The antihypertensive effect of calcium antagonists is altered little by high salt intake or concomitant diuretic treatment. We therefore investigated whether modest changes in the salt balance might alter the acute response of the renin-angiotensin system to the calcium antagonist isradipine in conscious rabbits. Mongrel rabbits with indwelling arterial and venous catheters were pretreated with either a single subcutaneous injection of 20 mg/kg furosemide 24 h before the experiment [sodium depletion (SD)] or the addition of 0.45% NaCl to the drinking water, which was available ad libitum for 24 h [sodium loading (SL)]. Compared with SL, SD pretreatment modestly increased plasma renin activity and lowered body weight; mean arterial pressure and heart rate were unchanged. Isradipine (10, 30, and 100 micrograms/kg) infused into the femoral vein catheter decreased blood pressure and increased heart rate similarly in both groups. Increases in plasma renin activity plotted as a function of the decreases in blood pressure showed a significantly steeper slope in SD than in SL animals. When blood pressure started to recover 15 min after the end of drug infusion, plasma renin activity decreased in SL animals only. Therefore, SL or SD strongly influences the responsiveness of the renin-angiotensin system to calcium antagonists, and this may be one reason why high salt intake does not diminish the antihypertensive effect of calcium antagonists and a calcium antagonist/diuretic combination may not yield optimal therapeutic results.