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)

Inotropic agents are used widely for pharmacological bridging of the failing heart either until recovery after surgical intervention or until transplantation. EMD 57033 is a novel specific Ca++ sensitizing agent with purportedly minor phosphodiesterase (PDE) III-inhibiting properties. It acts as an inotropic agent without raising intracellular Ca++ levels. In turn, the PDE III-inhibitor enoximone has been used for several years to treat low cardiac output syndrome. However, little is known about its effects on postischemic reperfused (stunned) myocardium. We investigated the effects of EMD 57033 (EMD; 30 microM) and enoximone (E20 micrograms/ml) on stunned myocardium. The experiments were performed on 16 isolated rabbit hearts perfused with an erythrocyte suspension (hematocrit = 30%; [Ca++] = 2.5 mM). Hearts were reperfused after a 20 min no-flow ischemia. Measurements were performed at control, 30 min after the onset of reperfusion, and after administration of one of the drugs. Both agents significantly improved the depressed systolic function [left ventricular pressure (LVP)max from 61 +/- 12 to 93 +/- 18 mmHg, and its derived pressure (dP/dt)max from 860 +/- 220 to 1340 +/- 300 mmHg/s and LVPmax from 78 +/- 9 to 83 +/- 15 mmHg, and its derivative dP/dtmax from 1040 +/- 230 to 1385 +/- 300 mmHg/s, respectively] and early relaxation (dP/dtmin from 810 +/- 250 to 1260 +/- 345 mmHg/s and from 1000 +/- 200 to 1135 +/- 295 mmHg/s, respectively) that occurred during postischemic reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison between the effects of a novel Ca++ sensitizer and a phosphodiesterase inhibitor on stunned myocardium. 853 Nov 13

Several forms of cardiac adaptation to stress are known, differing in the evoking stress, in the time needed for adaptation and in the duration of the protective effect. A delayed adaptation produced a late appearing, prolonged protection against consequences of ischemia, such as early morphological changes, early and late postocclusion and reperfusion arrhythmias due to coronary artery occlusion or ouabain intoxication. Delayed adaptation was evoked by ischemic stress (repeated brief periods of rapid cardiac pacing or brief coronary occlusions) or by drugs (prostaglandin I2 and its stable derivatives). The protection produced by delayed adaptation proved to be time- and dose-dependent. Optimal effects appeared 24 to 48 h after treatment with an optimal dose of 50 microg/kg 7-oxo-prostacyclin or 10 microg/kg Iloprost. It is suggested that the mechanism of delayed cardioprotection is based on the fact that the stress-evoking adaptation stimulates the adenylate-cyclase/cyclic adenosine monophosphate (cAMP) system; the resulting elevation of cardiac cAMP level triggers the induction of some key enzymes such as Na/K-ATPase and phosphodiesterase (PDE) isoforms I and IV. Increased amount and activity of Na/K-ATPase accounts for preservation of normal membrane function and moderation of ischemic loss of potassium, and accumulation of sodium and calcium in the myocardium, as well as for reduced ouabain toxicity. The detrimental consequences of heavy stress-induced accumulation of cAMP in the heart are mitigated by hydrolysis of the latter, carried out by an enhanced amount and activity of PDE isoforms. Response to beta-adrenergic stimuli is also attenuated. In addition, electrophysiological changes such as prolongation of the effective refractory period and of the action potential duration may attenuate arrhythmias due to ischemia and reperfusion.
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PMID:On the mechanism and possible therapeutic application of delayed cardiac adaptation to stress. 860 40

