Nitroglycerin (NTG) patches provide potentially therapeutic NTG blood levels for 24 hours, but their effects on exercise tolerance (ExT) in patients with angina have not been well characterized. Therefore, blinded, randomized trials were performed of the acute effects of both low-dose and maximal-tolerated-dose NTG patches and placebo on ExT in 14 patients with coronary artery disease and typical exertional angina. The bicycle exercise protocol of the National Institutes of Health was used and sublingual NTG administered as a positive control. In 7 subjects, low-dose patches produced no statistically significant effect on ExT at 4, 8 or 24 hours after administration. Comparable doses of sublingual and oral isosorbide dinitrate, NTG ointment and transmucosal NTG in previous studies have produced effects similar to those of conventional doses of sublingual NTG. Maximally tolerated doses of 2 types of NTG patches were then tested. The first (n = 8, mean NTG dose delivered 25 mg) produced increases in ExT of 82 and 72 seconds at 4 and 8 hours, respectively (both p less than 0.01), but was ineffective at 24 hours. The second patch type (n = 5, mean NTG dose delivered 22 mg) was also ineffective at 24 hours. Furthermore, even at maximal doses, peak effects on ExT were about half of those of sublingual NTG. Thus, NTG patches, even at maximal doses, appear to have smaller therapeutic effects than other long-acting nitrates and are ineffective at 24 hours. These results suggest rapid attenuation of NTG effect during prolonged maintenance of constant blood levels.