IS THERE A BENEFICIAL EFFECT OF THE CALCIUM-CHANNEL BLOCKER DILTIAZEMON CYCLOSPORINE-A NEPHROTOXICITY IN RATS

To investigate whether or not there is a beneficial effect of diltiaze m (D) on cyclosporine A (CsA) nephrotoxicity, renal function, CsA bloo d levels, and effects of CsA on biotransformation in the liver and on lipid peroxidation were characterized in rats. A single administration of D (60 mg/kg b.wt.) reduced urinary volume (UV), GFR and excretion of Na+ and K+, whereas a single dose of CsA (60 mg/kg b.wt.) alone had no respective effects. P-aminohippurate excretion was almost equal in all groups. Lower doses of D land CsA) were without effects. After re peated CsA treatment a retardation in body weight gain was seen, with little effect of a co-administration with D hereon. In all tests, thym us mass was reduced by CsA, the weight of spleen, liver, adrenal gland s, and kidney were not generally affected by any of the treatments. Fu rthermore, after repeated administration of CsA and/or D, urinary volu me, GFR and Na+ excretion were reduced by CsA, too. Electrolyte concen trations in plasma showed no evident changes by any of the treatments for Na+ and Ca2+. After long time treatment, CsA and CsA + D quite sim ilarly led to higher K+ but lower Mg2+ concentrations in plasma. Only with 7 days highest dosage treatment PAH excretion was reduced signifi cantly by CsA and CsA + D treatment. Surprisingly, CsA levels measured in blood and in kidney tissue, showed lower values after co-administr ation with D compared to CsA treatment alone. This could be caused by higher activities of monooxygenase functions revealed after pretreatme nt with D alone. Reduced glutathione (GSH) contents in kidney were ele vated in CsA and CsA + D treated groups. In general no significant dif ferences were to be observed concerning lipid peroxidation and stimula ted H2O2 formation. Altogether evident protective effects of diltiazem on CsA nephrotoxicity in rats could not be proven.