1. Functional and antiischaemic effects of monoacetyl-vitexinrhamnoside (AVR), a flavonoid with phosphodiesterase (PDE)-inhibitory properties contained in Crataegus species (Hawthorn, Rosaceae) were studied in several in-vitro models. 2. In rabbit isolated femoral artery rings, AVR concentration-dependently reduced developed tension. Vasodilation by AVR was reduced after inhibiting EDRF formation by L-NG-nitro arginine. 3. In spontaneously-beating Langendorff-guinea pig hearts, AVR concentration-dependently enhanced heart-rate, contractility, lusitropy and coronary flow. 4. In isolated electrically-driven Langendorff-rabbit hearts, acute regional ischemia (MI) was induced by coronary artery occlusion and quantified from epicardial NADH-fluorescence photography. AVR (5 x 10(-5) mol/l) induced a slight numerical increase of left ventricular pressure and coronary flow (p > 0.05). MI was reduced (p < 0.05). 5. Monoacetyl-vitexinrhamnoside is an inodilator whose vasodilatory action may be mediated in part by EDRF in addition to PDE-inhibition. Monoacetyl-vitexinrhamnoside does possess marked antiischemic properties even in isolated hearts, suggesting an improvement of myocardial perfusion.
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PMID:Functional and antiischaemic effects of Monoacetyl-vitexinrhamnoside in different in vitro models. 869 Feb 47

We investigated the effect of a new Ca++ sensitizer, MCI-154, which is known to increase myofibrillar Ca++ sensitivity and maximal Ca(++)-activated force, on Ca++ transients and left ventricular (LV) function in indo-1-loaded Langendorff guinea plg hearts subjected to a reduction in coronary perfusion pressure from 80 to 40 mm Hg. During low-flow ischemia, LV contractility decreased by 50%, whereas systolic and diastolic indo-1 fluorescence ratios increased by 10%. The treatment with MCI-154 (10(-10) to 10(-6) M) 15 min after ischemia effectively restored the depressed LV function with little effect on indo-1 ratio. EMD 53998 (10(-9) to 10(-6) M), which also acts on maximal Ca(++)-activated force, restored LV function with a minimal impact on indo-1 ratio, but at 10(-5) M, EMD 53998 caused diastolic dysfunction, and its beneficial effect on systolic function disappeared. The relation between indo-1 ratio and LV contractility showed that MCI-154 and EMD 53998 restored ischemic contractile failure by Ca(++)-sensitizing action. It was noted that the restoration of LV dysfunction by MCI-154 or EMD 53998 was more pronounced than that by pimobendan, which acts primarily on Ca++ sensitivity. In contrast, the phosphodiesterase inhibitor milrinone restored LV function, but it doubled the increase in indo-1 ratio during ischemia. These findings suggest that a decrease in myofilament Ca++ responsiveness may be an important cause of ischemic contractile failure and that the restoration of depressed Ca++ responsiveness by intervention such as MCI-154 may be a promising approach for restoring the depressed function.
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PMID:Restoration of ischemic contractile failure of indo-1-loaded guinea pig heart by a calcium sensitizer, MCI-154. 885 74

In a randomized prospective experimental study on 48 adult white Elco rabbits biochemical and rhythmic changes after bolus administration of the phosphodiesterase inhibitor piroximone were investigated using a working heart model. The treatment group (n = 21) intravenously received 1 mg/kg of piroximone 15 min before thoracotomy. Twenty-three untreated hearts served as the control group. From 6 hearts of each group myocardial biopsies were taken before ischemia, 4 (2/2) hearts were excluded. Hemodynamic results of a previous study with an identical protocol were reanalyzed; a biochemical analysis of myocardial high-energy phosphates was investigated after 60 min of global ischemia and at the end of the experiments after 45 min of reperfusion. Already prior to ischemia, in the treatment group depletion of high-energy phosphates was detected. After 60 min of ischemia during early reperfusion in the treatment group ATP and creatine phosphate depletion became even more evident and increased until the end of the experiments. The incidence of reperfusion-induced arrhythmias was significantly lower in the treatment group. Consequently these results and the hemodynamic results of prior studies indicate a possible positive effect of piroximone during the early reperfusion period by optimizing hemodynamics and arrhythmias.
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PMID:Preischemic bolus application of piroximone studied on the isolated rabbit heart--a second look including biochemical data. 888 Jan 29

