Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular pathophysiology at the sites of bacterial infection and cancerous tissues share numerous common events similar to inflammatory tissue. Among them enhanced vascular permeability is the universal and hallmark event mediated by bradykinin. All 16 or more bacterial or fungal proteases we have examined activated one or more steps of the kinin generating Hageman-factor-kallikrein cascade. In the meantime, most of the microbial proteases rapidly inactivated various plasma inhibitors such as alpha 1-protease inhibitor and alpha 2-macroglobulin. In addition to the extracellular proteases, bacterial cell wall components (negatively charged LPS) of gram-negative bacteria and teichoic acid moieties of gram-positive bacteria activate the Hageman-factor-kallikrein system and exert hypotensive effects via kinin generation. Endotoxin (LPS) also induces nitric oxide synthase (NOS) which appears to exhibit a rather slow, but significant, effect in relaxing the vascular tone of the infected animal (thus hypotension). Furthermore, bacterial proteases can activate the matrix metalloproteinase (collagenase) resulting in exacerbation of tissue injury in the diseased animal. Many tumor cells or tissues excrete plasminogen activator, and hence activate plasminogen. The plasmin thus generated activates procollagenases, as well as the Hageman-factor-kallikrein system, resulting in pronounced extravasation. Fluid accumulation in pleural and ascitic carcinomatoses is largely due to the activated bradykinin-generating system. We can also demonstrate and control enhanced vascular permeability using kallikrein inhibitors, especially the polymer-conjugated soybean trypsin inhibitor which exhibits a prolonged plasma t1/2, kinin antagonists, NOS inhibitors, NO scavengers, inhibitors of prostaglandins and others. Bacterial proteases induce shock in mice which can be prevented by the soybean trypsin inhibitor by blocking the kallikrein-kinin cascade. Therapeutic use of kinin antagonists and a kallikrein inhibitor has been made for infectious diseases such as septicemia and in tumor pathology.
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PMID:Bradykinin and nitric oxide in infectious disease and cancer. 885 54

To examine the participation of the theca-interstitial (TI) compartment in cytokine modulation of ovarian function, the effects of interleukin-1beta (IL-1) on plasminogen activator (PA) activity and on prostaglandin E (PGE) and nitric oxide (NO) production were examined in cultures of pregnant mare serum gonadotrophin (PMSG)-primed rat TI cells. Exposure to IL-1 (10 ng/ml) resulted in a 25% reduction (P < 0.001) in PA activity, concurrent with a 4.6-fold increase in the ability of the corresponding conditioned media to inhibit exogenous urokinase activity. IL-1 also produced a 4.7-fold increase in PGE content and a 2.8-fold increase in NO generation. These effects of IL-1 were abolished by the IL-1 receptor antagonist, suggesting specific IL-1 receptor-mediated effects. Transforming growth factor (TGF)-beta1 (10 ng/ml) significantly attenuated the IL-1-stimulated PGE production and NO generation but did not affect the ability of IL-1 to suppress PA activity and stimulate urokinase inhibitor production. The NO synthase inhibitor N-nitro-L-arginine attenuated the IL-1-induced NO generation but had no effect on PA activity or PGE production. Thus, NO is not an obligatory mediator of IL-1 effects on plasminogen activation and PGE generation in rat ovary. The present observations attest to a pleiotropic response of PMSG-primed TI cells to IL-1, and suggest a paracrine/autocrine function for the TI compartment in ovulation and corpus luteum formation.
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PMID:In-vitro modulation of plasminogen activator activity, prostaglandin E and nitric oxide production by interleukin-1 in pregnant mare serum gonadotrophin-primed theca-interstitial cells. 915 41

Sotalol is a beta-adrenoreceptor blocking drug, the clinical efficacy of which has been linked up to its negative chrono- and inotropic effects and its hypotensive action. In addition, beta-adrenolytic drugs are known to inhibit platelet aggregation in vitro possibly through lowering of calcium ions level. Here, we report that in rats sotalol at a dose of 10-20 mg/kg i.v., apart from hypotension, evokes instantaneous thrombolytic effect. This is associated with an increase in plasma level of tissue plasminogen activator (t-PA). In vitro, sotalol at a concentration of 1-100 microM inhibits thrombogenesis on surface of rabbit aorta endothelium superfused with blood. Sotalol also has a weak anti-aggregatory activity (IC50 approximately 500-1000 microM) in human platelet rich plasma (PRP). Since the thrombolytic and fibrinolytic but not hypotensive effects of sotalol were inhibited by cyclooxygenase inhibitor, indomethacin, while its hypotensive but not thrombolytic potency was dimished by an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (L-NNA), we have linked up the sotalol-induced effects in vivo with the release of prostacyclin and nitric oxide. Our data point out to a possibility that prostacyclin and nitric oxide concomitantly released from endothelium and/or from other blood cells after administration of sotalol, may play different roles: prostacyclin may be responsible for fibrinolytic, thrombolytic and antithrombotic properties, while nitric oxide may take part in the mechanism of sotalol-induced hypotension.
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PMID:Thrombolytic activity of beta-adrenolytic drug, sotalol. 959 10

