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)

We hypothesized that Iloprost, a long-acting prostacyclin analog, would inhibit neutrophil (PMN)-induced lung injury and decrease PMN adherence to vascular endothelium. Human PMNs infused into isolated buffer-perfused rat lungs subsequently stimulated with phorbol myristate acetate (PMA) resulted in lung injury as assessed by the accumulation of [125I]bovine serum albumin (125I-BSA) in lung parenchyma and alveolar lavage fluid. Addition of Iloprost to the lung perfusate, prior to activation of the PMNs, reduced lung injury as assessed by a decrease in the accumulation of 125I-BSA in the lung. This protective effect was not due to the vasodilatory effect of Iloprost. Protection by Iloprost was not linked to a reduction in PMA-induced PMN superoxide production since Iloprost did not reduce the amount of superoxide released into lung perfusate. In vitro, Iloprost caused a dose-dependent inhibition of PMA-stimulated PMN adherence to endothelial cells. Iloprost did not affect the number of Mo1 adhesion molecules constitutively expressed or the number of receptors expressed on the PMNs following PMA. Addition of cAMP or dibutyryl cAMP to the endothelial cells mimicked the effects of Iloprost, diminishing PMA-stimulated PMN adhesion. In separate experiments, addition of the phosphodiesterase inhibitor IBMX to Iloprost resulted in a greater inhibition of PMA-stimulated PMN adherence, while addition of an adenylate cyclase inhibitor, SQ 22,536, or cAMP antibodies with the Iloprost abolished Iloprost's inhibitory effect on PMN adhesion. Thus, Iloprost inhibits PMA-activated PMN-induced lung injury despite continued superoxide production. Iloprost inhibition of PMN adhesion is dependent on cAMP.
Am J Respir Cell Mol Biol 1990 Oct
PMID:Iloprost inhibits neutrophil-induced lung injury and neutrophil adherence to endothelial monolayers. 169 99

Myocardial ischemia leads to the damage of cellular membranes and release of intracellular enzymes. We studied the influence of the prostacyclin analog, iloprost, on alterations in membrane phospholipid content and composition in rat myocardium during ischemia. Infusion of iloprost (100 ng/kg/min) or its vehicle started 20 min after coronary artery ligation, and the hearts were analyzed after 6 h. Myocardial creatine kinase activity was significantly reduced by approximately 25% in the ischemic areas of hearts from rats receiving vehicle. This reduction in myocardial creatine kinase activity was totally abolished by infusion of iloprost. Total phospholipid content was significantly reduced by 10% in ischemic areas of hearts obtained from vehicle infused animals. Iloprost infusion also prevented the loss of total phospholipids in the ischemic areas. The data show that coronary artery ligation is associated with a significant loss of total membrane phospholipids in ischemic regions of rat myocardium, characterized by significant decreases in phosphatidylcholine, phosphatidylethanolamine and cardiolipin. The decrease in cardiac phosphatidylcholine and phosphatidylethanolamine content was prevented by iloprost, whereas the decrease in cardiolipin content was unaltered. Infusion of the prostacyclin analog iloprost almost totally inhibited the ischemia induced loss of phospholipids, suggesting that this may be an important component of its cytoprotective mechanism of action.
J Mol Cell Cardiol 1987 Mar
PMID:Protective actions of a stable prostacyclin analog in ischemia induced membrane damage in rat myocardium. 243 96