Sepsis is intricately associated with mesenteric ischemia. The remote complications of mesenteric ischemia are essentially those of sepsis, whether as a cause or as a consequence. Experimental endotoxic shock induces bowel hypoperfusion, erythrocyte extravasation and intestinal necrosis. The effects of pentoxifylline, rolipram and denbufylline, three phosphodiesterase inhibitors, were studied on endotoxin-induced bowel erythrocyte extravasation and intestinal and renal hypoperfusion, in conscious rats and anaesthetized dogs, respectively. Two hours after lipopolysaccharide i.v. injection in rats, erythrocyte extravasation was evident throughout the intestinal musculature and mucosa, apparently without affecting lungs, heart, kidneys, liver or pancreas. Pretreatment with the non-selective phosphodiesterase inhibitor, pentoxifylline, or selective phosphodiesterase IV inhibitors such as denbufylline or rolipram reduced intestinal haemoconcentration. In the anaesthetized dog, pentoxifylline and denbufylline both inhibited the E. coli lipopolysaccharide-induced mesenteric blood flow fall, without affecting renal blood flow or cardiac index. In conclusion, phosphodiesterase inhibitors protected from intestinal damage and bowel hypoperfusion after lipopolysaccharide challenge. This action may thus play a role in the protective effects against endotoxin-induced lethal toxicity previously described for phosphodiesterase inhibitors.
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PMID:Inhibition of lipopolysaccharide-induced bowel erythrocyte extravasation in rats, and of mesenteric hypoperfusion in dogs, by phosphodiesterase inhibitors. 890 Oct 18

We recently reported that pretreatment with the type IV phosphodiesterase inhibitor Ro 20-1724 attenuates the development of endotoxin-induced acute renal failure in rats. Norepinephrine is an important therapeutic agent in human endotoxemia, but its efficacy is limited by its deleterious side effect of potent renal and mesenteric vasoconstriction. In this study we examined whether posttreatment with Ro 20-1724 after endotoxin infusion 1) attenuates increased renal vascular resistance and the development of acute renal failure in the absence and presence of norepinephrine infusion, 2) improves mesenteric blood flow in the presence of norepinephrine and 3) improves survival rates in the absence and presence of norepinephrine infusion. Forty-eight rats were anesthetized and instrumented, and eight 20-min clearance periods were performed. Endotoxin (20 mg/kg i.v.) was administered after the first period, and a constant-rate i.v. infusion of either Ro 20-1724 (10 micrograms/kg/min) or vehicle was initiated after period 3, in the absence and presence of norepinephrine infusion (1 microgram/kg/ min, begun after period 4). Urinary cAMP excretion in the Ro 20-1724-treated groups was 2- to 3-fold (P < .001) higher, compared with the vehicle-treated groups. Ro 20-1724 markedly attenuated endotoxin-induced (P < .01) increases in renal vascular resistance and attenuated norepinephrine-induced (P < .05) increases in renal vascular resistance in rats pretreated with endotoxin. Moreover, Ro 20-1724 reduced endotoxin-induced decreases in renal blood flow (P < .05) and glomerular filtration rate (P < .01) in the absence and presence of norepinephrine. In animals pretreated with endotoxin, Ro 20-1724 attenuated norepinephrine-induced increases in mesenteric vascular resistance (P = .054) and decreases in mesenteric blood flow (P < .01). Ro 20-1724 also improved survival rates for endotoxin-treated rats, whether or not the rats were administered norepinephrine (P < .01). Type IV-specific phosphodiesterase inhibitors warrant further study as selective therapeutic agents that protect against endotoxin/vasopressor-induced renal and mesenteric ischemia and death.
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PMID:Treatment with the type IV phosphodiesterase inhibitor Ro 20-1724 protects renal and mesenteric blood flow in endotoxemic rats treated with norepinephrine. 896 41

