Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The effect of iloprost (Schering AG, Berlin), a stable prostacyclin analogue, was investigated in ischemic, reperfused porcine hearts. The left anterior descending coronary artery (LAD) was distally occluded in 18 pigs for 45 min followed by 3-d of reperfusion. Nine pigs were continuously treated with iloprost at a dose of 25 ng/kg per min. Treatment was started as intracoronary infusion into the proximal LAD 10 min before occlusion. The intercoronary infusion was replaced by an intravenous infusion after 45 min of reperfusion, which was continued until the end of the experiment. Infarct size was determined as the ratio of infarcted (tetrazolium stain) to ischemic myocardium (dye technique). Regional systolic shortening was assessed by sonomicrometry. Myocardial concentrations of adenosine triphosphate were evaluated at the end of the experiment. Generation of free radicals by stimulated polymorphonuclear neutrophils was determined by luminol-enhanced chemiluminescence. Histologic and immunohistologic techniques were applied to characterize the myocardial inflammatory response. Global hemodynamics did not differ between the two groups. Neither infarct size (control group 68 +/- 18%, treated group 74 +/- 14%), recovery of systolic shortening (control group 3 +/- 6%, treated group 6 +/- 6%), nor myocardial adenosine triphosphate concentrations were improved by iloprost treatment. Myocardial inflammatory response remained unaffected by this treatment. The capacity of coronary venous, stimulated polymorphonuclear neutrophils to generate free radicals was slightly suppressed in the treated group before ischemia, at the end of ischemia and during early reperfusion. In this preparation, iloprost did not exhibit any beneficial effect on infarct size, recovery of systolic shortening and myocardial adenosine triphosphate concentrations.
J Mol Cell Cardiol 1991 Aug
PMID:Failure of iloprost to protect the regionally ischemic, reperfused porcine heart. 171 23

Arachidonic acid (AA) metabolism was studied in freshly isolated type II alveolar epithelial cells of rabbits. Substantial basal secretion of prostanoids with predominance of prostaglandin (PG) I2 was noted. Challenge with the calcium ionophore A23187 resulted in a time- and dose-dependent increase in the generation of all AA cyclooxygenase products to severalfold values following the rank order of 12-heptadecatrienoic acid (12-HHT) greater than PGI2 greater than PGE2 greater than or equal to thromboxane A2 greater than PGF2 alpha approximately PGD2. Even larger augmentation of prostanoid generation was evoked by challenge with free exogenous AA. Generation of the different AA cyclooxygenase products was inhibited by acetylsalicylic acid with IC50 in the range between 250 and 500 microM. In addition to the prostanoid release, ionophore-challenged type II pneumocytes liberated substantial amounts of AA lipoxygenase products with leukotriene (LT) B4 greater than 15-hydroxyeicosatetraenoic acid (HETE) greater than 12-HETE greater than 5-HETE. Generation of LTs and HETEs was markedly increased upon simultaneous disposal of free exogenous AA. No omega-oxidation of LTB4 was noted, and no evidence for secretion of intact LTA4 was obtained. The epithelial cells displayed avid uptake of exogenously offered LTA4 with subsequent enzymatic conversion to LTB4. Co-stimulation of pneumocytes with neutrophils (PMN) resulted in an amplification of LTB4 generation, paralleled by a decrease in nonenzymatic decay products of PMN-derived LTA4; both phenomena were dose dependent on the pneumocyte-PMN ratio.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Jan
PMID:Type II alveolar epithelial eicosanoid metabolism: predominance of cyclooxygenase pathways and transcellular lipoxygenase metabolism in co-culture with neutrophils. 172 1