Ovulation, recurring every reproductive cycle of the mammalian female and triggered by a surge of luteinizing hormone (LH) released from the pituitary is an essential prerequisite for fertilization and subsequent embryonic development. Here we shall review two of the biological responses leading to follicle rupture -- vascular changes and proteolysis. Naturally, our present knowledge is based mainly on work in a few species, such as the rat, the mouse and, to lesser extent the pig and monkeys and observations in the human. Therefore any generalizations to other mammals, should be considered as a working hypothesis yet to be confirmed. The LH surge stimulates, in the preovulatory follicles, a cascade of proteolytic enzymes, including plasminogen activator (PA), plasmin and matrix metalloproteinases (MMPs). These enzymes bring about the degradation of perifollicular matrix and, most notably, the decomposition of the meshwork of collagen fibers which provides the strength to follicular wall. Pharmacological blockage of any of these enzymes resulted in the reduction of ovulation rate. The increased ovarian proteolytic activity associated with ovulation is controlled by locally produced specific inhibitors, plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteases-1 (TIMP-1). The increased synthesis of these two specific proteinase inhibitors in the theca of growing follicles ensures their development by protecting them from enzymes diffusing from ovulatory follicles. The stimulation of ovulation by the gonadotropin results in an increase in follicular blood flow, hyperemia, increase in vascular permeability and a marked increase in follicular volume. These vascular changes and the proteolytic activity are triggered either directly by LH or by local mediators and factors produced in response to the gonadotropic stimulus. These mediators allow the tight coordination of these two cascades culminating in the rupture of follicle wall. We shall review here, briefly, the various mediatory systems that have been implicated in follicle rupture. These include steroids, vascular endothelial growth factor (VEGF), cytokines, eicosanoids, platelet activating factor (PAF), nitric oxide and nitric oxide synthase (NO/NOS), kinins and oxygen radicals.
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PMID:Molecular aspects of mammalian ovulation. 1007 49

Nitric oxide (NO) is a multifunctional effector molecule that plays a central role in the regulation of vascular homeostasis. NO is synthesized from L-arginine by a family of enzymes called NO synthases. The principal source of NO in the vascular system of healthy mammals is the constitutively expressed NO synthase in endothelial cells. The basal endothelial formation of NO can be increased by receptor-dependent agonists (i.e., bradykinin) in a calcium-calmodulin-dependent manner, and also by physical forces (i.e., shear stress), predominantly without changes in the intracellular concentration of free calcium. Nitric oxide can diffuse toward the blood vessel wall where the major target is the smooth muscle cell. NO regulates vascular tone, and the free radical is also a potent inhibitor of smooth muscle cell proliferation, migration and synthesis of extracellular matrix proteins. NO can also diffuse toward the lumen of the blood vessel where it helps maintain blood fluidity. NO inhibits platelets' and leucocytes' adhesion to endothelial cells. In addition, NO inhibits platelet aggregation and facilitates the dissolution of small platelet aggregates. However, the regulatory action of NO on blood cells is most likely limited to the luminal surface of endothelial cells since NO is rapidly scavenged by hemoglobin in erythrocytes and inactivated by oxygen-derived radicals such as superoxide anions. NO can also affect the fibrinolytic activity by regulating the release of tissue-type plasminogen activator and plasminogen activator inhibitor-1. The crucial role of vascular NO in the control of blood fluidity has been demonstrated by the regulation of the bleeding time in humans.
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PMID:Vascular biosynthesis of nitric oxide: effect on hemostasis and fibrinolysis. 1066 93

