Recently, a radio-, and chemoprotective drug, WR-2721 (S-2-[3-aminopropylamino]-,ethylphosphorothioic acid) proved to be a potent inhibitor of parathyroid hormone (PTH) secretion. In human subjects, it not only decreased plasma Ca, but also induced a significant fall in the plasma magnesium level. In the present study in rats we investigated the mechanism(s) of this hypomagnesemic effect. In intact rats WR-2721 (0.7 mmol/kg s.c.) decreased plasma Mg from 0.96 +/- 0.03 to 0.67 +/- 0.02 mmol/l (p less than 0.001) within 2 h. In thyroparathyroidectomized (TPTX) animals plasma Mg fell from 0.93 +/- 0.03 to 0.72 +/- 0.03 mmol/l (p less than 0.001) 2 h after the same dose of WR-2721. In both intact and TPTX animals renal clearance experiments revealed that the WR-2721-induced hypomagnesemia was associated with an increase in urinary Mg excretion. This renal effect was not accompanied by a significant elevation in urinary sodium excretion, contrasting strikingly with the magnesuric action of furosemide. In bilaterally nephrectomized rats the hypomagnesemic effect of WR-2721 was abolished. Finally, the intracellular and/or tissue Mg contents of circulating lymphocytes, red blood cells, skeletal muscle, liver, bone and salivary glands were not significantly influenced by hypomagnesemic doses of WR-2721. In conclusion, these results indicate that the effects of WR-2721 on Mg metabolism cannot be ascribed to alterations in PTH and calcitonin secretion. Furthermore, they strongly suggest that the WR-2721-induced hypomagnesemia is mainly due to an inhibition of tubular Mg reabsorption.