretreatment of the macrophages with 100 and 300 microM amrinone increased the lipopolysaccharide-elicited translocation of nuclear factor-kappa B. Taken together, our results indicate that the phosphodiesterase III inhibitor amrinone modulates the activation/production of many pro- and anti-inflammatory factors in endotoxin-stimulated cells. It remains to be further investigated how such immunomodulatory effects contribute to the clinical profile of the agent.
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PMID:Effect of the phosphodiesterase III inhibitor amrinone on cytokine and nitric oxide production in immunostimulated J774.1 macrophages. 947 38

Amrinone-a phosphodiesterase III inhibitor-is used in the treatment of acute heart failure. In addition to its hemodynamic effects, amrinone has been shown to inhibit thromboxane synthesis in vitro. We investigated the effects of amrinone on thromboxane, prostaglandin, and leukotriene synthesis in humans. Eight healthy male volunteers took part in this single-blind study in which either amrinone (a 1.5-mg/kg bolus in 30 min and after that 10 microg/kg/min for 1 h 30 min) or placebo (0.9% NaCl) were infused. Amrinone infusion increased systolic blood pressure but had no significant effect on diastolic blood pressure or heart rate. Amrinone did not modulate thromboxane B2 synthesis stimulated by either spontaneous clotting or calcium-ionophore A23187 in whole blood. Amrinone had no effects on prostaglandin E2 or leukotriene E4 production in A23187-stimulated whole blood, nor did it affect urinary excretion of 11-dehydrothromboxane B2 or 2,3-dinor-6-keto-prostaglandin F1alpha, the index metabolites of thromboxane A2 and prostacyclin productions, respectively. We conclude that amrinone has no effects on eicosanoid production in humans at the dose level used in this study, and that the hemodynamic effects noticed are not mediated via cyclooxygenase or lipoxygenase products of arachidonic acid metabolism.
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PMID:Amrinone, a phosphodiesterase III inhibitor, and arachidonic acid metabolism in humans. 989 Apr 9


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