Effects of OKY-046 and nifedipine in cyclosporine-induced renal dysfunction in rats.
Cyclosporine (CsA) (37.4 mumol/kg per day for 7 days) treated female Wistar rats exhibited significantly decreased creatinine clearance (Ccr) and body weight loss (BWL), but had neither proteinuria (PU) nor alteration in their urine volume (V). Light microscopic (LM) sections of rat kidneys showed that all kidneys were affected by lesions, mainly diffuse vacuolization. These changes were associated with decreased urinary excretion ratios of 6-ketoprostaglandin F1 alpha to thromboxane B2 (6kPGF1 alpha/TXB2) and prostaglandin E2 to TXB2 (PGE2/TXB2). When OKY-046, a TXA2-synthetase inhibitor or nifedipine (NFD), a calcium channel blocker and an antagonist of endotheline (ET), were administered in addition to CsA, they restored Ccr and increased urine V but they did not prevent BWL. LM sections showed that only 5 or 7 out of 9 kidneys of animals were affected, respectively. These changes were associated with prevention of the diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 mainly in the OKY-046 treated animals. In conclusion, our results suggest that inhibitors of TXA2 or antagonists and/or inhibitors of endothelin play a protective role in the development of the dysfunction induced by CsA. However, the protection observed using OKY-046 and NFD did not reach that obtained by evening primrose oil (EPO) or Ketanserine (KTS), substances which prevented the fall of Ccr and BWL. Furthermore, with these protective agents only 5 out of 9 kidneys were affected and the lesions were of minor importance.
Papanikolaou
N
N
Centre Franco-Hellenique de Recherches Biomedicales, Hôpital Général d'Agrinion, Greece.
Darlametsos
I
I
Tsipas
G
G
Morphake
P
P
Bokas
S
S
Gkikas
G
G
Hornych
A
A
Bariety
J
J
Gkika
E L
EL
Karageorgou
I
I
Patsialos
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D003404:Creatinine / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000633:toxicity*; D004347:Drug Interactions; D015777:Eicosanoids / Q000652:urine; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005228:Fatty Acids, Essential / Q000627:therapeutic use; D005260:Female; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007650:Ketanserin / Q000627:therapeutic use; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000473:pathology; D008041:Linoleic Acids; D008657:Metabolic Clearance Rate; D008689:Methacrylates / Q000627:therapeutic use*; D009543:Nifedipine / Q000627:therapeutic use*; D031665:Oenothera biennis; D010938:Plant Oils; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000517:prevention & control*; D017965:gamma-Linolenic Acid
D002121:Calcium Channel Blockers; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D005228:Fatty Acids, Essential; D007166:Immunosuppressive Agents; D008041:Linoleic Acids; D008689:Methacrylates; D010938:Plant Oils; C028498:evening primrose oil; D017965:gamma-Linolenic Acid; D016572:Cyclosporine; D007650:Ketanserin; D003404:Creatinine; D009543:Nifedipine; C034364:ozagrel