Male Wistar rats were injected intraperitoneally for 3 consecutive days with hydrochlorothiazide (HCTZ; 15 mg/kg), chlorothiazide (CTZ; 100 mg/kg), bendroflumethiazide (BFTZ; 1.5 mg/kg), chlorthalidone (CHLOR; 15 mg/kg), methyclothiazide (METH; 1.0 mg/kg) or metolazone (MET; 1.5 mg/kg). Magnesium content was measured in the hypothalamus, medulla oblongata, cerebral cortex, heart, skeletal muscle and serum. Although there was no consistent alteration of Mg in the serum, skeletal muscle and heart, there was a significant effect on hypothalamic and medullary Mg. Compared to a control value of 17.20 +/- 1.24 mEg/kg in the hypothamus there was a decrease by HCTZ (26%; p less than 0.01), CTZ (24%; p less than 0.01) and BFTZ (30%; p less than 0.01). Similarly, there was a decrease by HCTZ (22%; p less than 0.01), CTZ (30%; p less than 0.01) and BFTZ (25%; p less than 0.01) on Mg in medulla. In contrast MET increases Mg in hypothalamus (31%; p less than 0.01) and medulla (26%; p less than 0.01). Furthermore, digoxin infusion (0.051 ml/min) in animals pretreated with HCTZ induced arrhythmias earlier than in animals receiving digoxin alone (30 vs. 60 min; p less than 0.01). The effects of digoxin toxicity in HCTZ-pretreated animals were partially reversed by CNS administration of 50 micrograms of Mg. These findings strongly suggest that thiazide-induced depletion of Mg in the CNS predisposes to digoxin intoxication.