The protection of angiotensin converting enzyme (ACE) inhibitors, captopril and ramiprilat, against free radical-mediated myocardial injury were studied in isolated working rat hearts. Free radicals were generated by electrolysis of Krebs-Henseleit solution with 10 mA direct current for 1 min. Both captopril (360 mumol/l) and ramiprilat (12.5 mumol/l) significantly reduced the decrease of left ventricle dP/dt'max, coronary flow (CF), myocardial superoxide dismutase (SOD) and creatine kinase (CK) activities and the elevation of S-T segment of epicardial ECG as well as the rise of myocardial malondialdehyde (MDA) content caused by electrolysed perfusate. Captopril afforded a dose-dependent protection on cardiac functions with various concentrations of 45, 90, 180 and 360 mumol/l. Iloprost (30 nmol/l), a stable mimetic of prostacyclin, could also alleviate free radical-mediated myocardial injuries. All the beneficial effects of ramiprilat (12.5 mumol/l) were abolished by the administration of indomethacin (5 mumol). In contrast, captopril (90 mumol/l) still exhibited significant protective effects after indomethacin (9 mumol) was administered, though these protective effects were insignificantly weakened. In order to assess the role of sulfhydryl (-SH) group in the effects of captopril, a SH-containing drug S8 and a disulfide DG4, both are deficient in ACE inhibitory properties in vitro, were examined. Data showed that S8 (180 mumol/l) provided a significant protection while DG4 showed no protective effect. It is concluded that ACE inhibitors can protect against free radical-induced myocardial damage. Ramiprilat, a non-SH-containing ACE inhibitor, inhibits free radical-induced damages mainly by stimulation of prostacyclin synthesis and/or release. In addition to this effect, captopril, a SH-containing ACE inhibitor, may exert additional anti-free radical effects by a mechanism which is probably related to the sulfhydryl group.
J Mol Cell Cardiol 1989 Dec
PMID:Captopril and ramiprilat protect against free radical injury in isolated working rat hearts. 269 63

Effects of dexamethasone, retinoic acid, prostaglandin E2 (PGE2), and Iloprost as a agonist of prostacyclin (A-PGI2) on DNA synthesis and production of a precursor of matrix metalloproteinase 1 (tissue procollagenase/proMMP-1) by human aortic smooth muscle cells were investigated. When after treatment with platelet-derived growth factor (PDGF), these agents were added to the cultures, DNA synthesis and production of proMMP-1 were inhibited in a dose-dependent manner. These results suggest that these agents are negative regulators of PDGF. Since these agents are present in the blood or produced in the blood wall, in addition, since PDGF plays the most important role in the process of atherosclerosis, we propose that these agents function in vivo as a systems of protection against atherosclerosis.
Biochem Mol Biol Int 1993 Oct
PMID:Down-regulation in the production of matrix metalloproteinase 1 by human aortic intimal smooth muscle cells. 750 89

Effects of iloprost, which is a stable prostacyclin analogue, on the ischemic myocardium were examined in the open-chest dog heart in terms of biochemical parameters. Ischemia was initiated by ligating the left anterior descending coronary artery. When the coronary artery was ligated for 3 min, the levels or glycogen, fructose-1,6-diphosphate (FDP), adenosine triphosphate and creatine phosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased. During ischemia, therefore, energy charge potential was significantly decreased from 0.89 +/- 0.01 to 0.82 +/- 0.01, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were significantly increased from 1.75 +/- 0.30 to 29.05 +/- 5.70 and 13 +/- 3 to 393 +/- 112, respectively. Iloprost (0.1, 0.3, or 1 microgram.kg-1) was injected intravenously 5 min before the onset of ischemia. Iloprost (0.1, 0.3, and 1 micrograms.kg-1) reduced the ischemia-induced decrease in energy charge potential to 94, 74, and 86%, respectively, the increase in ([G6P] + [F6P])/[FDP] to 38, 29, 32%, respectively, and the increase in [lactate]/[pyruvate] to 67, 45, 65%, respectively. These results suggest that iloprost lessens the myocardial metabolic derangements produced by ischemia, and the most potent effect was obtained at the dose of 0.3 microgram.kg-1.
Mol Cell Biochem 1993 Feb 17
PMID:Effects of iloprost, a PGI2 derivative, on ischemic myocardial energy and carbohydrate metabolism in dogs. 768 Nov 40

