The hemodynamic and anti-ischemic efficacy of organic nitrates is rapidly blunted due to the development of nitrate tolerance. The mechanisms underlying this phenomenon remain poorly understood and likely involve several independent factors. More recent experimental observations suggest that tolerance may be the consequence of intrinsic abnormalities of the vasculature, including enhanced vascular superoxide and endothelin production. Superoxide anions degrade nitric oxide derived from nitroglycerin, whereas autocrine-produced endothelin within vascular smooth muscle sensitizes the vasculature to circulating neurohormones, such as catecholamines and angiotensin II, all of which may compromise the vasodilator potency of nitroglycerin. Interestingly, these vascular consequences of in vivo nitroglycerin treatment can be mimicked by incubating cultured endothelial and smooth muscle cells with angiotensin II. Further, nitrate tolerance and rebound following sudden cessation of prolonged nitroglycerin therapy can be prevented by concomitant treatment with high-dose angiotensin-converting enzyme inhibition or angiotensin-I receptor blockade. These data strongly suggest that increased circulating levels of angiotensin II, which are encountered during in vivo nitroglycerin treatment, initiate cellular events that ultimately attenuate the nitroglycerin vasodilator effects during prolonged treatment periods.