Effect of chronic treatment with a cyclooxygenase inhibitor on reproductive parameters in male rat

Indomethacin is a member of non-steroidal anti-inflammatory drugs [NSAIDs] commonly used for treatment of gout, arthritis, and other inflammatory conditions. It has been shown to inhibit ovarian prostaglandins synthesis in mammals, birds, fish and reptiles. However, the effects of its chronic administration on male reproductive functions remain largely unknown. Using rat as a model, we studied the effect of chronic treatment with indomethacin on the male reproductive system. Testosterone was measured in the serum, testicular tissue, and testicular interstitial fluid by radioimmunoassay. Moreover, we also studied the direct effect of indomethacin in vitro on luteinizing hormone stimulated testosterone secretion from the Leydig cells isolated from various treatment groups. Indomethacin treatment for 50 days caused a significant but reversible decrease in prostate weight, epididymal sperm reserves and sperm motility score compared with control rats [p<0.05]. In vitro stimulation of Leydig cells isolated from treated rat's testes with luteinizing hormone [250 micro IU] produced significantly reduced testosterone compared with cells from control groups [p<0.05]. Furthermore, stimulatory effect of luteinizing hormone on the control Leydig cells was significantly reduced when these cells were challenged with luteinizing hormone in the presence of reduced after indomethacin treatment [p<0.05]. Due to its significant inhibition of key reproductive hormones, indomethacin effectively inhibits reproductive functions if used on a long-term basis. In his, study we have identified potential risks in the long-term use of cyclooxygenase inhibitors

Co-activation of Gi and Gq proteins exerts synergistic effect on human platelet aggregation through activation of phospholipase C and Ca2+ signalling pathways

Our previous studies have shown that subthreshold concentrations of two platelet agonists exert synergistic effects on platelet aggregation. Here we studied the mechanism of synergistic interaction of 5-hydroxytryptamine (5-HT) and epinephrine mediated platelet aggregation. We show that 5-HT had no or little effect on aggregation but it did potentiate the aggregation response of epinephrine. The synergistic interaction of 5-HT (1-5 microM) and epinephrine (0.5-2 microM) was inhibited by alpha2-adrenoceptor blocker (yohimbine; IC50= 0.4 microM), calcium channel blockers (verapamil and diltiazem with IC50 of 10 and 48 mM, respectively), PLC inhibitor (U73122; IC50=6 microM) and nitric oxide (NO) donor, SNAP (IC50=1.6 microM)). The data suggest that synergistic effects of platelet agonists are receptor-mediated and occur through multiple signalling pathways including the activation PLC/Ca2+ signalling cascades.

Effects of lipoproteins on cyclo-oxygenase and lipoxygenase pathways in human platelets

The products of arachidonic acid [AA] metabolism in platelets play an important role in platelet shape change, adhesion and aggregation which may participate in the pathogenesis of ischemic heart disease and thrombosis. Since lipoproteins are also involved in the pathogenesis of thrombo-embolic disorders, the effect of human lipoproteins [HDL, LDL, VLDL] on AA metabolism in human platelets was investigated. Lipoproteins were separated by density gradient zonal ultracentrifugation. The effects of lipoproteins on production of AA metabolites in human platelets i.e., thromboxane A2 [TXA2] and hydroxy-eicosatetraenoic acids [HETEs] were examined using radiometric thin layer chromatography coupled with automated data integrator system. In human platelets, HDL inhibited 12-HETE and TXA2 formation in a concentration-dependent manner. LDL had a strong inhibitory effect on TXA2 production and a weak inhibitory effect on 12-HETE production. VLDL had no effect on platelet AA metabolism. These findings point to a new facet of lipoproteins action and suggest that lipoproteins may have a physiological role in the regulation of AA metabolism in platelets