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)

Arterial endothelial cells, which are capable of phagocytizing carbon particles of the same size as beta- and pre-beta-lipoprotein, were found only in endothelial cells of arterial segments susceptible to atheromatous changes in susceptible animal species, and the distribution closely corresponded to the susceptibility. The distribution of such endothelial cells is dense in large arteries, in the openings to their branches, especially in downstream portions, of rabbits, hens, and cocks; however, the distribution is relatively scanty in arteries of rhesus monkeys and is very scanty in dogs. Carbon particles were also rare in the suckling rabbit and tended to increase with age. They were not found in Wistar rats but were found in spontaneously hypertensive rats, which showed a characteristically diffuse distribution, even in relatively small arteries. The carbon particles, phagocytized, were released to the subendothelial space but were difficult to pass through the internal elastic lamina and tended to stagnate there for more than one month. The authors therefore call these cells hyperreactive endothelial cells. Various vasoactive substances, such as angiotensin II, histamine, and serotonin, significantly enhanced the phagocytic activities of arotic endothelial cells in rabbits; epinephrine and norepinephrine also slightly enhanced these activities. Various smooth muscle relaxants, such as ATP, pyridinol carbamate (ATP synthesis-enhancing substance), cycli-AMP, dibutyryl cycli-AMP, phthalazinol (cyclic-AMP phosphodiesterase inhibitor), iproveratril (calcium entry-inhibiting substance), colchicine, and vinblastine, with their different modes of action, commonly inhibited phagocytic activities, a finding that suggests a significant role for contractile protein in the permeability problem of atherogenesis. The atheromatous lesions of cholesterol-fed rabbits exhibited a striking increase in hyperreactive endothelial cells, accompanied by a marked rise in the activity of low-Km cyclic-AMP phosphodiesterase activity in atheromatous lesions and adjacent muscular layers, especially in rabbits with rapidly progressing atheroma.
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PMID:Hyperreactive arterial endothelial cells: a clue for the treatment of atherosclerosis. 18 68

1. Experiments were carried out to examine the biochemical changes, such as contractile protein biochemistry and membrane bound enzyme alterations associated with skeletal muscles of myd/myd. 2. Our studies demonstrate that there was a progressive decline in myofibrillar ATPase activity, and this decrease is greatest in 30 weeks old animals of myd/myd as compared to controls. 3. The proteolytic activity of myofibrils isolated from myd/myd was significantly higher than controls. 4. There was no significant difference in Ca2+ ATPase activity of myosin and actin-activated myosin ATPase activity of myd/myd and their controls. 5. Mg2+ ATPase and Na(+)+K(+)-ATPase of myodystrophic SL showed significant increase compared to controls. 6. Isoproterenol stimulated adenylate cyclase activity was significantly lower in the SL of dystrophic mice compared to controls. 7. GTP+isoproterenol stimulate adenylate cyclase was significantly higher in control SL and SR when compared to SL and SR isolated from myd/myd. 8. Guanylate cyclase activity was greater in myodystrophic mice both in the absence and presence of Triton X-100. cGMP and cAMP phosphodiesterase activities were greater in dystrophic mice as compared to controls. 9. These observations suggest that there are significant changes in myofibrillar ATPase, myofibrillar protease and membrane bound enzymes of myd/myd compared to control.
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PMID:Myofibrillar and membrane-bound enzymes in skeletal muscle from myodystrophic mice. 135 51

In experimental informational neurosis, accompanied by the development of stable arterial hypertension, tachycardia and dystrophic alterations in myocardium, the contractile protein ability to generate force and produce work as well as the power of the contractile process are significantly decreased and so is the intensity of Ca2+ transport through membranes of sarcoplasmic reticulum and mitochondria. Ca2+ content in these structures and energetic supply to the cardiac muscle do not change as compared with the control. Noradrenaline content in myocardium increases 5-fold compared with the control and 2.5-fold compared with the norm, while blood content falls to zero (sympathetic neuro-muscular contact is 'locked up' for noradrenaline outflow into the blood); dopamine content increases. Adenylate cyclase sensitivity to the stimulating effect of noradrenaline and NaF diminishes. Basal activity of phosphodiesterase increases, and its sensitivity to the inhibitory action of high calcium concentrations decreases. The disturbance in these systems may, on the one hand, be due to neural effects, and pressure overload of the heart, on the other hand, to the sharp rise in noradrenaline content in the myocardium and the change in the activity of cyclic adenosine monophosphate enzymes. It is suggested that similar changes may take place in the human myocardium and may underlie the cardiac weakness.
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PMID:Subcellular bases of cardiac disturbance in experimental informational neurosis. 243 90

