Organic nitrate-induced oxidant stress and cardiovascular therapy

Abstract

First clinically introduced in the 19th century, organic nitrates are likely to remain the mainstay of nitrovasodilator-based therapy of angina pectoris, acute myocardial infarction and congestive heart failure well into the future. However, the utility and affordability of continuous cardiovascular disease management with organic nitrates has historically been compromised by the rapid development of nitrate tolerance, the requirement for nitrate-free periods and rebound phenomena. While recent landmark research has proposed a novel nitrate-induced oxidant stress mechanism of nitrate tolerance that may be readily modifiable in the clinic, the implications of these findings for the future of nitric oxide (NO) pharmacotherapy in cardiovascular disease have yet to be fully explored. In particular, organic nitrate-induced oxidant stress may not only have a pivotal role in attenuating organic nitrate bioconversion and vascular NO bioavailability vis-à-vis nitrate tolerance development, but may also potentially aggravate both endothelial dysfunction and insulin resistance in cardiovascular disease and Type 2 diabetes. Such deleterious actions may now help account for the disappointing neutral effects of organic nitrate therapy on mortality in coronary care documented in large-scale clinical trials.

• cardiovascular disease
• endothelial dysfunction
• insulin resistance
• nitrate tolerance
• nitric oxide
• organic nitrates
• oxidant stress
• Type 2 diabetes