Pentamidine does not interfere with nitrite formation in activated RAW 264.7 macrophages but inhibits constitutive brain nitric oxide synthase.
Pentamidine effects on the interferon-gamma- or interferon-gamma plus bacterial lipopolysaccharide-induction of nitric oxide synthase in the macrophage cell line RAW 264.7, determined by measuring nitrite release into culture supernatants, were investigated. At concentrations above 10 microM, pentamidine caused visible toxic effects including cell lysis which also was assessed by measuring lactic dehydrogenase release. A progressive inhibitory effect of pentamidine could not be clearly dissociated from these toxic and lytic effects which were extensive at 100 microM. At 1 microM pentamidine, the dose response dependence of nitrite formation on interferon-gamma was not affected. Tumor necrosis factor-alpha caused some enhancement of interferon-gamma-induced nitrite release only at high doses of 100 and 10,000 unit/ml. Pentamidine had no effect on isolated inducible nitric oxide synthase from RAW 264.7 cells but inhibited the constitutive enzyme from pork cerebellum non-competitively. The lack of any stimulatory effect of pentamidine on nitrite production in RAW 264.7 cells suggests that NOS induction and NO production by macrophages is not the mechanism of the antimicrobial effects of this drug.
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology*; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D004790:Enzyme Induction; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism*; D010419:Pentamidine / Q000494:pharmacology* / Q000633:toxicity; D013552:Swine
D008070:Lipopolysaccharides; D009573:Nitrites; D010419:Pentamidine; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase