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 mechanism responsible for the attenuated heart rate (HR) response to exercise in patients with congestive heart failure (CHF) was investigated in 46 normal subjects and 59 patients with CHF stratified by peak exercise oxygen consumption (VO2). The peak exercise HR and the increment in HR from rest to peak exercise were decreased in CHF patients, and both correlated strongly with peak VO2 (r = 0.810, p less than 0.0001; r = 0.863, p less than 0.0001, respectively). Peak exercise norepinephrine level (NE) and the increment in NE from rest to peak exercise were not attenuated in CHF patients. Resting NE was elevated in CHF patients and correlated inversely with peak VO2 (r = -0.595, p less than 0.001). However, no significant correlation occurred between peak VO2 and either peak exercise NE or the exercise increment in NE. The ratio of the exercise increments in HR and NE, and indirect index of sinoatrial node sympathetic responsiveness, was markedly reduced in CHF patients and was inversely related to the severity of exercise impairment. Likewise, the HR response to a graded isoproterenol infusion was markedly reduced in CHF patients. Age-matching of normal subjects and CHF patients did not affect the foregoing observations. Infusion of CHF patients with the phosphodiesterase inhibitor milrinone caused a significant increase in the ratio of the exercise increments in HR and NE. These data strongly suggest that the attenuated HR response to exercise in CHF patients is due, at least in part, to postsynaptic desensitization of the beta-adrenergic receptor pathway.
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PMID:Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization. 254 98

Several new positive inotropic drugs with vasodilating properties for which a major mechanism of action is believed to be inhibition of phosphodiesterase (PDE) have been introduced in the treatment of congestive heart failure. Hydrolysis of cyclic nucleotides is catalyzed by multiple forms of PDE, which may vary between organs and cell-types. These enzymes can be selectively inhibited by various agents, theoretically making it possible to produce tissue-selective responses. An enzyme, which belongs to a subclass of cGMP inhibited low Km cAMP PDE, was recently purified from rat adipose tissue. The enzyme was specifically and potently inhibited by the cilostamide derivative OPC 3911 (OPC) and milrinone (mil). We studied the relaxant effects of OPC and mil on isolated human mesenteric arteries and veins in vitro. In preparations contracted by noradrenaline (NA), both agents produced about 60% maximum relaxation; OPC was 3-4 times more potent than mil. Both OPC and mil caused rightward displacement of the NA concentration-response curve and depressed the maximum responses. Arteries, as compared to veins, were more sensitive to this inhibition of NA contraction. Both drugs relaxed arteries contracted by 30 mM K+, but not 127 mM K+; maximum relaxation was between 60 and 70%. OPC was 10 times more potent than mil. The interactions between mil/OPC and isoprenaline, forskolin and ouabain were also studied. In preparations pretreated with isoprenaline or forskolin, the relaxant effects of mil and OPC were additive to those of isoprenaline and forskolin. Ouabain pretreatment did not affect the actions of the phosphodiesterase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relaxant effects of the selective phosphodiesterase inhibitors milrinone and OPC 3911 on isolated human mesenteric vessels. 254 28

Beta-adrenergic sympathomimetic agents such as dobutamine and dopamine, and phosphodiesterase inhibitors such as amrinone, milrinone, and enoxamone, exert a direct positive inotropic effect upon the myocardium by causing an increase in cyclic AMP levels. The phosphodiesterase inhibitors also exert a substantial direct vasodilator effect. Both the sympathomimetic agents and the phosphodiesterase inhibitors can be of value in the acute, short-term management of myocardial failure. At present, the use of these agents for long-term therapy of congestive heart failure is unproven, and remains investigational.
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PMID:Positive inotropic/vasodilator agents. 256 61

