PROJECT SUMMARY/ABSTRACT 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 heart rate, function to increase arterial blood flow and oxygen 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 afferents whose endings are located in and near the muscle interstitium. Group III and IV afferents are commonly affected by diabetes which often results in peripheral neuropathy causing a range of problems from allodynia to hyperalgesia to hypoalgesia as the disease progresses. Chronic inflammation is one of the known mechanisms for peripheral neuropathy, directly affecting group III and IV afferents, and is present in diabetes, aging, and cardiovascular disease. The overall goal of the experiments proposed is to shed light on the role of pro-inflammatory cytokines on the exercise pressor reflex as diabetes progresses. In the proposed experiments, we will pay particular attention to two important pro-inflammatory cytokines known to be upregulated in diabetics and those with cardiovascular disease, namely interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). We will also pay particular attention to two important anti-inflammatory cytokines known to be downregulated in diabetics and those with cardiovascular disease, namely interleukin 10 (IL-10), and interleukin 4 (IL-4).We will examine in decerebrated, unanesthetized rats the pressor, cardioaccelerator, and sympathetic activity responses to static and intermittent contraction both before and during pharmacological blockade of the cytokine receptors. The proposed experiments will also quantify the potential up-regulation or down-regulation of these circulating cytokines using serum samples in multiplex assays. We anticipate that these experiments will provide new information about the role of pro- and anti-inflammatory cytokines in the progression of diabetes on the autonomic control of circulation during exercise.