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Diesel-Induced Vascular Dysfunction: Role of Endothelin

Nancy L. Kanagy1, Matthew J. Campen2, and Benjimen R. Walker1
1University of New Mexico Vascular Physiology Group, Albuquerque, NM;
2Lovelace Respiratory Research Institute, Albuquerque, NM

EPA Grant Number: RD831860

Project Description:

There is a clear association between air pollution exposure and cardiovascular mortality. However, the mechanisms linking air pollution to cardiovascular events are poorly understood. Inhalation of particulate matter (PM) air pollution has been shown to increase the release of vasoactive cytokines such as endothelin while individuals with vascular disease have augmented vasoconstrictor responses to this peptide. Therefore, diesel exhaust-released endothelin could contribute to air pollution-induced cardiovascular events in sensitized individuals. We propose to use a novel model of endothelindependent hypertension and endothelial dysfunction, paired with state-of-the-art methods for generating whole diesel exhaust, to investigate cardiovascular effects of PM. Our recent studies demonstrate that simulating sleep apnea by exposing rats to 90 second episodes of intermittent hypoxia/hypercapnia (IH) for 8 hours a day causes hypertension that is reversed by endothelin antagonists and associated with increased endothelin synthesis, augmented endothelin vasoconstriction and both right and left ventricular hypertrophy. Our preliminary studies show that whole diesel exhaust stimulates ET-1 synthesis and increases oxidative stress. Our central hypothesis is that inhalation of whole DE augments ROS stimulation of ET vasoconstriction in rats with IH-induced hypertension. Our specific aims are: (1) To determine the effect of 6 hours of DE inhalation on plasma and tissue ET levels in Sham and IH hypertensive rats. These studies will test the hypothesis that DE stimulated ET synthesis is augmented in IH rats. We will examine tissue and plasma levels of ET-1, -2, and -3 and vascular expression of ETA- and ETB-receptors. (2) To determine the role of ROS in ET synthesis in IH and Sham rats at baseline and following DE inhalation. These studies will determine if elevated basal ROS levels sensitize IH rats to DE stimulation of ET vasoconstriction and if DE stimulation of ROS is necessary for increased ET synthesis. Tissue and plasma thiobarbiturate reactive substances (TBARS) will be measured at baseline and following DE inhalation as a measure of ROS generation. The effect of systemic antioxidants (Tempol 30 mg/kg/day) on ET synthesis will determine the contribution of ROS to DE stimulation of ET synthesis. These studies will be conducted as part of an ongoing collaboration between Nancy Kanagy and Ben Walker of the Vascular Physiology Group (VPG) at the University of New Mexico and Dr. Matthew Campen at the Lovelace Respiratory Research Institute (LRRI). This unique research collaboration between NIEHS Center members brings together expertise in environmental exposure toxicology and cardiovascular/hypertension physiology.

 



 



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