Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of prostaglandins (PGs) on rat pineal metabolism were examined in vitro. PGE2 (0.01-1 microM) increased the activity of serotonin-N-acetyltransferase (SNAT), the stimulation curve exhibiting a maximum at 0.1 microM. PGE1 increased SNAT activity only at the highest dose (1 microM) whereas PGF2 alpha, 15-keto-PGF2 alpha or PGI2 did not affect the enzymic activity. The stimulation of SNAT activity brought about by PGE2 in pineals from ganglionectomized rats was greater than in sham-operated controls at all the doses studied, suggesting that the observed effect is predominantly post-synaptic. Only PGE2 significantly increased pineal cAMP accumulation in vitro at doses between 0.01 and 1 microM, and depressed the unoccupied cAMP-binding sites in pineal 900 g supernatants. The total number of cAMP-binding sites remained unaltered after incubation of PGE2. The present observations together with the previously reported NE-induced release of PGs in incubated pineal glands, the occurrence of pineal PG-binding sites and the indomethacin blockade of the nocturnal rise of pineal SNAT and melatonin content, support a role for PGs in the control of melatonin synthesis.
Mol Cell Endocrinol 1981 Aug
PMID:Prostaglandin E2 increases adenosine 3',5'-monophosphate concentration and binding-site occupancy, and stimulates serotonin-N-acetyltransferase activity in rat pineal glands in vitro. 626 70

Adenosine diphosphate (ADP) is known to induce platelet shape change, aggregation and fibrinogen binding, followed by secretion. These processes are mediated by the binding of ADP to an externally oriented protein of the platelet plasma membrane. An affinity analog of ATP, a competitive inhibitor of the action of ADP, has been utilized to probe the structure and function of this receptor. FSBA (5'-p-fluorosulfonylbenzoyl adenosine) covalently modifies a single protein in intact platelets with Mr = 100 000 and concomitantly inhibits platelet shape change, aggregation and fibrinogen binding. Studies on platelet membranes demonstrate non-covalent association of ADP-binding protein with actin which is also labeled by FSBA but only in isolated membranes. This finding suggests a structural and functional coupling of the receptor to the contractile process. The putative ADP receptor covalently modified with FSBA is cleaved by chymotrypsin, a process that reverses the inability of the platelets to bind fibrinogen. Thus, the Mr = 100 000 polypeptide may be involved in the proteolytic exposure of fibrinogen binding sites on the platelet surface. The ability of FSBA to inhibit platelet aggregation and fibrinogen binding by prostaglandin H2 derivatives and epinephrine suggest that ADP is involved in these processes. However, the interaction is not at the receptor level since shape change, stimulated by PGH2 derivatives and yohimbine (epinephrine antagonist) binding are unaffected by FSBA. Finally, the action of ADP to inhibit PGE1- or PGI2-stimulated adenylate cyclase appears to be mediated by a receptor distinct for the protein modified by FSBA.
Mol Cell Biochem 1984
PMID:Characteristics of an ADP receptor mediating platelet activation. 632 60

Deep dermal injuries elicit discrete reaction patterns dependent on the type of injury sustained. Full thickness burn injuries produce an avascular focus of dead and dying tissue surrounded by a peripheral zone of secondary vascular dilation. In contrast, equivalent freeze injuries demonstrate vascular patency both centrally and peripherally. The basis for these differences are unknown. Because of their potent vasoactive and hematologic properties, the presence of two endogenously generated eicosanoids, thromboxane A2 (Tx A2) and prostacyclin (PGI2), were examined in this process. Implanted stainless steel mesh chambers served as an in vivo interstitial collecting reservoir permitting repeated sampling of the wound fluid without tissue disruption. Standard burn and freeze injuries were administered to the skin covering the implanted chambers. The major metabolites of these eicosanoids: 6-keto PGF1 alpha and TxB2 were measured in wound fluid during the first 24 hr following injury. Although both TxB2 and 6-keto PGF1 alpha increased significantly following either injury, treatment with indomethacin did not alter the vascular sequelae despite evident cyclooxygenase inhibition. Latex infusion of whole rats confirmed the considerable difference between these two types of injury, with or without indomethacin. Thus, little evidence was found to support the importance of either TxA2 or PGI2 in the vascular alterations which follow burn or freeze injury.
Exp Mol Pathol 1983 Jun
PMID:The role of prostacyclin and thromboxane in rat burn and freeze injuries. 634 13

With electrophysiological methods, mechanisms of the restorative action of coenzyme Q10 (CoQ10) in 2,4-dinitrophenol-depressed electrical and mechanical activities of isolated guinea-pig hearts were studied. Isoproterenol (3 X 10(-8) M)-induced action potential and contraction of the heart in 27 mM KCl Tyrode solution were abolished by 6 X 10(-6) M 2,4-dinitrophenol, while the additional application of CoQ10 (50 micrograms/ml) restored both these activities of the heart. This restorative action of CoQ10 was dose related (2 to 50 micrograms/ml) and was inhibited by 10 micrograms/ml 15-hydroperoxyarachidonic acid (15-HPAA) or pretreatment of the animals with indomethacin (5 mg/kg i.v.). When exogenously applied, 200 ng/ml prostacyclin also restored the 2,4-dinitrophenol-depressed electrical and contractile activities of the heart, but this restorative action of prostacyclin was affected neither by 15-HPAA nor by indomethacin pretreatment. These results suggest the possible participation of prostacyclin in the restorative action of CoQ10 in 2,4-dinitrophenol-depressed electrical and mechanical activities of the heart.
J Mol Cell Cardiol 1983 Sep
PMID:The restorative action of coenzyme Q10 in 2,4-dinitrophenol-depressed electrical and contractile activities of guinea-pig heart. 635 90

