Diethylcarbamazine inhibits endothelial and microfilarial prostanoid metabolism in vitro.
Diethylcarbamazine (DEC) rapidly lowers the number of microfilariae in the peripheral circulation. The mechanism of action is unknown, but may involve alterations of arachidonic acid metabolism in vascular tissues. We studied the effects of DEC on arachidonic acid metabolism by bovine pulmonary arterial endothelium monolayers, human platelets and Brugia malayi microfilariae. DEC at a concentration of 2.5 microM, a level achieved in vivo, rapidly decreased prostacyclin, prostaglandin E2 and thromboxane B2 release from endothelial monolayers by 78% (P less than 0.001), 57% (P = 0.05), and 75% (P less than 0.05), respectively. High-pressure liquid chromatography of extracts of endothelial monolayers incubated with DEC showed similar inhibition of these cyclooxygenase pathway products, but exposure to the drug did not result in formation of new eicosanoids. DEC did not inhibit endothelial phospholipase A2-dependent release of arachidonate from membrane stores, whereas prostaglandin H2 synthase activity (cyclooxygenae, EC 1.14.99.1) was reduced to a degree similar to that effected by acetylsalicylic acid. Microfilarial but not platelet synthesis of cyclooxygenase products was also reduced by DEC. These data suggest that the mechanism by which DEC lowers the level of microfilariae in the circulation may in part involve its effects on host endothelial and parasite eicosanoid production.
Kanesa-thasan
N
N
Case Western Reserve University, Department of Pediatrics, OH.
Douglas
J G
JG
Kazura
J W
JW
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002009:Brugia / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004049:Diethylcarbamazine / Q000494:pharmacology*; D015777:Eicosanoids / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008842:Microfilariae / Q000187:drug effects* / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism; D054467:Phospholipases A2; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*
D015777:Eicosanoids; D011453:Prostaglandins; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A; D054467:Phospholipases A2; D004049:Diethylcarbamazine