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)

When keratome-sliced pig epidermis was floated on Hank's balanced salt solution, we observed a rapid decrease in the intracellular level of cyclic GMP. A portion of the lost cyclic GMP was detected in the incubation medium. When the epidermis was kept in air at room temperature, the cyclic GMP level also decreased rapidly but to a lesser degree. Incubating the epidermal slice at 37 degrees C in Hank's balanced salt solution with the addition of 3-isobutyl-1-methyl xanthine (IBMX) prevented the decrease. Also, after the cyclic GMP level had fallen, it could be raised to be the in vitro level by the addition of IBMX. Increased amounts of cyclic GMP were detectable in the medium in this case. These data indicate that the decrease in cyclic GMP in ischemic epidermis is due to sudden activation of epidermal cyclic GMP-phosphodiesterase and also in part due to leakage of cyclic GMP extracellularly. In contrast to the rapid decline in the cyclic GMP level, ischemia caused a rapid and transient increase in epidermal cyclic AMP. This confirms previous data by ourselves and by others (Br J Dermatol 92: 249-254, 1975; J Invest Dermatol 68:125-127, 1977). These "ischemic effects" must be avoided in order to measure the "in vivo level" of cyclic nucleotides in epidermis.
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PMID:Cyclic GMP System in epidermis: I. Effect of ischemia. 8 73

Insulin accelerates the entry of glucose and amino acids into muscle cells by acting upon the 'carrier-facilitated' transport mechanism. For glucose this process is passive and leads to equilibration of intracellular and extracellular concentrations. In heart muscle, glucose transport is a rate-limiting step for glucose uptake. During hypoxia and ischemia the heart turns to anaerobic glycolysis for energy production and therefore, maximal glucose transport becomes important. Insulin is necessary to insure proper protein synthesis, probably at the level of membrane-bound polyribosomes. However, during myocardial hypoxia, insulin alone cannot restore the associated depression in protein synthesis. Although insulin hyperpolarizes the cell, a change in the ratio of intracellular to extracellular activities of potassium is not its primary mode of action. An insulin-induced configurational change in the plasma membrane could simultaneously account for the effects of insulin on sodium and potassium permeability and the action on facilitated transport. Intracellular levels of cyclic adenylate may be reduced by insulin in adipose tissue because of inhibition of adenyl cyclase or stimulation of phosphodiesterase. However, at this time there is little evidence that insulin alters cyclic AMP levels in the heart. Insulin secretion is depressed in patients with heart disease in proportion to the reduction of cardiac index sustained. Since the ischemic heart is dependent upon glucose as the major fuel, insulin lack may deprive the heart of adequate substrate.
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PMID:Insulin: fundamental mechanism of action and the heart. 18 67

Postischemic alteration of cyclic adenosine monophosphate phosphodiesterase was investigated in the rat brain, using [3H]rolipram in vitro autoradiography. After 90 min of middle cerebral artery (MCA) occlusion, [3H]rolipram binding sites decreased rapidly in the brain areas supplied by the occluded MCA. Moreover, 3 days after the ischemia, significant decreases of [3H]rolipram binding sites were observed in the thalamus and the substantia nigra, both areas had not been directly affected by the original ischemic insult. These results suggest that alteration of second messenger pathways may be involved in neuronal degeneration caused by transsynaptic process and that alteration of intracellular signal transduction may precede the neuronal damage in the exo-focal postischemic brain areas.
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PMID:Autoradiographic analysis of cyclic adenosine monophosphate phosphodiesterase using [3H]rolipram in the postischemic rat brain. 133 13