Tumor necrosis factor alpha (TNFalpha) has been shown to be a potent stimulator of prostaglandin (PG) F(2alpha) secretion in the bovine endometrium. The aims of the present study were to determine the cell types in the endometrium (epithelial or stromal cells) responsible for the secretion of PGF(2alpha) in response to TNFalpha, and the intracellular mechanisms of TNFalpha action. Cultured bovine epithelial and stromal cells were exposed to TNFalpha (0.006-6 nM) or oxytocin (100 nM) for 4 h. TNFalpha resulted in a dose-dependent increase of PGF(2alpha) production in the stromal cells (P < 0.001) but not in the epithelial cells. On the other hand, oxytocin stimulated PGF(2alpha) output in the epithelial cells but not in the stromal cells. When the stromal cells were incubated for 24 h with TNFalpha and inhibitors of phospholipase (PL) C or PLA(2), only PLA(2) inhibitor completely stopped the actions of TNFalpha (P < 0.001). When the stromal cells were exposed to TNFalpha and arachidonic acid, the action of TNFalpha was augmented (P < 0.001). When the stromal cells were incubated for 24 h with a nitric oxide (NO) donor (S-NAP), S-NAP stimulated the PGF(2alpha) production dose-dependently. Although an NO synthase (NOS) inhibitor (L-NAME) reduced TNFalpha-stimulated PGF(2alpha) production, an inhibitor of phosphodiesterase augmented the actions of TNFalpha and S-NAP (P < 0. 05). The overall results indicate that the target of TNFalpha for stimulation of PGF(2alpha) production in cattle is the endometrial stromal cells, and that the actions of TNFalpha are mediated via the activation of PLA(2) and arachidonic acid conversion. Moreover, TNFalpha may exert a stimulatory effect on PGF(2alpha) production via the induction of NOS and the subsequent NO-cGMP formation.
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PMID:Production of prostaglandin f(2alpha) by cultured bovine endometrial cells in response to tumor necrosis factor alpha: cell type specificity and intracellular mechanisms. 1077 56

A short term exposure of PC12 cells to a concentration of tert-butylhydroperoxide (tB-OOH) causing peroxynitrite-dependent DNA damage and cytotoxiticity promoted a release of arachidonic acid (AA) that was sensitive to phospholipase A(2) (PLA(2)) inhibitors and insensitive to phospholipase C or diacylglycerol lipase inhibitors. The extent of AA release was also mitigated by nitric oxide synthase (NOS) inhibitors and peroxynitrite scavengers. Low levels (10 microM) of authentic peroxynitrite restored the release of AA mediated by tB-OOH in NOS-inhibited cells whereas concentrations of peroxynitrite of 20 microM, or higher, effectively stimulated a PLA(2) inhibitor-sensitive release of AA also in the absence of additional treatments. These results are consistent with the possibility that endogenous as well as exogenous peroxynitrite promotes activation of PLA(2).
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PMID:Peroxynitrite-mediated release of arachidonic acid from PC12 cells. 1078 Sep 56

Recent studies have indicated that a number of factors contribute to the pathophysiology in response to nitric oxide synthase (NOS) inhibition. We previously demonstrated that plasminogen activator inhibitor-1 deficient (PAI-1-/-) mice are protected against hypertension and perivascular fibrosis induced by relatively short-term NOS inhibition. In this study, we compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis induced by long-term treatment with N(omega)-nitro- L -arginine methyl ester (L -NAME) in wild type (WT), PAI-1(-/-) and tissue-type plasminogen activator deficient (t-PA-/-) mice. After initiating L -NAME, systolic blood pressure increased in all groups at 2 weeks. Over a 16 week study period, systolic blood pressure increased to 143+/-3 mmHg (mean+/-SEM) in WT animals, 139+/-2 in t-PA-/- mice vs 129+/-2 in PAI-1-/- mice (P < 0.01). Coronary perivascular fibrosis increased in L -NAME-treated WT and t-PA(-/-) mice compared to each control group (P<0.01 in WT, P<0.05 in t-PA-/-), while PAI-1-/- mice were protected against fibrosis induced by L -NAME. t-PA deficiency did not accentuate the vascular pathology or the changes in blood pressure. In situ zymography demonstrated augmented gelatinolytic activity in PAI-1-/- mice at baseline, suggesting that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Plasma TGF-beta1 levels increased in L -NAME-treated WT and PAI-1-/- mice (P < 0.01), but not in L -NAME-treated t-PA-/- mice. These findings support the hypothesis that the plasminogen activator system protects against the structural vascular changes induced by long-term NOS inhibition. While PAI-1 deficiency protects against L -NAME-induced hypertension and perivascular fibrosis, t-PA deficiency does not exacerbate the vascular pathology or hypertension.
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PMID:Potential roles of plasminogen activator system in coronary vascular remodeling induced by long-term nitric oxide synthase inhibition. 1205 49