New knowledge and insight into cardiac muscle physiology and pharmacology together with the development of novel drugs may change the treatment of congestive heart failure in the future. This article reviews two newer inotropic mechanisms currently under investigation. It will place special emphasis on the mechanisms of action of selective cardiac phosphodiesterase inhibition and of alpha 1-adrenoceptor mediated stimulation of the phosphoinositide pathway.
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PMID:New positive inotropic agents acting by phosphodiesterase inhibition or alpha 1-adrenergic stimulation. 257 Apr 16

Evaluation of the impact of therapeutic interventions in congestive heart failure (CHF) with compounds such as the phosphodiesterase (PDE) III inhibitors must include the determination of regional blood flow and functional changes. Thus, whereas PDE III inhibitors produce a significant increase in cardiac output and reduction of systemic vascular resistance, it is necessary to understand their effects on the kidney and neurohormonal parameters. The evaluation of these effects must take into consideration both the baseline renal and neurohormonal abnormalities in CHF, and the cellular actions of PDE III inhibition, which include an increase in cyclic adenosine monophosphate and cytosolic calcium. In a group of 13 patients with CHF, milrinone therapy for 1 month did not increase renal blood flow or glomerular filtration rate, or favorably affect neurohormonal parameters. However, forearm blood flow increased proportionately with cardiac output. Therefore PDE III inhibition produces a preferential increase in skeletal muscle blood flow, which may be a relative shunting of blood from the kidney. Alternatively, PDE III inhibition may activate renal cellular mechanisms that offset the anticipated favorable response to the increase of cardiac output produced by milrinone.
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PMID:Renal and hormonal effects of phosphodiesterase III inhibition in congestive heart failure. 264 28

In recent years several agents have been developed as selective inhibitors of the low Michaelis constant cyclic adenosine monophosphate (cAMP) phosphodiesterase (peak III), a fraction of the cyclic nucleotide phosphodiesterases that is specific for the metabolic breakdown of cAMP. These agents are often referred to as PDE III inhibitors and share similar pharmacologic profiles. The principal interest in these agents--the therapy of congestive heart failure--is based on the cardiovascular effects that result from sequential elevation of intracellular cAMP, cAMP-dependent protein kinase activation, phosphorylation of cellular proteins and change in cellular function. The selective PDE III inhibitors have a triad of cardiovascular activities that provide hemodynamic benefit to patients with congestive heart failure. As a representative drug from this class of compounds, milrinone increases myocardial contractility, increases the rate of ventricular relaxation, and unloads the heart by way of a peripheral vasodilator action. The selective PDE III inhibitors offer a new modality for oral therapy of congestive heart failure.
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PMID:Overview of cardiovascular physiologic and pharmacologic aspects of selective phosphodiesterase peak III inhibitors. 264 30

New cardiotonic agents are an original approach in the treatment of severe heart failure. They can be classified into two groups: --beta-adrenergic agonists which stimulate beta-adrenergic receptors and, therefore, increase cyclic AMP production and intracellular calcium concentration; --phosphodiesterase inhibitors which block the cyclic AMP intracellular degradation pathway. Rapid tachyphylaxis may occur with beta-adrenergic agonists through a down-regulation phenomenon and, therefore, limits the value of this group to short-term treatment. Several different biochemical compounds are under evaluation in the second group. Short-term effects appear beneficial but cardiac side-effects may occur. The value and indications of these drugs in long-term treatment of chronic congestive heart failure remain to be determined.
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PMID:[Value and limitations of new cardiotonic agents]. 267 75

The action mechanisms of the inotropic agents are reviewed: adrenergic stimulants, dopaminergic agents, phosphodiesterase inhibitors direct adenylcyclase stimulants. The hemodynamic effects of these drugs are compared. According with the items proposed by Braunwald e Colucci the inotropic agents are classified. The therapeutic effect is concluded from the published randomized trials placebo. The value of these drugs on the therapy of Congestive Heart Failure is discussed.
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PMID:[Non-digitalis inotropic agents in the treatment of congestive heart insufficiency]. 269 14

