Delayed Preconditioning-Mimetic Actions of Nitroglycerin in Patients Undergoing Exercise Tolerance Tests

Abstract

Background— Nitroglycerin (NTG) induces delayed preconditioning (PC)-mimetic effects in animal models and in humans during coronary angioplasty. We tested the hypothesis that NTG mitigates ischemia and enhances functional capacity during an exercise tolerance test (ETT) in patients with coronary artery disease. Methods and Results— Twenty-eight patients with stable angina and ischemia documented by a stress test were randomized in a double-masked, crossover design to receive a titrated intravenous infusion of NTG or normal saline over 4 hours. At 24 to 28 hours after study medication infusion, each patient underwent 2 ETTs separated by a 1-week washout period. Compared with control patients, pretreatment with NTG was associated with a dose-dependent increase in exercise duration averaging 40 seconds (412±19 versus 372±24 seconds, P =0.014) and an improvement in ECG manifestations of ischemia, as shown by a decrease in maximal ST-segment depression (1.84±0.14 versus 1.63±0.13 mm, P =0.011), sum of ST-segment depressions in 12 leads (7.64±1.01 versus 6.61±0.83 mm, P =0.027), and time to resolution of ST-segment depression (229±30 versus 207±28 s, P =0.018). These benefits occurred despite an increase in myocardial workload after NTG, as indicated by a higher peak rate-pressure product (24 492±1054 versus 22 536±1019 mm Hg/min, P =0.015). Conclusions— NTG produces a late PC-mimetic effect that mitigates the ECG manifestations of ischemia during exercise and improves exercise capacity. To our knowledge, this is the first study to demonstrate that NTG can alleviate exercise-induced ischemia 24 hours after its administration, long after the hemodynamic effects have subsided. The finding that nitrate-induced late PC ameliorates a common manifestation of coronary artery disease has potentially significant implications for the management of this disorder and for the design of clinical trials.