Abstract Radiocontrast exposure is associated with vasoconstriction of the renal vascular bed and, in certain circumstances, with acute renal failure. This may be influenced by the volume of contrast infused or underlying disease, such as diabetes or renal failure. Changes in circulating vascular regulators, such as endothelin and atrial natriuretic peptide (ANP), may play a role in the development and/or prevention of acute renal failure. Nineteen patients undergoing arteriographic procedures were divided into two groups: large-volume contrast (≥150 mL; n = 7) and small-volume contrast (<150 mL; n = 12). Circulating endothelin levels increased significantly (from 12.3 ± 1.1 pmol/L to 19.4 ± 2.2 pmol/L; P < 0.05) following large-volume contrast exposure (group 1) but not following small-volume contrast exposure (group 2) (13.9 ± 1.7 pmol/L to 12.2 ± 0.09 pmol/L). ANP levels increased significantly in both groups: 43 ± 15 pg/mL to 75 ± 21 pg/mL in group 1 and 33 ± 16 to 106 ± 39 pg/mL in group 2. Data from an additional eight patients with underlying diabetes mellitus and/or renal insufficiency also were obtained and were considered separately. Endothelin levels were higher at baseline and increased significantly after contrast (25.7 ± 5 pmol/L to 55.4 ± 18 pmol/L) despite the relatively small average volume of contrast infused (112 ± 15 mL). ANP levels were also highest in these patients (211 ± 43 pg/mL precontrast and 323 ± 65 pg/mL postcontrast). No group had a significant change in serum creatinine following contrast exposure. In conclusion, large-volume radiocontrast exposure is associated with an increase in both circulating endothelin and ANP levels. Patients with underlying diabetes or renal insufficiency may have higher baseline levels and a greater tendency to increase endothelin after contrast exposure. While an increase in endothelin may contribute to renal vasoconstriction following radiocontrast exposure, simultaneous increases in ANP may serve to offset this response and protect against changes in renal function.