A large number of chemical substances increase contractility of isolated animal myocardial preparations. Their augmentation is the result of a number of mechanisms which ultimately increase the available calcium for contractile protein coupling. Although there is some research with drugs which activate calcium channels, present clinical research is mainly confined to agents whose major action on contraction is mediated by an increase in myocyte cyclic AMP. Species and age variations in the inotropic effect are common. These agents have additional cardiac effects (e.g. chronotropic, lusitropic) and non-cardiac actions. They are potent vasodilators. In isolated human myocardium obtained from patients without heart failure, they increase contractility at high concentrations. Generally this effect is attenuated in isolated myocardium obtained from patients and animals with chronic cardiac failure. In myocardium from patients with the most severe heart failure, even very high concentrations fail to increase contractility. Part of this attenuation may be due to reduced receptor number (or sensitivity) when the drug's effect is due to receptor-coupled adenylate cyclase activation. However, a reduced ability to produce and/or respond to cyclic AMP itself is suggested by impaired responses to phosphodiesterase inhibitors. In vivo, these agents have frankly harmful effects in patients with near normal cardiac function. Despite increasing contractility indices, they lower blood pressure, raise heart rate and impair myocardial lactate metabolism without increasing cardiac output. In patients with severe heart failure they produce beneficial resting haemodynamic changes; increased cardiac output and reduced filling pressures with only small changes in blood pressure and heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New positive inotropic substances--true inotropy or peripheral effects? 306 33

The purpose of these studies was to characterize mechanisms of activation of vascular tissues in order to clarify possible theoretical bases for Ca2+-antagonist (CAt) selectivity. Activation of rabbit aorta, mesenteric artery, and mesenteric resistance vessels by agonists and depolarizing potassium (K+) solution, and inhibition by CAts were studied by measurement of contractions, 45Ca fluxes, and membrane potentials (via intracellular electrodes). We found that the CAts studied (D-600, diltiazem, and nisoldipine) inhibited K+-induced Ca2+ influx and contractions in a closely correlated manner, suggesting inhibition of Ca2+ entry as their primary, if not sole, mechanism of action. Diltiazem and nisoldipine had no effect on intracellular Ca2+ release or on the contractile protein system. The following evidence was obtained to support the tenet that norepinephrine (NE) and 80 mM K+ open two distinct Ca2+ channels, one receptor-operated (ROC) and the other potential-operated (POC): (a) NE activated the rabbit aorta without eliciting a change in membrane potential; (b) NE activation of the rabbit mesenteric resistance vessels was accompanied by membrane depolarization, but this depolarization was blocked by 10(-5) M diltiazem, whereas that induced by 80 mM K+ was not; (c) 45Ca influx stimulated by 80 mM K+ and that stimulated by a maximal [NE] were additive when the two agents were administered together in the aorta and the resistance vessels; (d) the Ca2+-channel agonist Bay K8644 opens the POC but not the ROC in rabbit aorta, as it is capable of stimulating Ca2+ influx in addition to 10(-5) M NE, but not to 80 mM K+; (e) the CAts show selective inhibition of the POC over the ROC in the aorta, whereas diltiazem preferentially inhibits the ROC in the resistance vessels; and (f) alpha adrenoreceptor occupation, phosphodiesterase inhibition, or dibutyryl cyclic AMP selectively inhibits the POC over the ROC in the aorta.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Theoretical bases for vascular selectivity of Ca2+ antagonists. 608 5

