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)

SIN-1--a pharmacologically active metabolite of the vasodilating agent molsidomine--caused an increase in plasminogen activator release of about 50 per cent at a final concentration of 10(-7) mol/l on perfusion of isolated pig ears. An increase in SIN-1 concentration did not produce a further increase in activator release. The released activator is of the tissue-type. After repeated perfusion of the isolated pig ear with SIN-1 no further significant increase in plasminogen activator release occurred.
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PMID:[Release of plasminogen activator by SIN-1]. 310 66

The long-acting antianginal drug molsidomine has been shown experimentally to reduce myocardial infarct size when administered prior to or after cardiac insult. This is due to several drug actions. Dilation of postcapillary capacitance vessels diminishes venous return, preload, heart dimensions, and myocardial oxygen consumption. Relaxation of stenosed conductive coronary arteries increases the perfusion of myocardial areas at risk of infarction due to enhanced collateral circulation. Increased regional blood supply nourishes predominantly subendocardial cardiac muscles as a result of reduction of extravascular coronary pressure, and resistance. The stable heart rate and cardiac contractility favor improved heart performance. The inhibition of platelet aggregation in vivo by molsidomine or its active metabolites, SIN-1 and SIN-1A, is linked to the stimulation of prostacyclin synthesis, inhibition of thromboxane release with induction of thrombosis and vasoconstriction, and enhanced concentrations of cyclic guanosine monophosphate. Dilation of coronary arteries after intracoronary administration of SIN-1, with inhibition of platelet aggregation by restrained release of adenosine diphosphate and stabilization of platelet membranes, facilitates the recanalization of stenosed arteries and reduces coronary muscle tone at the site of thrombosis. Activation of the human fibrinolytic system and drug-induced release of a plasminogen activator favor dysaggregatory effects. The drug's inhibiting actions on lipoxygenase products of arachidonate (e.g., 12-hydroperoxy-eicosatetraenoic acid and leukotrienes) may shift prostaglandin catabolism to cyclooxygenase products (e.g., prostacyclin) that protect against the expansion of ischemia and the induction of coronary spasm. Experimentally, the hemodynamic effectiveness of molsidomine can be antagonized by catecholamines (afterload effects) and dihydroergotamine (preload and afterload effects) respectively. Further clinical investigations will clarify the application of these mechanisms for the therapeutic success of the drug in human myocardial infarction.
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PMID:Molsidomine: alternative approaches to treat myocardial ischemia. 355 58

In vitro prostacyclin (PGI2) and nitric oxide (NO) synergise in their anti-aggregatory actions on blood platelets. Presently, we have studied an interaction of molsidomine (ML--pro-drug for the NO-donor SIN-1) and PGI2 in 20 patients with peripheral arterial disease (PAD) on the plasma fibrinolytic system and platelet aggregability. A synergism of these drugs in their fibrinolytic action as measured by shortening of euglobulin clot lysis time (ECLT) and in their anti-platelet action as measured by an increase in the ratio of free platelets to platelet aggregates was observed. It seems that PGI2 and ML activated the fibrinolytic system by two independent mechanisms i.e. by a PGI2-induced direct release of pro-fibrinolytic t-PA from endothelial cells and by a ML-induced suppression of the release of anti-fibrinolytic PAI-1 from platelets. This may constitute a basis for the synergism. A synergism between PGI2 and ML in their anti-platelet action seems to be rooted in the potentiation by cyclic-GMP on the anti-aggregatory action of cyclic-AMP in platelets. On the other hand, no synergism between PGI2 and ML was observed in their hypotensive effects as measured by systolic and diastolic arterial blood pressure. It may well be that the synergism in fibrinolytic and anti-platelet actions between stimulators of adenylate and guanylate cyclases accompanied by a lack of synergism in their hypotensive actions may allow reduction of the therapeutic doses of either stimulator, thus avoiding hazards of their hypotensive side effects.
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PMID:Prostacyclin and molsidomine synergise in their fibrinolytic and anti-platelet actions in patients with peripheral arterial disease. 843 99

This study was undertaken in order to investigate the possible interactions between nitric oxide and arachidonic acid (AA) in Venus verrucosa oocytes. We perifused isolated oocytes to determine the effect of the following substances on [3H]arachidonic acid release ([3H]AA): (1) A 23187, a calcium ionophore; (2) nitric oxide (NO) donors; (3) 1,1,1-trifluoromethyl-6,9,12,15 heicosatetraen-2-one (AACOCF(3)), a specific phospholipase A(2) (PLA(2)) inhibitor; (4) [5'-hydroxymethyl-2'-furyl]-1-benzyl indazole (YC-1) and 1H-[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), specific soluble guanylyl cyclase activator and inhibitor, respectively; (5) L-arginine, the substrate of nitric oxide synthase; (6) L-nitroarginine methyl esther (L-NAME), an inhibitor of nitric oxide synthase. Our results demonstrated that: (a) the calcium ionophore dose-dependently increased [3H]arachidonic acid release; (b) the NO donors sodium nitroprusside (SNP) and linsidomine (SIN-1) highly increased [3H]arachidonic acid output, while S-nitroso-N-acetylpenicillamine (SNAP) was without effect; (c) AACOCF(3) completely blocked the [3H]arachidonic acid release induced by SNP and SIN-1; (d) YC-1 increased [3H]arachidonic acid release, while ODQ completely counteracted SNP response; (e) [3H]arachidonic acid output was also increased by L-arginine; (f) a similar effect was, paradoxically, obtained in the presence of L-NAME. Furthermore, using RT-PCR we demonstrated in the same cells the presence of a nitric oxide synthase (NOS) mRNA, whose expression was not modulated by interleukin 1beta (IL-1beta). These results demonstrate the presence of a both calcium-dependent and NO-sensitive PLA(2) and of nitric oxide synthase in V. verrucosa oocytes. Our data also suggest a co-action of the two pathways in the control of reproduction in this bivalve.
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PMID:Nitric oxide-mediated arachidonic acid release from perifused Venus verrucosa oocytes. 1260 64

