ALKYLATING AGENTS AND THE EFFECTS OF ANTIDIURETIC HORMONE IN THE TOAD BLADDER

¹ Department of Pharmacology, State University of New York, Upstate Medical Center, Syracuse, New York

Mechlorethamine, a potent alkylating agent of the nitrogen mustard class, can interfere with the ability of antidiuretic hormone to increase the short-circuit current, the oxygen consumption and the net movement of water across the isolated urinary bladder of the toad. The same effect of mechlorethamine was noted when adenosine 3',5'-phosphate (cyclic AMP) rather than vasopressin was used to stimulate short-circuit current or water movement. Cysteine or sodium thiosulfate, when present in the system prior to addition of the nitrogen mustard, afforded some protection against these inhibitory effects on stimulation of short-circuit current. Increasing the concentration of vasopressin or cyclic AMP in the medium in the short-circuit current experiments did not result in reversal of the nitrogen mustard effect, which suggests that the inhibition is not competitive. Amphotericin B, a polyene antibiotic with the ability to atimulate short-circuit current in the toad bladder, was not inhibited by mechlorethamine. Thus the effect of the alkylating agent appears to show some specificity. Also, the finding suggests that the mechanisms by which amphotericin B and vasopressin affect the short-circuit current differ in some way. These findings support the hypothesis that the water diuresis which has been observed after administration of some of the alkylating agents results from inhibition of the effects of antidiuretic hormone at the renal tubular level. That this effect is related to these compounds' ability to alkylate biologically active centers is further indicated by the fact that Dibenamine, a compound with a single moiety capable of alkylation, can also block the vasopressin-induced stimulation of short-circuit current.