The effects of the antithrombotic drug nafazatrom (BAY g 6575) were investigated in chloralose-anaesthetized greyhounds subject to coronary artery occlusion and reperfusion. Pretreatment with nafazatrom 10 mg/kg p.o. did not significantly reduce the number of extrasystoles or the incidence of ventricular fibrillation (VF) during the first 30 min occlusion of the left anterior descending coronary artery. However, the incidence of VF resulting from release of a 40-min coronary artery occlusion was markedly reduced (from 88% in the controls to 14% in the nafazatrom group). Both thromboxane B2 (TxB2) and 6-keto PGF1 alpha (breakdown products of TxA2 and prostacyclin respectively) were released from the acutely ischaemic myocardium in control dogs. Nafazatrom did not alter the release of TxB2 but the concentrations of 6-keto PGF1 alpha were elevated in blood draining from both the ischaemic and normal regions of the myocardium. The pronounced anti-fibrillatory effect of nafazatrom during reperfusion of the ischaemic myocardium may be related to the ability of this drug to elevate prostacyclin concentrations in the coronary circulation.
J Mol Cell Cardiol 1984 Jan
PMID:The effects of nafazatrom on arrhythmias and prostanoid release during coronary artery occlusion and reperfusion in anaesthetized greyhounds. 636 41

Coronary blood flow decreases cyclically in a partially occluded coronary artery of anesthetized dogs. Spontaneous aggregation and deaggregation of platelet plugs in the constricted artery have been indicated to be responsible for this phenomenon. A current hypothesis is that platelet aggregation may be determined by a balance between proaggregatory platelet product, thromboxane A2 (TXA2), and antiaggregatory substance, prostacyclin (PGI2). To elucidate the relationship between the cyclical reduction of coronary flow (CRCF) and metabolic alterations of TXA2 and PGI2, we attempted to determine the plasma levels of their stable catabolites, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), in the coronary circulation of 69 dogs. Of 40 cases, 20 cases exhibited CRCF accompanying a significant increase in TXB2 in the coronary sinus (CS) (P less than 0.05) and constant levels of 6-keto-PGF1 alpha in the CS and aorta (Ao). Another 20 cases did not exhibit CRCF that accompanied a marked increase in 6-keto-PGF1 alpha (P less than 0.05) with virtually no change in TXB2 in the CS and Ao. A higher dose of indomethacin (10 mg/kg, i.v.) was capable of evoking CRCF in cases not exhibiting CRCF spontaneously. Under these conditions, a significant decrease in 6-keto-PGF1 alpha was seen both in the CS and Ao compared with lower doses of indomethacin (1 to 3 mg/kg, P less than 0.01), that produced less pronounced reduction of 6-keto-PGF1 alpha without CRCF. Intravenous infusion of PGI2 (0.1 microgram/kg/min.) completely abolished spontaneously and indomethacin-induced CRCF with a marked elevation of 6-keto-PGF1 alpha in the CS and Ao. Although OKY-1580, a TXA2 synthetase inhibitor, relieved spontaneously-evoked CRCF with a marked increase in 6-keto-PGF1 alpha and a slight reduction of TXB2, indomethacin-induced CRCF was not abolished by this agent. These results are consistent with the hypothesis that the reduction of endogenous PGI2 synthesis in the vascular wall is related to the occurrence of CRCF after partial constriction of coronary artery and indomethacin.
J Mol Cell Cardiol 1984 Dec
PMID:Reduction of prostacyclin synthesis as a possible cause of transient flow reduction in a partially constricted canine coronary artery. 639 70

The administration of the thromboxane synthetase inhibitor UK38485, 3 mg/kg i.v. 30 min prior to occlusion of the LAD in chloralose-anaesthetized dogs reduced the number of extrasystoles that occurred in the first 30 min of ischaemia from 832 +/- 158 in controls to 193 +/- 126 (P less than 0.01). VF induced by the release of the occlusion after 40 min was also markedly reduced from seven out of nine in controls to two out of seven in the drug group. UK38485 did not alter blood gases or haemodynamics prior to LAD occlusion and the changes in PO2, PCO2 and pH in blood draining from the ischaemic myocardium during occlusion were similar in control and drug-treated dogs. The haemodynamic changes induced by coronary artery occlusion were attenuated by UK38485. This drug also prevented the thromboxane release that normally occurs during acute myocardial ischaemia but did not suppress prostacyclin release. These results provide further evidence in support of the hypothesis that thromboxane is arrhythmogenic during acute myocardial ischaemia and is a particularly important contributory factor in reperfusion-induced VF.
J Mol Cell Cardiol 1984 Jul
PMID:Further evidence that thromboxane exacerbates arrhythmias: effects of UK38485 during coronary artery occlusion and reperfusion in anaesthetized greyhounds. 643 26