The recent development of new positive inotropic agents, such as milrinone, sulmazole and AR-L100 might provide new insights for the treatment of congestive heart failure. Although it has been reported that milrinone and sulmazole have cardiac phosphodiesterase III inhibiting properties, the pharmacological action of these drugs cannot be explained by these mechanisms alone. Despite the presence of cardiac phosphodiesterase III in the rat, the effect of milrinone on the rat heart has been reported to be small or even absent. In this study we have compared the effects of milrinone and sulmazole with these of AR-L100 on isolated hearts of normal rats and of rats with an experimentally induced myocardial infarction. A perfused heart preparation was used to assess the direct positive inotropic effect of milrinone, sulmazole and AR-L100 as well as their effect on isoprenaline-evoked increase of contractile force. The increase in left ventricular systolic pressure (LVP) in hearts of control animals amounted to 42.0 +/- 3.9 mm Hg, 18.2 +/- 2.4 mm Hg and 8.0 +/- 1.7 mm Hg for AR-L100, milrinone and sulmazole, respectively. The average initial LVP was 70.4 +/- 5.3 mm Hg. In infarcted hearts, the increase in LVP was 25.5 +/- 5.9 mm Hg, 12.6 +/- 2.3 mm Hg and 6.7 +/- 1.2 mm Hg for AR-L100, milrinone and sulmazole, respectively. In infarcted hearts, the average initial LVP was 38.6 +/- 1.6 mm Hg. These data show that these drugs have positive inotropic effects on rat hearts, although the effects of milrinone and AR-L100 on hearts from myocardial infarcted rats are smaller. However, interaction studies with isoprenaline showed a stronger potentiating effect of milrinone and sulmazole in infarcted hearts than in control hearts. Only in this respect sulmazole was more active than milrinone, while AR-L100 had no potentiating effect at all. These results suggest that milrinone and sulmazole are effective agents in conditions where higher levels of circulating catecholamines exist. Therefore, they might be particularly effective in the treatment of congestive heart failure.
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PMID:Positive inotropic effects of milrinone, sulmazole and AR-L100 on isolated normal and infarcted hearts of the rat. 273 Feb 43

UDCG-115 is a new cardiotonic agent which in vitro increases the sensitivity of the contractile proteins to calcium ions, inhibits the activity of phosphodiesterase, and prolongs the duration of the action potential. The influence of UDCG-115 (i.v.) on hemodynamics and myocardial energetics was investigated in patients with idiopathic dilated cardiomyopathy (NYHA II-III) and compared to the effects of the pure vasodilator nitroprusside. UDCG-115 increased cardiac index from 3.2 +/- 0.4 to 4.2 +/- 0.8 l/min/m2 (p less than 0.01) and decreased left ventricular end-diastolic wall stress (preload) from 52 +/- 21 to 28 +/- 18 10(3) dyn/cm2 (p less than 0.01) and end-systolic wall stress (afterload) from 201 +/- 61 to 129 +/- 43 10(3) dyn/cm2 (p less than 0.01) compared to control conditions. Compared to nitroprusside, for a similar decrease in preload and afterload. UDCG-115 increased cardiac index by 40% (p less than 0.01), stroke volume index by 37% (p less than 0.01) and maximum rate of left ventricular pressure rise by 23% (p less than 0.05). Heart rate did not significantly change with either drug. Myocardial oxygen consumption per beat decreased by 33% (p less than 0.05) with UDCG-115 and by 30% (p less than 0.01) with nitroprusside. With both drugs, the decrease of myocardial oxygen consumption correlated significantly with the decrease of left ventricular systolic stress-time integral. The slopes of the respective linear regression lines were not significantly different. Thus, UDCG-115 given intravenously in patients with idiopathic dilated cardiomyopathy and moderate congestive heart failure exhibits significant inotropic and vasodilating properties. The systemic hemodynamic actions are associated with favorable effects on myocardial energetics.
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PMID:Influence of the calcium-sensitizer UDCG-115 on hemodynamics and myocardial energetics in patients with idiopathic dilated cardiomyopathy. Comparison with nitroprusside. 281 56


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