Extramural Research
Presentation Abstract
Grantee Research Project Results
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.