Renal effects of drugs that inhibit prostaglandin synthesis.
AB - Exogenous lysolecithin inhibits prostaglandin E2 synthesis from arachidonic acid in bovine seminal vesicle microsomes at plausible physiological levels (lysolecithin-to-protein ratios ≥ 0.03 [w/w]) by inhibiting fatty acid cyclo-oxygenase activity. Structurally defined lysolecithins with varying fatty acid chain length exhibit varying effectiveness as inhibitors. Addition of equimolar quantities of free fatty acid lowers the lysolecithin concetration required for inhibition. Exogenous lysolecithin inhibits unstimulated and thrombin-stimulated prostaglandin E2 synthesis from endogenous substrate in SVBalb/3T3 cells. Serum treatment of SVBalb/3T3 cells, which generates endogenous lysolecithin and free fatty acids, decreases the efficiency of conversion of free arachidonic acid to prostaglandins. These results suggest a possible role for the products of phospholipase A2 action in the regulation of prostaglandin synthesis.
Prostaglandin Synthetase Inhibitors | SpringerLink
AB - Prostaglandins (PG) have been postulated to be involved in both tumor metastases to bone and in tumor-induced bone resorption. The anthracenedione antineoplastic agents ametantrone (HAQ) and mitoxantrone are potent antioxidants and inhibit hydroperoxide-dependent initiation and propagation reactions. Therefore, these compounds may inhibit PG production and could also inhibit tumor metastases and tumor-induced resorption. The ability of HAQ, a prototypic anthracenedione, to inhibit PG synthesis and PG-mediated bone resorption was investigated using neonatal mouse calvaria in organ culture. Epidermal growth factor (EGF) stimulates bone resorption in this tissue by inducing PG synthesis. Consequently, if HAQ inhibits EGF-stimulated PG synthesis, it should also inhibit EGF-stimulated bone resorption. HAQ, at 10 μM, completely abolished EGF-stimulated PG synthesis and calcium release. Moreover, HAQ (1.0-30 μM) inhibition of EGF-stimulated PGE2 synthesis correlated with the inhibition of EGF-stimulated Ca release in a concentration-dependent manner. In contrast to EGF, parathyroid hormone stimulates resorption by a PG-independent pathway. HAQ at 10 μM had no effect on parathyroid hormone stimulated Ca release. These results suggest that HAQ inhibition of bone resorption appears to be primarily mediated by inhibition of PG biosynthesis.
Resident rat peritoneal macrophages synthesize a variety of prostanoids and leukotrienes from arachidonic acid. Overnight treatment with lipopolysaccharide (LPS) induces the synthesis of cyclooxygenase-2 (COX-2) and an altered prostanoid profile that emphasizes the preferential conversion of arachidonic acid to prostacyclin and prostaglandin E2. In these studies, we report that exposure to LPS also caused a strong suppression of 5-lipoxygenase but not 12-lipoxygenase activity, indicated by the inhibition of synthesis of both leukotriene B4 and 5-hydroxyeicosatetraenoic acid (5-HETE), but not of 12-HETE. Inhibition of 5-lipoxygenase activity by LPS was both time- and dose-dependent. Treatment of macrophages with prostaglandin E2 partially inhibited leukotriene synthesis, and cyclooxygenase inhibitors partially blocked the inhibition of leukotriene generation in LPS-treated cells. In addition to COX-2, nitric oxide synthase (NOS) was also induced by LPS. Treatment of macrophages with an NO donor mimicked the ability of LPS to significantly reduce leukotriene B4 synthesis. Inhibition of NOS activity in LPS-treated cells blunted the suppression of leukotriene synthesis. Inhibition of both inducible NOS and COX completely eliminated leukotriene suppression. Finally, macrophages exposed to prolonged LPS demonstrated impaired killing of Klebsiella pneumoniae and the combination of NOS and COX inhibitors restored killing to the control level. These results indicate that prolonged exposure to LPS severely inhibits leukotriene production via the combined action of COX and NOS products. The shift in mediator profile, to one that minimizes leukotrienes and emphasizes prostacyclin, prostaglandin E2 and NO, provides a signal that reduces leukocyte function, as indicated by impaired killing of Gram-negative bacteria.
term:nsaids = inhibit prostaglandin synthesis ..
The nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, reduce PGE2 biosynthesis by inhibiting both COX-1 and COX-2, and thereby suppress inflammation, fever, and pain . However, long-term use of these drugs can cause life threatening side effects, mainly gastrointestinal injury and renal pathology . COX-2 specific inhibitors were designed to minimize these side effects, but recent clinical studies indicated small but significantly increased risks for cardiovascular events such as sudden myocardial infarction and thrombosis due to imbalance in the levels of PGI2 and TXA2 . This suggests a need for effective and safe alternative approaches to reduce PGE2 levels. As a consequence, the focus of research has shifted to efforts to devise inhibitors for enzymes downstream of COX-2, such as mPGES-1, as potential anti-inflammatory therapies.
Notes: Aspirin Inhibit Prostaglandin Synthesis
PGE2 is one of the most abundant prostaglandins in the human body, and has been implicated in numerous physiological and pathological processes, including immune responses and cancer . Diverse pathological and physiological stimuli can initiate prostaglandin synthesis by first activating phospholipase A2 (PLA2), that liberates arachidonic acid (AA) from membrane phospholipids into the cytoplasm . This AA is then converted into prostaglandin G2 (PGG2) and prostaglandin H2 (PGH2) by cyclooxygenase (COX). There are two isoforms of COX, designated as COX-1 and COX-2. COX-1 is constitutively expressed in most cell types and has been implicated in a number of homeostatic processes including stomach acidity, endometrial cycling and renal function . In contrast, COX-2 expression is inducible, and is highly upregulated in response to infection, atherosclerosis and cancers , .