Twenty-one patients with documented coronary atherosclerotic heart disease were studied to determine the effect of high dose oral isosorbide dinitrate (ISDN) on heart rate, blood pressure, and exercise time until angina pectoris. Patients were tested in two phases, initially with 0.4 mg of sublingual nitroglycerin and with sublingual placebo, and then with oral ISDN, mean dose 29 mg, and oral placebo. Both phases of the study were conducted in a randomized, double-blind, crossover manner. After ISDN was compared to oral placebo, heart rate increased at 30 to 300 min (P less than 0.01) (peak increase 18 beats/min at 60 min), and systolic blood pressure decreased from 45 to 300 min (P less than 0.005) (peak decrease 18 mm Hg at 60 min). Exercise time at 2 min after sublingual nitroglycerin increased 51% as compared to oral placebo, exercise time increased 54% at 1 hr (P less than 0.005), 37% at 3 hr (P less than 0.01), and 12% at 5 hr (NS). Twelve of 21 patients (57%) improved their exercise time until angina larger than or equal to 25% at 1 hr after oral ISDN. The exercise response to sublingual nitroglycerin was a good predictor of this response to oral ISDN.