Peripheral edema without fluid retention is a common side effect of treatment with calcium antagonists (CA). The possibility that CA may alter extracellular fluid partition between plasma and interstitium, as suggested for atrial natriuretic peptide (ANP) was explored in binephrectomized anesthetized rats by measuring changes in hematocrit and plasma protein concentration during infusion of synthetic 103-126 ANP (Wy 47.663) and the dihydropyridine derivate nicardipine. After a forty minutes infusion of ANP (1 microgram/kg/mn), hematocrit and plasma protein increased 9.1 +/- 0.3 and 3.9 +/- 0.3 p. 100 respectively; the calculated loss of plasma volume during ANP infusion was 14.5 +/- 1.1 p. 100 as compared to 3.9 +/- 0.6 p. 100 in rats receiving vehicle only. Infusion of nicardipine at 1 microgram/kg/mn increased hematocrit by 5.7 +/- 0.2 p. 100 (corresponding to a 9.1 +/- 0.9 p. 100 decrease in plasma volume), and plasma proteins by 3.7 +/- 0.2 p. 100. To document and localize an alteration in vascular leak of proteins induced by the drugs, albumin-bound Evans blue (EB) extravasation was measured spectrophotometrically in different tissues after extraction by methyl-formamide. Both ANP and nicardipine increased vascular penetration of EB-albumin, mainly in skeletal and cardiac muscle; no changes was observed in brain, liver, spleen as compared to rats receiving the vehicle; ANP but not nicardipine increase EB-albumin permeability in intestine. These results suggest that nicardipine as well as ANP reduce plasma volume by increasing vascular leak of fluids and macromolecules.