Effect of ketanserine in cyclosporine-induced renal dysfunction in rats

Cyclosporine (CsA)-treated female Wistar rats, in dose of 37.5 microM (45 mg)/kg/day for 7 days, exhibited significantly decreased creatinine clearance (Ccr), and provoked body weight loss (BWL), which is consistent with the development of nephrotoxicity (NT). Urine volume (V) did not change and proteinuria (PU) was not provoked. These changes were associated with significantly diminished ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 excretions. Light-microscopic (LM) sections of rat kidneys showed that all kidneys were affected but the lesions (mainly diffuse vacuolization) were reversible. When CsA-treated animals were pretreated with ketanserine (KTS), which antagonizes (a) the direct vasoconstrictor effect of serotonin (5-HT), and (b) the amplifying effects of 5-HT on other vasoactive substances (such as noradrenaline (NA), alpha 1-receptors, histamine, H2 receptors, and prostaglandin F2 alpha), Ccr and urine volume significantly increased, BWL was partially prevented and the ratios of urinary PGE2/TXB2 and 6kPGF1 alpha/TXB2 excretions were significantly enhanced. LM sections showed that only 5 of 9 rats were affected but the lesions were of less importance. These observations indicate that the NT induced by CsA in our studies was mediated by 5-HT, a potent vasoconstrictor agent, and by the metabolites of arachidonic acid. However, other vasoactive agents and additional mechanisms could also be implicated.