title: Olprinone reduces ischemia/reperfusion-induced acute renal injury in rats through enhancement of cAMP.
abstract: Activated leukocytes are implicated in development of ischemia/reperfusion (I/R)-induced organ injuries. Phosphodiesterase 3 inhibitors have anti-inflammatory effects by preventing cyclic adenosine monophosphate (cAMP) degradation. We examined the effects of olprinone, a specific phosphodiesterase 3 inhibitor, on I/R-induced acute renal injury model in rats. Forty-five minute renal I/R was induced in uni-nephrectomized rats. Rats were divided into a vehicle group, an olprinone group, and a dibutyril (DB) cAMP group. Olprinone (0.2 microg/kg/minute) infusion began 30 min after reperfusion and continued for 3 h. DBcAMP (5 mg/kg), a stable analog of cAMP, was intraperitoneally administered 5 min after reperfusion to clarify the effect of cAMP in our model. Olprinone reduced the I/R-induced increases in serum levels of blood urea nitrogen and creatinine, and improved histological changes, including acute tubular necrosis in the outer medulla. Hemodynamic status was not affected by olprinone. I/R-induced a decrease in renal tissue blood flow, an increase in renal vascular permeability, and an enhancement of leukocyte activation, reflected by renal tissue levels of myeloperoxidase activity, and the tissue levels of cytokine-induced neutrophil chemoattractant (an equivalent of human interleukin 8) and tumor necrosis factor-alpha were all significantly decreased by olprinone. Olprinone also increased the renal tissue and plasma levels of cAMP in rats subjected to renal I/R. DBcAMP showed similar effects. Our results indicated that olprinone reduced the I/R-induced acute renal injury, probably by inhibiting leukocyte activation. The effects of olprinone could be explained through its action on cAMP levels.
authors.affiliation: Division of Intensive Care Unit, Oita University Faculty of Medicine Hospital, Hasama-machi, Oita, 879-5593, Japan. mizutani@med.oita-u.ac.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Mizutani
authors.forename: Kazunori
authors.initials: K
authors.lastname: Murakami
authors.forename: Kenji
authors.initials: K
authors.lastname: Okajima
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Kira
authors.forename: Sachiko
authors.initials: S
authors.lastname: Mizutani
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Kudo
authors.forename: Junji
authors.initials: J
authors.lastname: Takatani
authors.forename: Koji
authors.initials: K
authors.lastname: Goto
authors.forename: Seiji
authors.initials: S
authors.lastname: Hattori
authors.forename: Takayuki
authors.initials: T
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D006439:Hemodynamics; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D007668:Kidney / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D002316:Cardiotonic Agents; D007093:Imidazoles; D016209:Interleukin-8; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D014409:Tumor Necrosis Factor-alpha; C059498:olprinone; D003404:Creatinine; D000242:Cyclic AMP; D009195:Peroxidase