The cardiac and hemodynamic effects of R80122, a new specific phosphodiesterase III inhibitor, were studied in a closed-chest canine model of acute global left ventricular ischemia complicated by heart failure. The results obtained were compared with those obtained with milrinone. Intravenous infusion of the compounds (0.005 mg/kg/min for both) was started when stable heart failure had developed and was continued for 50 min followed by a washout period of 60 min. Both R80122 and milrinone improved the function of the acutely failing heart, as indicated by the increase in the values of the variables related to left ventricular function, but differences existed. The most striking differences were the normalization of the left ventricular external mechanical efficiency with R80122, but not with milrinone, and the maintenance of aortic blood pressure during infusion of R80122, which decreased during infusion of milrinone. Milrinone tends to induce ventricular tachycardia more frequently than R80122. It can be concluded that R80122 and milrinone improve the function of the acutely failing heart, but that the changes induced by R80122 are better balanced, i.e., enhancement of external mechanical efficiency with maintenance of aortic blood pressure.
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PMID:Cardiac and hemodynamic effects of intravenous R80122, a new phosphodiesterase III inhibitor, in a canine model of myocardial ischemia and heart failure. 138 27

A new cyclic adenosine monophosphate phosphodiesterase inhibitor, DN-9693, was examined to see whether myocardial reperfusion injury could be reduced in a setting of cardioplegic arrest through its antiaggregation effect on leukocytes. Isolated rabbit heart models with whole blood perfusion were used, and 18 hearts were divided into three groups according to the reperfusion method: control (G-1, n = 5), DN-9693 (G-2, n = 7), and leukocyte depletion (G-3, n = 6). The hearts were subjected to 120 minutes of cold global ischemia under crystalloid cardioplegia followed by 30 minutes of reperfusion. A dose of 20 micrograms.kg-1.min-1 of DN-9693 was administered in G-2, and a leukocyte removal filter was used in G-3 during reperfusion. Ultrastructural changes in mitochondrial injuries, intracellular edema, and capillary injuries of the myocardium showed worse changes in G-1 than in G-2 and G-3. Under microscopic study, the intracapillary leukocyte count was significantly higher in G-1 than in G-2 and G-3. Recovery of rate-pressure product, left ventricular developed pressure, and coronary flow were significantly better in G-2 and G-3 than in G-1. There were no significant differences between G-2 and G-3 for all these indices. These results indicate that reperfusion with leukocyte-depleted blood attenuates reperfusion myocardial injury and DN-9693 has a comparable myocardial protective effect with possible inhibition of leukocyte aggregation.
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PMID:Effect of a cyclic adenosine monophosphate phosphodiesterase inhibitor, DN-9693, on myocardial reperfusion injury. 165 68

Hydrogen peroxide produces marked antigonadotropic and lytic actions in luteal cells, but the effects of superoxide, the archetypal oxygen radical, are unknown. Xanthine oxidase generates superoxide, and the activity of this enzyme, and purine substrate, are increased under ischemia, such as that seen at luteal regression. We therefore examined the actions of xanthine oxidase on luteal cells to assess the effects of this enzyme and the superoxide anion on luteal function. Xanthine oxidase, in the presence of hypoxanthine (50 microM), produced marked inhibition of LH-sensitive cAMP and progesterone production with complete inhibition at 25 mU/ml and half-maximal inhibition at about 5 mU/ml. These antigonadotropic actions of xanthine oxidase were rapid with maximal effects within 5 min, followed several minutes later by substantial depletion of ATP. Heat, superoxide dismutase, and catalase or catalase alone abolished the actions of xanthine oxidase. While depletion of ATP by xanthine oxidase was prevented by 3-amino-benzamide, an inhibitor of DNA repair, inhibition of cAMP and progesterone production was still evident. Xanthine oxidase also inhibited progesterone synthesis stimulated by 8-bromo-cAMP. Isobutylmethylxanthine, a cAMP phosphodiesterase inhibitor, did not reverse the inhibition of cAMP accumulation by xanthine oxidase, and the enzyme had no effect on LH receptor binding activity. Since catalase reversed the effects of xanthine oxidase, we conclude that superoxide was rapidly dismuted to hydrogen peroxide and mediated the antigonadotropic and antisteroidogenic actions of xanthine oxidase in luteal cells. The sensitivity of luteal cells to xanthine oxidase raises the possibility that this enzyme may serve as a significant source of hydrogen peroxide in the corpus luteum.
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PMID:Inhibition of gonadotropin action and progesterone synthesis by xanthine oxidase in rat luteal cells. 170 32

The importance of right ventricular (RV) function in maintaining global cardiac performance is the focus of this discussion. The physiological determinants of normal right ventricular function will be discussed, with particular emphasis on the afterload and contractility characteristics of the right ventricle. Numerous clinical conditions have been shown to affect RV performance. These conditions include positive-pressure ventilation, ischemia, pulmonary hypertension, and cardiac surgery. Present methods for the perioperative evaluation of RV function include angiography, radionuclide techniques, thermodilution techniques, echocardiography, and magnetic resonance imaging. Traditional modalities for the treatment of RV dysfunction consist of pharmacological interventions (i.e., vasodilators and inotropes) and/or mechanical assist devices. Newer pharmacological strategies for the treatment of RV failure and associated pulmonary hypertension include the phosphodiesterase fraction III inhibitors and the prostaglandins, specifically PGE1. In summary, the accurate evaluation of perioperative RV performance combined with new treatment options will ensure maximal preservation of RV performance.
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PMID:Right ventricular function and failure: a review. 181 51

Prostacyclin, the stable prostacyclin analogue carbacyclin, the thromboxane synthetase inhibitor UK-38,485, and the phosphodiesterase inhibitor dipyridamole were tested on rabbit epigastric free flaps for their ability to improve flap survival after a period of ischemia. Control flaps infused with a balanced salt solution had a 39.9% survival, whereas prostacyclin, carbacyclin, and dipyridamole significantly increased flap survival to 68.4% (P less than 0.05), 66.4% (P less than 0.05), and 66.9% (P less than 0.05), respectively. UK-38,485 improved survival slightly to 47.6% although not significantly. The improved flap survival correlated with the vasodilatory properties of the three successful agents whereas the antithrombotic properties of UK-38,485 were not sufficient, on their own, to increase flap survival.
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PMID:Prostacyclin and prostanoid modifiers aid ischemic skin flap survival. 199 Feb 15

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

Regulation of cardiac beta-adrenergic receptors during hypoxia and ischemia is an area of active investigation, with some investigators reporting an increase in sarcolemmal beta-receptor number after ischemia. Previous studies have been limited by the necessity of examining beta-adrenergic receptor properties in membrane preparations from hypoxic or ischemic cardiac tissue and drawing conclusions about receptor localization in intact tissue from the behavior of a fraction of total receptors in membrane populations. As an approach to examining beta-receptor properties under well-defined pathophysiological conditions in intact heart cells, we studied cell-surface beta-receptors and adenylate cyclase activity in intact cultured chick embryo ventricular cells under conditions of controlled hypoxia and reoxygenation. During 2 h of hypoxia (PO2 less than 1.5 Torr) there was a progressive decline in cell surface beta-receptors from 26 +/- 2 to 10 +/- 6 fmol/mg (P less than 0.003) with no change in antagonist or agonist affinity. Receptor number recovered fully during 2 h of reoxygenation. Basal adenosine 3',5'-cyclic monophosphate (cAMP) production was unchanged, but response to isoproterenol in the absence or presence of a phosphodiesterase inhibitor decreased to about half of the response for normoxic cells but fully recovered during reoxygenation in a pattern similar to that for receptor number. Although [ATP] declined significantly during hypoxia (from 35 to 25 nmol/mg), the decline in [GTP] was marginal (4.3 to 3.9 nmol/mg), making it unlikely that substrate for guanine nucleotide regulatory protein was limiting for beta-adrenergic signal transduction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Beta-adrenergic receptor regulation during hypoxia in intact cultured heart cells. 253 45


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