Nafazatrom, an antithrombotic and antimetastatic agent containing a pyrazolone functionality, is a reducing substrate for the peroxidase activity of prostaglandin H (PGH) synthase. Nafazatrom inhibits the hydroperoxide-dependent oxidation of phenylbutazone, stimulates the reduction of 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid, and is oxidized by microsomal or purified enzyme preparations from ram seminal vesicles. Consonant with the effects of other peroxidase-reducing substrates, nafazatrom stimulates the oxygenation of arachidonic acid to prostaglandin endoperoxides by the cyclooxygenase component of PGH synthase. In addition, nafazatrom causes an elevation in the levels of 6-keto-prostaglandin F1 alpha, the non-enzymatic hydrolysis product of prostacyclin (PGI2) biosynthesized from arachidonic acid by ram seminal vesicle microsomes. Elevation of PGI2 biosynthetic capacity by nafazatrom occurs under conditions in which prostaglandin endoperoxide biosynthesis is maximal, suggesting that nafazatrom has a stimulatory effect on the conversion of prostaglandin endoperoxides to PGI2. Nafazatrom has no effect on the ability of ram seminal vesicle microsomes to convert PGH2 to PGI2 but protects microsomal PGI2 synthase from inactivation by 15-hydroperoxy-5,8,11,13-eicosatetraenoic acid. Nafazatrom stimulates PGI2 biosynthesis in ram seminal vesicle microsomes by acting as a substrate for the peroxidase-catalyzed reduction of hydroperoxy fatty acids that are irreversible inactivators of PGI2 synthase. Several other compounds, including dipyridamole and triiodothyronine, exert similar effects. This may contribute to the reported ability of nafazatrom and related compounds to elevate the levels of bioassayable PGI2 in vivo and to the antithrombotic and antimetastatic activities of nafazatrom.
Mol Pharmacol 1984 Sep
PMID:Mechanism of the stimulation of prostaglandin H synthase and prostacyclin synthase by the antithrombotic and antimetastatic agent, nafazatrom. 643 40

The effect of an atherogenic diet on the endothelium of the central artery of the rabbit ear was studied by scanning and transmission electron microscopy. Examination of the inner surface of the artery after only 5 weeks on the diet revealed morphological changes including irregularly shaped cells, breaks at intercellular junctions, swelling of the membrane over the central part of the cells, and occasional holes in the cells. By 9 weeks more severe damage was seen including lifting off of cells and some holes. In addition, arrays of dark spots were seen by scanning electron microscopy in some cells in arteries of rabbits fed the diet for 5 to 9 weeks. The dark spots may correspond to abnormally large vacuoles seen inside endothelial cells by transmission electron microscopy. The central ear artery and aorta of some rabbits were tested for their ability to convert arachidonic acid into prostacyclin and thromboxane A2 by radioimmunoassay of the stable metabolites 6-keto-prostaglandin F1 alpha and thromboxane B2. The vessels from rabbits fed the atherogenic diet did not differ from vessels of rabbits on the control diet in their production of either metabolite.
Exp Mol Pathol 1983 Feb
PMID:Early morphological changes in the endothelium of a peripheral artery of rabbits fed an atherogenic diet. 668 74

Thromboxane A2 stimulation of smooth muscle cells contributes to the development of vascular lesions after percutaneous transluminal coronary angioplasty. In view of this, we examined the signaling pathways stimulated by a thromboxane receptor agonist, U-46619, in cultures of rat aortic smooth muscle cells. Treatment of rat aortic smooth muscle cells with U-46619 induced cellular hypertrophy ([14C]leucine incorporation) without stimulating mitogenesis ([3H]thymidine incorporation). Analysis of signaling pathways elicited by U-46619 revealed enhanced tyrosine phosphorylation and increased enzymatic activity of mitogen-activated protein (MAP) kinase (Erk2). U-46619 also activated signaling proteins upstream of p21-ras, inducing tyrosine phosphorylation on Shc and complex formation between Shc and growth factor receptor binding protein-2 (GRB2). Exposure of cells to a stable prostacyclin analogue, ciprostene calcium, attenuated U-46619-induced cellular hypertrophy and MAP kinase activity. Ciprostene treatment elevated cellular cAMP and inhibited U-46619-induced tyrosine phosphorylation on Shc and Shc/GRB2 complex formation. These results demonstrate that stimulation of thromboxane A2 and prostacyclin receptors have opposing effects on smooth muscle cell hypertrophy and the signaling pathways associated with this process. We conclude that inhibition of Shc/GRB2 complex formation and MAP kinase activity by ciprostene may contribute to its ability to limit restenosis injury.
Mol Pharmacol 1995 Nov
PMID:Activation of thromboxane and prostacyclin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades. 747 20


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