Diethylcarbamazine (DEC) rapidly lowers the number of microfilariae in the peripheral circulation. The mechanism of action is unknown, but may involve alterations of arachidonic acid metabolism in vascular tissues. We studied the effects of DEC on arachidonic acid metabolism by bovine pulmonary arterial endothelium monolayers, human platelets and Brugia malayi microfilariae. DEC at a concentration of 2.5 microM, a level achieved in vivo, rapidly decreased prostacyclin, prostaglandin E2 and thromboxane B2 release from endothelial monolayers by 78% (P less than 0.001), 57% (P = 0.05), and 75% (P less than 0.05), respectively. High-pressure liquid chromatography of extracts of endothelial monolayers incubated with DEC showed similar inhibition of these cyclooxygenase pathway products, but exposure to the drug did not result in formation of new eicosanoids. DEC did not inhibit endothelial phospholipase A2-dependent release of arachidonate from membrane stores, whereas prostaglandin H2 synthase activity (cyclooxygenae, EC 1.14.99.1) was reduced to a degree similar to that effected by acetylsalicylic acid. Microfilarial but not platelet synthesis of cyclooxygenase products was also reduced by DEC. These data suggest that the mechanism by which DEC lowers the level of microfilariae in the circulation may in part involve its effects on host endothelial and parasite eicosanoid production.
Mol Biochem Parasitol 1991 Nov
PMID:Diethylcarbamazine inhibits endothelial and microfilarial prostanoid metabolism in vitro. 177 51

We examined bradykinin-induced 45Ca2+ efflux and prostaglandin synthesis in guinea pig tracheal smooth muscle cells maintained in tissue culture. We also studied the effects of a B1 receptor agonist and antagonist, a B2 receptor antagonist, and the cyclooxygenase inhibitor indomethacin. In cultured smooth muscle cells, bradykinin (0.1 nM to 10 microM) stimulated efflux of 45Ca2+ and induced the synthesis of prostaglandin E2 and the prostacyclin metabolite 6-keto-prostaglandin F1 alpha. DesArg9-bradykinin, a B1 receptor agonist, had no effect on 45Ca2+ efflux or prostaglandin synthesis, and no responses to bradykinin were unaffected by the B1 receptor antagonist desArg9-[Leu8]-bradykinin. Indomethacin (1 microM) abolished bradykinin-induced prostaglandin synthesis but was without effect on 45Ca2+ efflux. NPC 567 (DArg[Hyp3,DPhe7]-bradykinin), a B2 receptor antagonist, had no effect on bradykinin-induced 45Ca2+ efflux, but abolished prostaglandin synthesis. Unlike in membranes prepared freshly from guinea pig tracheal smooth muscle, the B2 receptor antagonist inhibited completely (Ki, 12 nM) binding of [3H]-bradykinin to membranes prepared from cultured tracheal smooth cells. These data suggest that tracheal smooth muscle cells, maintained in culture, express B2 receptors that mediate bradykinin-induced prostaglandin synthesis. The observation that bradykinin-induced efflux of calcium ions was unaffected by B1 or B2 antagonists provides further evidence that airway smooth muscle may contain a novel B3 receptor.
Am J Respir Cell Mol Biol 1991 Mar
PMID:Evidence that cultured airway smooth muscle cells contain bradykinin B2 and B3 receptors. 184 87

To elucidate the conformation of receptor-associated prostacyclin (PGI2), we first performed structure-activity correlation analysis of over 200 PGI2 analogues and derived from this analysis several crucial features pertaining to structural requirements for PGI2 activity [Ah-lim Tsai and Kenneth K. Wu, Eicosanoids, 2 (1989) 131-143]. These structural features proved to be useful guidelines for selecting 'model molecules' for further investigations by molecular mechanics. By properly selecting four analogues with either rigid or uniquely oriented alpha-side chain structure for geometric fitting, we succeeded in maximally minimizing the degree of freedom of the carboxylate terminus of PGI2. We were able to define the spatial relationship among the four critical functional groups, i.e., C1-COOH, C6a-O, C11-OH and C15-OH. More information is needed, however, to define the geometry of the omega-side chain, particularly for the moiety beyond C15. Nevertheless, results from structure-activity correlation analysis and molecular modeling provide useful information regarding the conformation of receptor-associated PGI2, which assumes an 'elongated' conformation instead of the traditional 'hairpin' structure.
J Comput Aided Mol Des 1991 Apr
PMID:Conformation of receptor-associated PGI2: an investigation by molecular modeling. 186 97