Cavinton was introduced into the clinical practice some twenty years ago in Hungary for the treatment of cerebrovascular disorders and related symptoms. Since then, its active ingredient, vinpocetine, beside its therapeutical utilization, has become a reference compound in the pharmacological research of cognitive deficits caused by hypoxia and ischaemia as well as in the cellular and biochemical investigations related to cyclic nucleotides. In this review a survey is given on the experimental data obtained with vinpocetine and an attempt is made to outline the drug's mechanism of action. Early experiments with vinpocetine indicated five main pharmacological and biochemical actions: (1) selective enhancement of the brain circulation and oxygen utilization without significant alteration in parameters of systemic circulation, (2) increased tolerance of the brain toward hypoxia and ischemia, (3) anticonvulsant activity, (4) inhibitory effect on phosphodiesterase (PDE) enzyme and (5) improvement of rheological properties of the blood and inhibition of aggregation of thrombocytes. Later studies in various laboratories confirmed the above effects and clearly demonstrated that vinpocetine offers significant and direct neuroprotection both under in vitro and in vivo conditions. Evidence has been obtained that neuroprotective action vinpocetine is related to the inhibition of operation of voltage dependent neuronal Na(+)-channels, indirect inhibition of some molecular cascades initiated by the rise of intracellular Ca(2+)-levels and, to a lesser extent, inhibition of adenosine reuptake. Vinpocetine has been shown to be selective inhibitor of Ca(2+)-calmodulin dependent cGMP-PDE. It is assumed that this inhibition enhances intracellular a GMP levels in the vascular smooth muscle leading to reduced resistance of cerebral vessels and increase of cerebral flow. This effect might also beneficially contribute to the neuroprotective action.
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PMID:[Mechanism of action of vinpocetine]. 908 41

In this study the effect of post-treatment with rolipram, an inhibitor of cAMP phosphodiesterase, on neuronal damage following global ischemia was evaluated. Global cerebral ischemia was induced in male Wistar rats by four-vessel occlusion for 20 minutes. Rolipram was administered 6 hours after onset of ischemia and thereafter the following 7 days daily once at a dose of 0.3 or 3.0 mg/kg intraperitoneally. Four weeks after ischemia the amount of intact neurons in the hippocampus and in the striatum was assessed following perfusion fixation. The ischemia-induced neuronal damage in the CA1 sector of the hippocampus and in the striatum was reduced by rolipram at either dose. The present results show that treatment with rolipram reduces ischemic neuronal damage at a therapeutic window of 6 hours.
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PMID:Delayed treatment with rolipram protects against neuronal damage following global ischemia in rats. 942 78

Leukocytes have been shown to contribute to ischemia-reperfusion injury in skeletal muscle. Pentoxifylline (PTXF), a xanthine-derived phosphodiesterase inhibitor, has received recent attention because of its action on leukocytes. To clarify the effects of PTXF in reperfusion injury, we measured the resting transmembrane potential difference (Em) and evaluated postcapillary venule microcirculation using intravital microscopy in rat skeletal muscle during ischemia and reperfusion. The infrarenal aorta was clamped for 90 min and then reperfused for 60 min. Persistent depolarization of the resting Em was observed in an ischemia-reperfusion (IR) group and was significantly repolarized in a PTXF group during the reperfusion period. The tissue water content was significantly reduced in the PTXF group, although no difference was noted in the tissue lactate content. Flowing erythrocyte velocity and wall shear rate in the PTXF group were significantly higher than in the IR group during the reperfusion period but without significant differences in vessel diameter and hemoglobin oxygenation. Blood flow measured by laser-Doppler flowmeter was also significantly improved in the PTXF group. Furthermore, the adherent leukocyte count was significantly reduced in the PTXF group during this same period. These results indicate that PTXF attenuated reperfusion-associated membrane injury and tissue edema and that PTXF suppressed leukocyte adhesion and improved hindlimb blood flow during the reperfusion period.
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PMID:Pentoxifylline attenuates reperfusion injury in skeletal muscle after partial ischemia. 961 47


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