Restriction of motor activity and motor-alimentary conditioning in dogs reduced the adrenaline (A) and noradrenaline (NA) contents in the myocardium, dopamine, too, revealing a tendency to reduction. Basal activity of the sarcolemma adenylate cyclase (AC), its sensitivity to A, NA and NaF did not change as well as the basal activity of sarcolemma phosphodiesterase (PDE) and its sensitivity to the inhibitory effect of high concentrations of Ca2 (10(-4) M). In experimental informational neurosis, NA content in the myocardium increased 5-fold compared to control values, the dopamine content also increasing. Basal activity of the sarcolemma AC did not change whereas its sensitivity to NA and to activating effect of NaF decreased. Basal activity of PDE increased and its sensitivity to Ca2 effect decreased in this condition. The increase of PDE activity and increase of its sensitivity to the inhibitory effect of high concentrations of Ca2+ in combination with desensitization of the regulatory subunit AC to NA followed by changes in its catalytic subunit, seem to lead to a decrease of cAMP content and cAMP-dependent phosphorylation in cardiomyocyte that may underlie the Ca2+ transport disturbance observed in informational neurosis, and reduction of contractility of the contractile protein system. Heart pressure overload, caused in informational neurosis by the stable arterial hypertension may play an important role in the genesis of this reduction.
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PMID:[Catecholamine concentration and adenyl cyclase and phosphodiesterase activities of the sarcolemma of myocardial cells during hypokinesia and in experimental information neuroses]. 609 71

LND-623 is a new aminosteroid analog of ouabain, with a greater separation between efficacy and toxicity than ouabain. To determine its mechanism of action, we studied its biochemical and physiological effects on human red blood cell sodium transports on different cellular structures regarded as sites of contractile control, and we compared its relative efficacy to ouabain in rat heart preparations and membrane-bound Na, K-ATPase isoenzymes. The response to ouabain was evaluated in Langendorff-perfused hearts and on purified membrane-bound Na, K-ATPase. LND-623 is 6.8-fold more efficient than ouabain in inhibiting the human Na+ pump (IC50 = 0.098 +/- 0.001 microM vs. 0.67 +/- 0.02 microM); (P < 0.0001). LND-623 had no effect on the following cellular functions: Na-Ca exchange, Na-K cotransport, Ca-ATPase, slow calcium channels, adenylate cyclase system, phosphodiesterase, and calcium sensitivity of the contractile protein system. The dose-response curve for the positive inotropic and inhibitory effects on rat cardiac isoenzymes produced by LND-623 were clearly biphasic. The amplitude of the maximum inotropic effect, without any toxic effect, was up to three-fold higher with LND-623 than with the same maximum dose of ouabain used. The strong positive inotropic effect of LND-623 in rats could be related to a specific inhibition of the two rat cardiac isoforms of the Na, K-ATPase.
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PMID:Mechanism underlying the strong positive inotropic effects of LND-623: specific inhibition of Na, K-ATPase isoforms and exclusion of cellular sites of contractile control. 1041 Aug 28

The benzimidazole molecule was modified to synthesize a Ca(2+) sensitizer devoid of additional effects associated with Ca(2+) overload. Newly synthesized compounds, termed 1, 2, 3, 4, and 5, were evaluated in spontaneously beating and electrically driven atria from reserpine-treated guinea pigs. Compound 3 resulted as the most effective positive inotropic agent, and experiments were performed to study its mechanism of action. In spontaneously beating atria, the inotropic effect of 3 was concentration-dependent (3.0 microM-0.3 mM). Compound 3 was more potent and more active than the structurally related Ca(2+) sensitizers sulmazole and caffeine, but unlike them it did not increase the heart rate. In electrically driven atria, the inotropic activity of 3 was well preserved and it was not inhibited by propranolol, prazosin, ranitidine, pyrilamine, carbachol, adenosine deaminase, or ruthenium red. At high concentrations (0.1-1.0 mM) 3 inhibited phosphodiesterase-III, whereas it did not affect Na(+)/K(+)-ATPase, sarcolemmal Ca(2+)-ATPase, Na(+)/Ca(2+) exchange carrier, or sarcoplasmic reticulum Ca(2+) pump activities of guinea pig heart. In skinned fibers obtained from guinea pig papillary muscle and skeletal soleus muscle, compound 3 (0.1 mM, 1 mM) shifted the pCa/tension relation curve to the left, with no effect on maximal tension and no signs of toxicity. Compound 3 did not influence the basal or raised tone of guinea pig isolated aorta rings, whose cells do not contain the contractile protein troponin. The present results indicate that the inotropic effect of compound 3 seems to be primarily sustained by sensitization of the contractile proteins to Ca(2+).
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PMID:Pharmacological characterization of a new Ca(2+) sensitizer. 1108 34

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