title: Nephroprotective mechanism(s) of pentoxifylline: reduction of erythrocyte-mediated vascular congestion and inhibition of nitric oxide release.
abstract: The present study attempted to evaluate pentoxifylline's mechanism(s) of action in the prevention of acute renal failure by examining its vascular decongestant activity in a rat model for acute renal failure and inhibitory activity of nitric oxide release from activated macrophage-like (RAW 264.7 cells) and murine mammary adenocarcinoma (EMT-6 cells) cell lines. Radiolabeled chromium-erythrocytes were injected intravenously into all rats. Following occlusion of the left kidney for 45 minutes, rats were treated with pentoxifylline or normal saline. The medulla of the left (ischaemic) kidney had significantly higher radioactive counts than the right (control kidney) following an intravenous dose of normal saline. The medulla to whole blood radioactivity ratio of the left kidney was significantly greater than for the right (control) kidney. Animals administered intravenous pentoxifylline (5 mg/kg) had significantly lower radioactive counts in the medulla of the left (ischaemic) kidney than animals administered intravenous normal saline. No differences in radioactivity counts in the medulla of the left (ischaemic) kidney were observed when animals received intraperitoneal pentoxifylline (45 mg/kg) versus normal saline. In a second set of experiments the nitrite synthesis and percent cytotoxicity of pentoxifylline- and dexamethasone-treated cells were determined. Pentoxifylline at concentrations of 4 mM and 8 mM significantly decreased nitrite synthesis in RAW 264.7 cells, and at pentoxifylline concentrations of 2 mM, 4 mM, and 8 mM in EMT-6 cells compared to untreated cells. Dexamethasone at a concentration of 1 microM decreased nitrite synthesis in RAW 264.7 and EMT-6 cells compared to untreated cells. Pentoxifylline at concentrations of 0.5 mM through 8 mM significantly decreased cytotoxicity in RAW 264.7 and EMT-6 cells compared to untreated cells. Dexamethasone at a concentration of 1 microM decreased cytotoxicity in RAW 264.7 and EMT-6 cells compared to untreated cells. These finding suggest that pentoxifylline's ability to prevent acute renal failure may be a consequence of reduced vascular congestion and inhibition of nitric oxide release from activated macrophages.
authors.affiliation: Wyeth Laboratories, Inc., Philadelphia, PA 19101, USA.
authors.forename: K
authors.initials: K
authors.lastname: Vadiei
authors.forename: S D
authors.initials: SD
authors.lastname: Tucker
authors.forename: G
authors.initials: G
authors.lastname: Lopez-Berestein
authors.forename: K M
authors.initials: KM
authors.lastname: Wasan
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000187:drug effects*; D007511:Ischemia / Q000517:prevention & control; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism*; D007674:Kidney Diseases / Q000517:prevention & control*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D010431:Pentoxifylline / Q000494:pharmacology*; D016491:Peripheral Vascular Diseases / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012078:Renal Artery Obstruction / Q000517:prevention & control; D014407:Tumor Cells, Cultured
chemical_list: D009569:Nitric Oxide; D010431:Pentoxifylline