The aim of this study was to investigate the cytoprotective effect of Iloprost on the liver against carbon tetrachloride induced necrosis. The serum histamine-like activity was found to be increased when compared with that of controls after treatment with carbon tetrachloride for 18 weeks while prostaglandin E2- and leukotriene C4-like activities were unchanged. After pretreatment with Iloprost for 18 weeks the increased activity of histamine was found to be unchanged while prostaglandin E2-like activity was increased. It is concluded that Iloprost protects the liver against carbon tetrachloride-induced damage and reduces the level of histamine that has a role in the pathogenesis of portal hypertension.
Res Commun Mol Pathol Pharmacol 1997 Mar
PMID:The cytoprotective effect of iloprost against carbon tetrachloride induced necrosis in rat liver. 914 40

A FLAG-tagged form of the human IP prostanoid receptor was expressed stably in HEK 293 cells. This bound [3H]iloprost with high affinity and stimulated cAMP production when exposed to agonist. Iloprost produced weak stimulation of GTPase activity and [35S]guanosine-5'-O-(3-thio)triphosphate binding in membranes of these cells. Pretreatment of cells with pertussis toxin did not modify iloprost-mediated stimulation, but this was blocked by cholera toxin. The effects of iloprost were not increased by coexpression of either Gsalpha or Gi1alpha. In contrast, coexpression of a chimeric G protein alpha subunit in which the carboxyl-terminal six amino acids of Gi1alpha were altered to those of Gsalpha resulted in robust stimulation by iloprost. Because the chimeric G protein alpha subunit (Gi1/Gs6alpha) is not a substrate for either pertussis or cholera toxin, pretreatment of cells coexpressing the IP prostanoid receptor and Gi1/Gs6alpha with a mixture of these toxins resulted in resolution of the signal derived from activation of the chimeric G protein. Agonist-stimulated [35S]guanosine-5'-O-(3-thio)triphosphate binding and GTPase activity assays are the most commonly used strategies to examine interactions between G protein-coupled receptors and G proteins. These usually are not appropriate for receptors such as the IP prostanoid receptor that interact with G proteins with low rates of guanine nucleotide exchange and hydrolysis. Chimeric G proteins such as Gi1/Gs6alpha that allow appropriate receptor contacts to be converted to the higher nucleotide turnover rates typical of the Gi family G proteins can overcome this and offer a novel means to examine agonist function at such receptors.
Mol Pharmacol 1998 Aug
PMID:Selective activation of a chimeric Gi1/Gs G protein alpha subunit by the human IP prostanoid receptor: analysis using agonist stimulation of high affinity GTPase activity and [35S]guanosine-5'-O-(3-thio)triphosphate binding. 968 65

Prostacyclin is an arachidonic acid metabolite that modulates vascular tone within the lung. The current study evaluated the hypothesis that prostacyclin can also modulate tissue remodeling by affecting fibroblast-mediated contraction of extracellular matrix. To accomplish this, fibroblasts were cultured in three-dimensional native type I collagen gels in the presence of prostacyclin analogs: carbaprostacyclin, iloprost, and beraprost. All three analogs significantly inhibited contraction of the three-dimensional collagen gels mediated by three different fibroblasts. All three analogs significantly inhibited fibronectin release and reduced fibroblast fibronectin mRNA expression. Addition of exogenous fibronectin restored the contractile activity to fibroblasts incubated in the presence of all three analogs. Iloprost and beraprost significantly activated cAMP-dependent protein kinase-A (PKA), and an action through this pathway was confirmed by blockade of the inhibitory effect on contraction and fibronectin release with the PKA inhibitor KT-5720. In contrast, carbaprostacyclin, which is not as selective for the prostacyclin (IP) receptor, did not activate PKA, and its effects on contraction and fibronectin release were not fully blocked by KT-5720. Finally, the cAMP analogs N(6)-Benzoyl- (6-Bnz-) cAMP and dibutyryl-cAMP inhibited contraction, and this contrasted with the activity of an Epac selective agonist 8-pCPT-2'-O-Me-cAMP, which had no effect. Taken together, these results indicate that prostacyclin, acting through the IP receptor and by activating PKA, can lead to inhibition of fibronectin release and can subsequently inhibit fibroblast-mediated collagen gel contraction. The ability of prostacyclin to modulate fibroblast function suggests that prostacyclin can contribute to tissue remodeling.
Am J Respir Cell Mol Biol 2007 Jul
PMID:Prostacyclin analogs inhibit fibroblast contraction of collagen gels through the cAMP-PKA pathway. 1736 76

Prostacyclin is a short-lived metabolite of arachidonic acid that is produced by several cells in the lung and prominently by endothelial cells. It increases intracellular cAMP levels activating downstream signaling thus regulating vascular mesenchymal cell functions. The alveolar wall contains a rich capillary network as well as a population of mesenchymal cells, i.e., fibroblasts. The current study evaluated the hypothesis that prostacyclin may mediate signaling between endothelial and mesenchymal cells in the alveolar wall by assessing the ability of prostacyclin analogs to modulate fibroblast release of VEGF. To accomplish this study, human lung fibroblasts were cultured in routine culture on plastic support and in three-dimensional collagen gels with or without three prostacyclin analogs, carbaprostacyclin, iloprost, and beraprost, and the production of VEGF was evaluated by ELISA and quantitative real-time PCR. Iloprost and beraprost significantly stimulated VEGF mRNA levels and protein release in a concentration-dependent manner. These effects were blocked by the adenylate cyclase inhibitor SQ-22536 and by the protein kinase A (PKA) inhibitor KT-5720 and were reproduced by a direct PKA activator but not by an activator of exchange protein directly activated by cAMP (Epac), indicating that cAMP-activated PKA signaling mediated the effect. Since VEGF serves to maintain the pulmonary microvasculature, the current study suggests that prostacyclin is part of a bidirectional signaling network between the mesenchymal and vascular cells of the alveolar wall. Prostacyclin analogs, therefore, have the potential to modulate the maintenance of the pulmonary microcirculation by driving the production of VEGF from lung fibroblasts.
Am J Physiol Lung Cell Mol Physiol 2008 Jun
PMID:Prostacyclin analogs stimulate VEGF production from human lung fibroblasts in culture. 1842 19

The writhing response to acute nociception has been used to test the analgesic activity of drugs in rodents. Dilute acetic acid is the most frequently used irritant to induce writhing behaviour. The administration of acetic acid intraperitoneally activates both peripheral and central mechanisms of nociception. It releases nociceptive mediators such as prostaglandins (PG) E(2)and I(2)at the site of noxious stimulation, the peritoneal cavity, and at central sites such as the dorsal horn of the spinal cord and some brain regions. We have used the PGI(2)mimetic, iloprost, an agonist at the IP receptor, to induce the writhing response in mice. Iloprost activates the IP receptors on peripheral nociceptors directly and thus does not release nociceptive prostaglandins into the peritoneal cavity. However, prostaglandins are still involved in nociceptive transmission at the spinal and supraspinal levels. Using this model of nociception, it is possible to identify the site of action of analgesic drugs which reduce prostaglandin release in central tissues through inhibition of cyclooxygenase. Thus, a drug that inhibits the iloprost-induced writhing response and reduces release of prostaglandins in the central nervous system is likely to be a centrally acting analgesic drug. This chapter compares the iloprost- and acetic acid-induced writhing responses in mice and describes a method for measuring central prostaglandin levels. Part of this work has been published previously.
Methods Mol Biol 2010
PMID:Iloprost-induced nociception: determination of the site of anti-nociceptive action of cyclooxygenase inhibitors and the involvement of cyclooxygenase products in central mechanisms of nociception. 2064 77


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