Prostacyclin production

Inhibition of phospholipase A2, thromboxane B4 and enhancement of prostacyclin production (Raederstorff et al., 2002 Qureshi and Qureshi, 1992). 

Studies also suggested that IL-6 causes endothelial cell dysfunction and decrease of prostacyclin production. Soluble IL-6 receptors seem to play a modulating and enhancing role in IL-6 activity (FI 8). The incidence of detection appears to be less influenced by the method of assay, as either ELISA or bioassay techniques yield consistent results, with a high correlation between these techniques. IL-6 values may be more constant and endocrine-like than those values of TNF and IL-1. 

Low doses of aspirin inhibit platelet aggregation and may be more effective than higher doses. Larger doses inhibit cyclooxygenase in arterial walls, interfering with prostacyclin production, a potent vasodilator and inhibitor of platelet aggregation. 

J.A. Frangos, L.V. Mclntire, S.G. Eskin, C.L. Ives, Flow effects on prostacyclin production by cultured human endothelial cells. Science 227 (1985) 1477-1479. 

Boucek. Uniqueness of dietary olive oil in stimulating aortic prostacyclin production in post-weanling rats. Prostaglandins Leukotrienes Essent Fatty... 

Similarly to what identified in the rat, histamine H3 receptor activation does not contribute to prostacyclin production in coltured human endothelial cells (Bull et al., 1992). There are no findings explaining any possible involvement of these receptors in the control of endothelial functions in humans. 

Ylikorkala O, Puolakka J, Viinikka L. Oestrogen containing oral contraceptives decrease prostacyclin production. Lancet 1981 1(8210) 42. 

The coxibs continue to be investigated to determine whether their effect on prostacyclin production could lead to a prothrombotic state. The frequency of other adverse effects approximates that of other NSAIDs. Celecoxib causes no more edema or renal effects than other members of the NSAID group, but edema and hypertension have been documented. 

Jia et al. (2001) have identified a 12-amino-acid synthetic peptide derived from exon 6 (based on sequence of VEGF189) that inhibits VEGF binding to HUVECs and porcine aortic ECs. It also inhibits VEGF-stimulated ERK activation and prostacyclin production. The peptide blocks the interaction of VEGF with KDR and neuropilin-1. 

Gliki, G., Abu-Ghazaleh, R., Jezequel, S., Wheeler-Jones, C., and Zachary I. 2001. Vascular endothelial growth factor-induced prostacyclin production is mediated by a protein kinase C (PKC)-dependent activation of extracellular signal-regulated protein kinases 1 and 2 involving PKC-delta and by mobilization of intracellular Ca2+. Biochem. J. 353 503-512. 

Wheeler-Jones, C., Abu-Ghazaleh, R., Cospedal, R., Houliston, R. A., Martin, J., and Zachary, I. 1997. Vascular endothelial growth factor stimulates prostacyclin production and activation of cytosolic phospholipase A2 in endothelial cells via p42/p44 mitogen-activated protein kinase. FEBS Lett. 420 28-32. 

Skinner SJM, Somervell CE, Olson DM. The effects of mechanical stretching on fetal rat lung cell prostacyclin production. Prostaglandins. 1992 43 413 133. 

Endothelial cells produce prostacyclins in response to ATP. AlF41 enhanced the stimulatory effect of ATP on prostacyclin release [101]. A dose-and time-dependent generation of inositol phosphates, release of arachidonic acid, and the production of prostacyclin (PGI2) in human umbilical vein endothelial cells was described [102], Stimulation of arachidonic acid release and prostacyclin production by AlF41 was described in cultured endothelial cells from rabbit coronary microvessels [103],... 

On the other hand, Mutanen et al. (128) found that canola oil and sunflower oil enhanced in vitro platelet aggregation. Similarly, McDonald et al. (113) found that both canola oil and sunflower oil increased prostacyclin production (an antiaggregating eicosanoid) and decreased thromboxane production (a proaggregating eicosanoid). Although the effect of canola oil on platelet activity and clot formation is not as well established as its favorable effect on plasma cholesterol and lipoprotein levels, there is evidence that it may impede clot formation. 

Guivemau M, Meza N, Baija P, and Roman O. (1994). Clinical and experimental study on the long-tem effect of dietary gamma-tinolcnic acid on plasma lipids, platelet aggregation, thromboxane formation, and prostacyclin production. ProsL Leukotrienes Essential Fatty Acids. 51,311-316. 

JaffeEA, WekslerBB Recovery ofendodidial cell prostacyclin production after inhibition by low doses of aspirin. J. Cliit hivest 532,1979... 

The data available from the literature [24,25] and our findings [16] enable us to explain the known fact of diminished prostacyclin production in the atherosclerotic aorta by accumulating lipoperoxides inhibiting prostacyclin synthetase. Thus, intensified lipoperoxidation in the atherosclerosis may be a direct cause of thrombosis which is the most frequent and severe event in this condition. 

The use of OEP with antiplatelets, thrombolytics, low-molecular-weight heparins, or anticoagulants may result in a delayed but increased risk of bleeding, and concomitant use is not advised (54,59). The mechanism of action is theorized to be decreased thromboxane B2 synthesis and increased prostacyclin production caused by y-linolenic acid, resulting in inhibition of platelet aggregation and prolonged bleeding time (42). 

Cardiovascular effects of prostaglandins are more complex. The coagulation system is clearly modulated by platelet-derived thromboxanes, which have procoagulation effects and the anticoagulative effects of endothelial cell-derived prostacyclin. Thromboxanes are clearly COX-1 derived because platelets do not express COX-2. The source of endothelial cell prostacyclin production is less clear with both enzymes expressed and mixed opinions on the relative contribution of the two enzymes. Recent results with Vioxx, a selective COX-2 inhibitor, imply a modest effect on myocardial infarction rate in patients taking the compound but do not define whether this is caused by a change in ratio simply by a lack of platelet effect or that inhibition of endothelial cell prostacyclin also skews the pro- and anticoagulant ratio. 

Guo et al. (1990) working with an in vivo rabbit model showed that pre- or posttreatment with indomethacin, an inhibitor of thromboxane and prostacyclin production but not of leukotriene production, partially blocked phosgene-induced pulmonary oedema. The leukotriene receptor blockers FPL 55712 and LY 171883 dramatically reduced the oedema when given post-exposure to phosgene. 

E. Interleukin-1 stimulates prostacyclin production by cultured human endothelial cells by increasing arachidonic acid mobilization and conversion. Arteriosclerosis 10, 129-134... 

Thromboxane synthetase inhibition is an appealing approach to antithrombotic therapy, since it would be more specific and not shut off the whole AA cascade as do the cyclooxygenase inhibitors such as aspirin. Such a drug should result in an accumulation of PGG2 and PGH2 that could then be diverted to increased prostacyclin production, itself an antithrombotic, thus offering a double-barreled effect. This actually occurs. 

---