Cisplatin is an
antineoplastic agent. Several nephrotoxic effects are associated with its use including chronic and
acute renal failure, renal
magnesium wasting, and
polyuria. We have investigated
polyuria in groups of rats treated with
cisplatin at doses of 2.5 and 5 mg/kg
body weight given once weekly for 3 weeks to determine possible mechanisms of this impairment. After
cisplatin administration, glomerular filtration rate was reduced and significant increases in
sodium and water loss were also seen. These changes were associated with decreases in urinary cAMP. Inner medullary collecting duct (IMCD) cells were removed from these animals and were stimulated with graded doses of
vasopressin. Cells from
cisplatin-treated rats showed an impaired response in cAMP generation to
vasopressin stimulation as compared to cells from normal animals. To determine more precisely the site of impairment, the
adenylate cyclase complex of the IMCD cells was further studied with
forskolin and NaF.
Forskolin was used to probe the catalytic unit activating
adenylate cyclase, and NaF the
guanine nucleotide regulatory
protein (
G protein). In response to
forskolin, cells from
cisplatin-treated rats and normal rats responded similarly in generating cAMP. However, following NaF, the cAMP response was blunted in the cells from the
cisplatin rats. These results suggested that the catalytic unit was not injured by
cisplatin (
forskolin study) but the
G protein was (NaF). In conclusion, the present study suggests that the
polyuria seen following
cisplatin administration is associated with an end-organ resistance to
vasopressin manifested by reduced cAMP generation, secondary in part or whole to a defect at the level of the
G protein.