# Project 3: Role Played by ASIC, P2X and EP4 Receptors in the Exercise Pressor Reflex in Health and Simulated PAD

> **NIH NIH P01** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2020 · $426,356

## Abstract

PROJECT SUMMARY/ABSTRACT – PROJECT 3
A reflex arising from the contraction of hindlimb skeletal muscles is an important neural mechanism that is
responsible for the cardiovascular adjustments to exercise. These adjustments, which include increases in
peripheral vascular resistance, cardiac contractility and rate, function to increase arterial blood flow and oxygen
supply to the exercising muscles, and in turn support their ability to contract. This neural mechanism has been
named the exercise pressor reflex and its afferent arm is comprised of group III and IV fibers whose endings
are located in and near the muscle interstitium. In patients with peripheral artery disease (PAD) the exercise
pressor reflex is exaggerated. The overall goal of the experiments proposed in this unit is to shed light on the
metabolic factors occurring in contracting muscles that are responsible for evoking this PAD-induced
exaggeration of the reflex. Metabolic factors produced by contracting skeletal muscles are believed to signal
the spinal cord and brain that the arterial blood supply to working muscle does not meet its metabolic demand.
These metabolites are therefore prime candidates for stimulating the group III and IV afferents responsible for
evoking the exaggerated exercise pressor reflex in PAD. In the proposed experiments, we will pay particular
attention to three important metabolic by-products of contraction, namely Lactic Acid, which stimulates the
ASIC3 channel, Prostaglandin E2, which stimulates the endoperoxide (EP)4 receptor, and ATP which
stimulates the P2X3 receptor. We will examine in decerebrated unanesthetized rats the responses to
contraction of group III and IV muscle afferents both before and during either pharmacological blockade of the
above receptors or after they have been “knocked down” with siRNA. The proposed experiments will also
examine the responses to contraction of these thin fiber afferents before and during knockdown of
myophosphorylase in the triceps surae muscles. The proposed experiments will be performed both in rats with
freely perfused femoral arteries and in rats with femoral arteries that have been ligated for 72 hours before the
start of the experiment. The latter preparation simulates the arterial blood flow patterns seen in patients with
PAD and therefore serves as a useful animal model of this disease. The proposed experiments are anticipated
to provide new information about metabolic factors that cause the exercise pressor reflex to be exaggerated in
PAD.

## Key facts

- **NIH application ID:** 9857652
- **Project number:** 5P01HL134609-04
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** Marc Peter Kaufman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $426,356
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857652

## Citation

> US National Institutes of Health, RePORTER application 9857652, Project 3: Role Played by ASIC, P2X and EP4 Receptors in the Exercise Pressor Reflex in Health and Simulated PAD (5P01HL134609-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9857652. Licensed CC0.

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