This study investigated interactions between nitric oxide synthesis and phospholipase A2 (PLA2) activation in lung epithelial cells. Nitrite formation, inducible nitric oxide synthase expression, and [3H]arachidonic acid (AA) release were determined following treatment with: (1) the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methyl esther (L-NAME) and aminoguanidine; (2) arachidonyl trifluoromethyl ketone (AACOCF3), a specific cytosolic PLA2 inhibitor; (3) S-morpholinosydnonimine (SIN-1), a nitric oxide donor which provokes peroxynitrite formation; (4) trolox, a free radical scavenger, and (5) the AA release agonists calcium ionophore, phorbol 12-myristate 13-acetate, and sodium vanadate. The results demonstrated that (1) L-NAME and aminoguanidine inhibited agonist-induced AA release by 40 and 65%, respectively; (2) AACOCF3 inhibited nitrite formation and inducible nitric oxide synthase expression in a dose-dependent manner; (3) SIN-1, together with AA release agonists, significantly increased the AA output, and (4) trolox counteracted the SIN-1 effects. Our results demonstrate cross talk between nitric oxide synthase and PLA(2) pathways, with a possible intermediary role for peroxynitrite and superoxide.
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PMID:Interactions between nitric oxide and arachidonic acid in lung epithelial cells: possible roles for peroxynitrite and superoxide. 1557 79

Peroxynitrite (ONOO-) and high mobility group box 1 protein (HMGB1) are important cytotoxic factors contributing to cerebral ischemia-reperfusion injury. However, the roles of ONOO- in mediating HMGB1 expression and its impacts on hemorrhagic transformation (HT) in ischemic brain injury with delayed t-PA treatment remain unclear. In the present study, we tested the hypothesis that ONOO- could directly mediate the activation and release of HMGB1 in ischemic brains with delayed t-PA treatment. With clinical studies, we found that plasma nitrotyrosine (NT, a surrogate marker of ONOO-) was positively correlated with HMGB1 level in acute ischemic stroke patients. Hemorrhagic transformation and t-PA-treated ischemic stroke patients had increased levels of nitrotyrosine and HMGB1 in plasma. In animal experiments, we found that FeTmPyP, a representative ONOO- decomposition catalyst (PDC), significantly reduced the expression of HMGB1 and its receptor TLR2, and inhibited MMP-9 activation, preserved collagen IV and tight junction claudin-5 in ischemic rat brains with delayed t-PA treatment. ONOO- donor SIN-1 directly induced expression of HMGB1 and its receptor TLR2 in naive rat brains in vivo and induced HMGB1 in brain microvascular endothelial b.End3 cells in vitro. Those results suggest that ONOO- could activate HMGB1/TLR2/MMP-9 signaling. We then addressed whether glycyrrhizin, a natural HMGB1 inhibitor, could inhibit ONOO- production and the antioxidant properties of glycyrrhizin contribute to the inhibition of HMGB1 and the neuroprotective effects on attenuating hemorrhagic transformation in ischemic stroke with delayed t-PA treatment. Glycyrrhizin treatment downregulated the expressions of NADPH oxidase p47 phox and p67 phox and iNOS, inhibited superoxide and ONOO- production, reduced the expression of HMGB1, TLR2, MMP-9, preserved type IV collagen and claudin-5 in ischemic brains. Furthermore, glycyrrhizin significantly decreased the mortality rate, attenuated hemorrhagic transformation, brain swelling, blood-brain barrier damage, neuronal apoptosis, and improved neurological outcomes in the ischemic stroke rat model with delayed t-PA treatment. In conclusion, peroxynitrite-mediated HMGB1/TLR2 signaling contributes to hemorrhagic transformation, and glycyrrhizin could be a potential adjuvant therapy to attenuate hemorrhagic transformation, possibly through inhibiting the ONOO-/HMGB1/TLR2 signaling cascades.
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PMID:Glycyrrhizin Prevents Hemorrhagic Transformation and Improves Neurological Outcome in Ischemic Stroke with Delayed Thrombolysis Through Targeting Peroxynitrite-Mediated HMGB1 Signaling. 3187 39