To evaluate whether there is cross-tolerance to the circulatory effects of isosorbide dinitrate and nitroglycerin, six subjects were given 120 mg/day of sustained-action isosorbide dinitrate in three divided doses for six to eight weeks. Prior to and during the last week of long-term isosorbide dinitrate administration, the effects of sublingually given nitroglycerin (0.9 mg) on plethysmographically measured calf blood flow and venous volume at 30 mm Hg (VV[30]) were measured on three occasions and averaged. Although the arteriolar dilation produced by nitroglycerin was unaltered by isosorbide dinitrate, the venodilation was significantly attenuated. The VV[30] increased from 3.00 to 3.28 ml/100 ml (P less than .02) with nitroglycerin prior to isosorbide dinitrate administration, but failed to increase with nitroglycerin during the long-term administration of isosorbide dinitrate (2.95 to 2.95 ml/100 ml, P greater than .5).