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)

The vascular endothelium, which envelopes the circulating blood in a continuous monolayer, is not only a physical barrier between blood and vessel wall, but a highly complex "organ" which is involved in the regulation of blood vessel tone and permeability, blood coagulation, angiogenesis, leukocyte and platelet reactivity, phagocytosis of bacteria and the metabolism of many vascular mediators. This article focuses on the biosynthesis, biological actions and interactions of endothelium-derived vasoactive mediators, namely, prostacyclin, endothelium-derived relaxing factor--now characterized as nitric oxide--and endothelin, in the regulation of blood vessel tone under physiological and pathophysiological conditions. The formation of these highly vasoactive substances in modulated by changes in intracellular messengers (cyclic adenosine monophosphate, cyclic guanosine monophosphate, calcium), by interactions of endothelium with blood-borne cells and plasma constituents and finally by the interaction of these mediators themselves. The current evidence supports the view that nitric oxide plays a pivotal role for the regulation of blood vessel tone under physiological conditions, while the generation of prostacyclin is primarily an important defense mechanism to maintain a sufficient blood vessel patency and tissue viability under conditions of a compromised blood supply. Although the physiological role of the endothelium-derived vasoconstrictor peptide endothelin-1 is less well defined, it is apparent that any potential harmful vasoconstrictor effects resulting from an enhanced formation of endothelin under pathophysiological conditions are modulated by the simultaneous generation of prostacyclin, nitric oxide and tissue-plasminogen activator, thus preventing excessive vasoconstriction and thrombotic occlusion of the vascular bed concerned.
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PMID:Biosynthesis and interaction of endothelium-derived vasoactive mediators. 178 95

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

Inhibitors of cyclic nucleotide phosphodiesterase hydrolysis of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate are known to inhibit platelet aggregation, which plays an important role in acute reocclusion after thrombolysis in acute myocardial infarction. In the present study of a canine preparation of coronary artery thrombosis superimposed on high-grade stenosis, we tested whether the antithrombotic agent cilostazol, an inhibitor of cAMP phosphodiesterase, could prevent acute reocclusion or sustain coronary blood flow after thrombolysis when used with recombinant tissue-type plasminogen activator (rt-PA) and heparin. Intravenous infusion of rt-PA (0.5 mg/kg body wt for 30 minutes) and heparin (a 150 IU/kg body wt i.v. bolus and then 25 IU/kg body wt per hour i.v.) was combined with cilostazol (0.6 or 1.8 mg/kg body wt for 60 minutes). Without cilostazol, reperfusion was observed in seven of eight dogs, but reocclusion occurred in six of these seven dogs after 9 +/- 2 minutes. After administration of 1.8 mg/kg body wt cilostazol (group B-2; a 120-minute observation after the start of rt-PA infusion), reperfusion occurred in all seven dogs (p < 0.05 versus control group), and brief cyclic reocclusion was observed in only one dog 63 minutes after reperfusion. At the same dose of cilostazol (group B-2L; a 240-minute observation after the start of rt-PA infusion), reperfusion occurred in all five dogs (p < 0.05 versus control group), and coronary blood flow was well maintained except for one short reocclusion in one dog. Cilostazol inhibited cyclic flow reduction in a dose-dependent fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cilostazol, a novel cyclic AMP phosphodiesterase inhibitor, prevents reocclusion after coronary arterial thrombolysis with recombinant tissue-type plasminogen activator. 838 80

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

Platelets play a vital role in mediating the activity of plasma fibrinolytic system. They have both the potential to inhibit as well as to activate fibrinolysis. Just as platelet can affect thrombolysis, thrombolytic agents can have reciprocal effects on platelet function. Accumulating evidence indicates that thrombolysis induced both by streptokinase and t-PA results in rapid activation of platelets, the phenomenon being possibly responsible for reocclusion of arteries after successful thrombolysis. However, caution is required in comparing the results of the various studies because of differences in the thrombotic models employed, with the major variables being the mechanism of thrombus formation (in vivo or in vitro), the platelet concentrations and the doses of investigated agent. Various studies indicate that adjunctive therapy with anti-platelet agents, such as inhibitors of cyclooxygenase, inhibitors of thromboxane A2-synthase and activators of platelet cyclic-AMP or -GMP may lower the dose of the thrombolytic agent required to attain reperfusion.
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PMID:Platelets in fibrinolytic system. 877 Jul 85

It has been hypothesized that L-arginine improves exercise performance by increasing nitric oxide synthesis and levels of insulin and growth hormone (GH). Metabolic and hormonal responses to chronic L-arginine supplementation may clarify the mechanisms underlying its putative physiologic effects on physical performance. Therefore, the aim of this study was to investigate the effects that 4 weeks of supplementation with L-arginine would have on metabolic and hormonal parameters at rest and in response to exercise. Fifteen healthy runners were divided into treatment (ARG; 6 g L-arginine) and placebo (PLA; 6 g cornstarch) groups. On the first visit, blood samples were collected for baseline, and the supplement or placebo was provided. After 4 weeks of supplementation (second visit), blood samples were collected at the following intervals: at rest, immediately after the first 5-km time-trial running test (5km-TT), immediately after the second 5km-TT, and after 20 minutes of recovery (+20). In addition to exercise performance (total running time), plasma nitrate, nitrite, nitrate plus nitrite, cyclic guanosine monophosphate, lactate, ammonia and serum insulin, GH, insulin-like growth factor 1, and cortisol concentrations were evaluated. There were significant increases in plasma nitrite, cyclic guanosine monophosphate, lactate, ammonia and serum GH, and cortisol at the first 5km-TT, immediately after the second 5km-TT, and +20 in both ARG and PLA. Nitrate plus nitrite and nitrate increased only at +20. No significant change was observed in serum insulin and insulin-like growth factor 1 in any sample period. Total running time did not differ significantly between the 2 tests, in either ARG or PLA. Thus, according to our results, 4 weeks of L-arginine supplementation did not cause beneficial changes in metabolic and hormonal parameters, beyond those achieved with exercise alone.
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PMID:L-arginine does not improve biochemical and hormonal response in trained runners after 4 weeks of supplementation. 2441 44