Mechanisms of augmented coronary artery constriction following exposure to diesel exhaust.

摘要

Numerous epidemiology studies demonstrate that acute increases in air pollutants correlate with an increase in cardiovascular disease-related mortality. The pollutant diesel exhaust (DE) has been shown to impair both flow-mediated and agonist-induced dilation of the brachial artery, used as a surrogate for coronary artery function. It is speculated that enhanced sensitivity to the endogenous vasoconstrictor ET-1 impairs cardiac blood flow and contributes to the immediate onset of myocardial ischemia and infarction in humans following DE exposure. In addition, impaired endothelium-dependent dilation can be improved with the restoration of nitric oxide (NO) synthase (NOS) activity. We therefore sought to determine the mechanism by which inhalation of DE impairs coronary artery function by assessing responses to ET-1 and to the endothelium-dependent vasodilator acetylcholine (ACh) in arteries from rats exposed to DE compared to responses in arteries from rats exposed to filtered air. Given that DE is a source of reactive oxygen species (ROS) we hypothesized that inhaled DE generates ROS which uncouples NOS-dependent dilation to augment coronary artery constriction. We observed augmented vasoconstrictor sensitivity to ET-1 and blunted vasodilator response to ACh in coronary arteries following DE exposure. Interestingly, these alterations in vascular reactivity appear to result not only from the loss of NO, but also from a gain in NOS-derived constrictors. Furthermore, basal activity of NOS was not altered by DE exposure. Elevated ROS are known to oxidize and deplete tetrahydrobiopterin (BH 4) a necessary cofactor that prevents the uncoupling of NOS. ROS scavenging or BH4 supplementation prevented the generation of superoxide in isolated arteries as did NOS inhibition. These treatments also restored dilation to ACh. Therefore, acute inhalation of DE appears to deplete bioavailable BH4, uncouple NOS and lead to NOS-dependent superoxide generation. The increased oxidative stress likely scavenges and decreases synthesis of NO leading to endothelial dysfunction which may contribute to the acute coronary events initiated by air pollution.