We have determined eicosanoid production from endogenous arachidonic acid by neonatal lamb lungs stimulated with calcium ionophore A23187 during normoxia and hypoxia. Lungs of lambs 19 to 25 d of age were isolated and perfused with cell-free Krebs' bicarbonate buffer at a flow rate of 15 to 20 ml/kg/min. After 30 min of equilibration in a recirculating system, A23187 was added to the perfusate in a 5-microM concentration and perfusion continued for 15 min more. Eicosanoids were measured in perfusate and lung homogenate supernatant. Cyclooxygenase metabolites prostaglandin (PG) E2, thromboxane A2, and PGI2, were measured by radioimmunoassay, and 5-lipoxygenase metabolites leukotrienes (LT) B4, C4, D4, and E4 by high performance liquid chromatography. During normoxia, all three cyclooxygenase metabolites were present in perfusate, but only PGI2 and thromboxane A2 were present in lung homogenate supernatant. Prostacyclin constituted 50% of all the cyclooxygenase products measured. LTC4 and LTD4 were detected in both perfusate and lung homogenate supernatant with little production of LTE4 and LTB4. During hypoxia, the profile of cyclooxygenase products was unchanged and prostacyclin production was not increased. However, the profile of leukotriene metabolites was altered. LTC4 synthesis was markedly reduced. The synthesis of LTE4 and LTB4 was increased 10-fold, with most of the leukotrienes being retained in lung tissue. We conclude that hypoxia significantly alters leukotriene metabolism of endogenous arachidonic acid by calcium ionophore-stimulated lungs. The increased production by stimulated lungs during hypoxia of LTE4, a substance that may increase lung capillary permeability, and that of LTB4, a powerful chemoattractant, may be important contributing factors to lung injury.
Am J Respir Cell Mol Biol 1991 Apr
PMID:Endogenous arachidonic acid metabolism by calcium ionophore A23187-stimulated lamb lungs: effect of hypoxia. 190 20

We have reported that thromboxane A2 and serotonin are two important mediators of coronary cyclic flow variations (CFVs) caused by recurrent platelet aggregation and dislodgement on a stenosed coronary arterial wall with endothelial injury. To test the hypothesis that blocking the synthesis of thromboxane A2 would not prevent serotonin release, 1.1, 4.6, and 9.2 mg/kg of aspirin were administered through the left atrium to 27 dogs with CFVs. The CFV elimination rate was 70% in the aspirin-treated dogs. Thromboxane B2 and serotonin concentrations were measured in different coronary arterial segments. There were significantly lower thromboxane B2 and 6-keto-PFG1a levels in the stenosed left arterior descending (LAD) segments with increasing dosage of aspirin-208 +/- 36, 24 +/- 31, 50 +/- 6 ng/g (P less than 0.0001) and 125 +/- 27, 58 +/- 38, 25 +/- 5 ng/g (P less than 0.0001), respectively. Serotonin levels were significantly higher in stenosed LAD (265.7 +/- 131.2 ng/g) than in LAD segments proximal or distal to the stenosis and in corresponding circumflex coronary artery segments, 17.1 +/- 3.7, 18.6 +/- 3.7, and 19.2 +/- 5.1 ng/g, respectively (P less than 0.05) following the highest dose of aspirin. In 41 additional dogs, electrical injury was used to initiate thrombosis in the circumflex artery and in those receiving aspirin (15 mg/kg) (n = 5), occlusive thrombus formation was inhibited. However, the local accumulation of serotonin was not significantly different between the control (194 +/- 27 ng/g) (n = 36) and the aspirin-treated group (167 +/- 19 ng/g) (n = 5). In vitro platelet aggregation induced by arachidonic acid was inhibited by the in vivo administration of 1.1 mg/kg of aspirin and abolished by 4.6 + 1.1 and 9.2 + 4.6 + 1.1 mg/kg of aspirin. However, serotonin-induced platelet aggregation was not affected following all doses of aspirin. Thus, aspirin eliminates CFVs in 70% of dogs, and markedly diminishes thromboxane A2 and prostacyclin concentrations in stenosed canine coronary arteries, but it does not prevent local serotonin accumulation. Similarly, aspirin prevents occlusive coronary thrombosis in dogs with electrically-induced endothelial injury, but it did not prevent local assumulation of serotonin. These experimental findings suggest that cyclo-oxygenese inhibition does not prevent serotonin accumulation at sites of coronary artery endothelial injury, and they thereby help provide a potential explanation of the lack of complete protection provided by aspirin in eliminating CFVs in this experimental model.
J Mol Cell Cardiol 1991 Apr
PMID:Effect of aspirin on local prostaglandin production and serotonin accumulation in a canine model with coronary cyclic flow variations or thrombosis. 194 81