Healthy vascular endothelium is a powerful generator of nitric oxide (NO), prostacyclin (PGI2), prostaglandin E2 (PGE2), and plasminogen activator (t-PA). These endothelial products protect vascular wall against aggression from activated blood platelets and leukocytes. In particular they protect against thrombosis, promote thrombolysis, maintain tissue perfusion, and inhibit remodeling of vascular and cardiac walls. Endothelial dysfunction appears on one hand as suppression in the release of the above mediators, and on the other as deleterious discharge of prostaglandin endoperoxides (PGH2, PGG2), superoxide anion O2-, peroxynitrite (ONOO-), and plasminogen activator inhibitor (PAI-1). Our data point to endothelial bradykinin (Bk) as a trigger for protective endothelial mechanisms. In cultured endothelial cells (CEC) Bk through kinin B2 receptors raised in a concentration-dependent manner (1pM-10 nM) free cytoplasmic calcium ions [Ca2+]i. This rise was accompanied by the release of NO as quantified by a porphyrinic sensor. Other endothelial agonists were weaker-stimulators of [Ca2+]i than Bk. In vivo we analyed the effects of exogenous Bk and of amplifiers of endogenous Bk, such as perindopril and quinapril ("tissue type" angiotensin converting enzyme inhibitors, ACE-I) on endothelial function using our original thrombolytic bioassay and EIA assays for 6-keto-PGF1alpha and t-PA antigen. A major difference found between exogenuous Bk and endogenous Bk (that rendered by "tissue ACE-I") was a) prolonged thrombolytic action (> 4h) of quinapril or perindopril. Moreover, only exogenous Bk evoked an immediate and profound hypotensive action. In vivo, Bk-induced thrombolysis was B2 kinin receptor-dependent, PGI2-mediated. The unexpected action of Bk came to light in CEC. Then appeared incubated for 4 h increased expression of mRNAs for haemoxygenase (HO-1), cyclooxygenase 2 (COX-2), prostaglandin E synthase (PGE-S), but hardly for nitric oxide synthase 2(NOS-2). We hypothesize that a network of interactions of Bk-induced enzymes may constitute a delayed phase of Bk effects in the endothelium, whereas the primary phase would be activation by BK of [Ca2+]i-dependent constitutive endothelial enzymes. In blood-perfused rat endotoxemic lungs, NO is the most eminent cytoprotective mediator. Summing up, in peripheral circulation endogenous Bk is the most efficient activator of protective endothelial function. Thrombolytic action of "tissue-type" ACE-Is relies on receptor B-2-mediated, [Ca2+]i-dependent release of PGI2. Bk also may act as a "microcytokine" by inducing mRNAs for HO-1, COX-2, or PGE-S. Activation of HO-1 may lead to a deficiency in intracellular heme required as a cofactor for both COX and NOS. This network of interactions triggered by Bk call for further studies.
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PMID:Bradykinin as a major endogenous regulator of endothelial function. 1205 3

In order to clarify the possible interactions between nitric oxide (NO) and arachidonic acid (AA) pathways, human amnion-like WISH cells were perifused to measure the effects of the following substances on [(3)H]arachidonic acid release: (1) sodium nitroprusside (SNP), a nitric oxide donor; (2) 1,1,1-trifluoromethyl-6,9,12,15-heicosatetraen-2-one, a cytosolic phospholipase A(2) (cPLA(2)) inhibitor; (3)L -arginine, the substrate of nitric oxide synthase (NOS); (4) 3-(5'-Hydroxymethyl-2'-furyl)-1-benzylindazole and 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one, activator and inhibitor of soluble guanylyl cyclase, respectively; (5) a membrane-permeable non-hydrolyzable analogue of guanosine-3',5'-cyclic monophosphate (cGMP). Furthermore, the effect of SNP on prostaglandin E(2) (PGE(2)) release was tested. Exogenous and endogenous NO, as well as the guanylyl cyclase activator and cGMP analogue, significantly increased [(3)H]arachidonic acid release. Both soluble guanylyl cyclase and PLA(2) inhibitors counteracted SNP response. Exogenous NO increased PGE(2) release, although to a much lesser degree compared with arachidonic acid release. Our results indicate that NO stimulates AA release in WISH cells by activating PLA(2) through a cyclic GMP-dependent mechanism.
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PMID:Effect of nitric oxide on arachidonic acid release from human amnion-like WISH cells. 1236 77


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