During physical activity, the exercise pressor reflex, a feed-back mechanism originating in skeletal muscle, increases mean arterial pressure and heart rate to ensure that the working muscle is provided with adequate blood flow and oxygen. The exercise pressor reflex is comprised of group III afferents and group IV afferents, which have been shown to be activated by the chemical by-products of muscle metabolism. Interestingly, the exercise pressor reflex has been shown to elicit exaggerated circulatory responses in rats with simulated peripheral artery disease. Peripheral arterial disease leads to ischemia of the limbs and can cause intermittent claudication. It is possible that muscle metabolites, specifically prostaglandins, are partially responsible for the exaggerated cardiovascular response to exercise pressor reflex activation observed in the rat model of this disease, as they have been shown to contribute to exercise pressor reflex activation. Exercise has been proven to improve walking economy in patients with peripheral artery disease by increasing collateral blood flow and microcirculation expression of vasodilators and by decreasing urinary excretion of thromboxane B2, the stable metabolite of thromboxane A2. Therefore, the proposed study will test the hypotheses that thromboxane A2, formed when prostaglandins are hydroxylized, is increased in peripheral artery disease and contributes to the exaggerated exercise pressor reflex and that treadmill training decreases thromboxane A2 production and, subsequently, the cardiovascular response to exercise pressor reflex activation in rats with simulated peripheral artery disease. With the proposed experiments, I will attempt to describe skeletal muscle thromboxane A2 levels both at rest and during static contraction in rats with and without simulated peripheral artery disease. Additionally, the contribution of thromboxane A2 to the exercise pressor reflex in peripheral artery disease will be elucidated by using thromboxane A2 receptor antagonists to attenuate the circulatory response to hindlimb contraction. These experiments will then be repeated in rats with and without simulated peripheral artery disease that have been subjected to a treadmill training program. Specifically, these studies will address how exercise training affects thromboxane A2 production during rest and isometric contraction and describe how exercise augments the circulatory response to exercise pressor reflex activation in healthy rats and rats with simulated peripheral artery disease.

Public Health Relevance

The proposed studies will ascertain what role the muscle metabolic by-product thromboxane A2 and its receptor has on the exaggerated exercise pressor reflex response observed in peripheral artery disease. Additionally, these experiments will help describe if and how treadmill training alleviates the exaggerated pressor and sympathetic responses elicited by exercise pressor reflex activation via reductions in thromboxane A2 production in rats with induced arterial insufficiency. These studies may lead to novel treatments that could potentially increase walking tolerance in individuals suffering from peripheral artery disease and reduce the risks and pain associated with physical activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL108406-03
Application #
8448112
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Meadows, Tawanna
Project Start
2011-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
3
Fiscal Year
2013
Total Cost
$53,942
Indirect Cost
Name
Pennsylvania State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Leal, Anna K; Stone, Audrey J; Yamauchi, Katsuya et al. (2013) Blockade of B2 receptors attenuates the responses of group III afferents to static contraction. Neurosci Lett 555:231-6
Leal, Anna K; Yamauchi, Katsuya; Kim, Joyce et al. (2013) Peripheral ?-opioid receptors attenuate the exercise pressor reflex. Am J Physiol Heart Circ Physiol 305:H1246-55
Leal, Anna K; McCord, Jennifer L; Tsuchimochi, Hirotsugu et al. (2011) Blockade of the TP receptor attenuates the exercise pressor reflex in decerebrated rats with chronic femoral artery occlusion. Am J Physiol Heart Circ Physiol 301:H2140-6