Studies in recent years have demonstrated that coronary vasospasm (Prinzmetal's Angina) is a consequence of endothelial cell damage. Normal endothelium, in response to increases in shear stress, or to platelet products and other agonists, releases endothelium-derived relaxing factor(s) (EDRF) with resultant vasodilatation. One substance released may be nitric oxide, another a hyperpolarizing factor. In addition EDRF like prostacyclin, inhibits platelet aggregation. In porcine coronary vessels the amount of EDRF released can be increased by a diet of codliver oil and decreased by a high cholesterol diet. When endothelium is damaged, the absence of EDRF and prostacyclin at the site leads to platelet aggregation with the release, among other substances, of serotonin (5HT) and thromboxane A2. These now act directly on the smooth muscle to cause contraction. In addition some serotonin is taken up by the sympathetic nerve endings and is released as a false transmitter to aggravate the constriction. The resultant hypoxia/anoxia can cause any functional endothelium to release contracting factor(s), further compounding the constriction. Evidence of platelet aggregation in humans is the presence of serotonin in the coronary sinus blood in resting patients with coronary artery disease.
J Mol Cell Cardiol 1991 Feb
PMID:Mechanisms of coronary vasospasm: role of endothelium. 203 73

Prostaglandins (PGs) in the embryo and endometrium are involved in processes that are important for implantation. Although the presence of PGs (PGE2, PGF2 alpha, PGI2) in decidualized endometrium has been widely reported, less is known about the capacity of the pre-implantation embryo to synthesize PGs. Prostaglandin H (PGH) synthase is necessary for the production of PGs. Using an immunohistochemical method, PGH synthase was localized in the mouse embryo and uterus from superovulation through embryo implantation. No PGH synthase was detected in oocytes at the time of ovulation or in single-cell embryos 1 day post-fertilization (PF). Circular areas of immunostaining became evident in the cytoplasm of blastomeres at the morula stage (day 3 PF). After implantation (day 5 PF), a low level of PGH synthase reactivity was observed in embryonic cells; no PGH synthase was detected in the embryo by day 7 PF. The endometrial glands exhibited maximal immunostaining by day 3 PF, and after implantation, PGH synthase appeared in decidual cells along the border of placentation. Low levels of PGH synthase reactivity were detected in myometrial cells during the period after superovulation through day 7 PF. This is the first demonstration of PGH synthase in the mouse embryo prior to apposition with glandular endometrial epithelium, supporting the hypothesis that the embryo has the potential to produce PGs that may mediate autocrine and/or paracrine responses at the time of nidation.
Mol Reprod Dev 1990 Apr
PMID:Immunohistochemical localization of prostaglandin H synthase in the embryo and uterus of the mouse from ovulation through implantation. 210 18

The cellular distribution of prostacyclin (PGI2) synthase and specific PGI2 binding sites was investigated by light microscope immunocytochemistry and quantitative autoradiography. The immunostaining for the enzyme was found in small (15-18 microns) and large (18-45 microns) cells as well as in non-luteal cells, arteriole smooth muscle and endothelium. There was no consistent difference between small and large luteal cells and luteal vs. non-luteal cells in the immunostaining. Vascular smooth muscle and endothelial cells, on the other hand, contained less immunostaining than the other cells. Contrary to wide-spread distribution of PGI2 synthase, specific PGI2 binding sites were only found in the luteal cells. On a per cell basis, large luteal cells contained more sites than small luteal cells and vice versa when expressed per unit cell area. The [3H]PGI2 binding to the luteal cells was time and temperature dependent and was inhibited by excess unlabeled PGI2 but not by its metabolite, 6-keto-PGF1 alpha or other eicosanoids which bind to their own receptors. In conclusion, while PGI2 synthase is widely distributed among different cell types in bovine corpora lutea, specific binding sites which may mediate luteotropic actions of PGI2 are only present in small and large luteal cells.
Mol Cell Endocrinol 1990 Jun 18
PMID:Cellular distribution of prostacyclin synthase and specific prostacyclin binding sites in bovine corpora lutea of pregnancy. 211 51


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