The role of P2X3 receptors in evoking the exaggerated exercise pressor reflex in type 1 diabetes mellitus rats

Previous studies suggest blood pressure (BP) responses to exercise are exaggerated in individuals with type 1 diabetes mellitus (T1DM), increasing their risk for myocardial infarctions and strokes. Purinergic 2X3 receptors (P2X3R) on group III and IV skeletal muscle afferent endings contribute to the exercise pressor reflex in both healthy and diseased states, as well as play a role in diabetic neuropathy through activation via increased adenosine triphosphate (ATP) release from peripheral tissues and nerves. Therefore, the purpose of this study was to determine the role of P2X3R in evoking the exaggerated exercise pressor reflex in T1DM rats. We hypothesized that pharmacologically blocking P2X3R would attenuate the exaggerated BP and heart rate (HR) responses evoked during static muscle contraction and tendon stretch in T1DM rats. This study was conducted using adult male and female Wistar-Kyoto T1DM rats (n=4; body weight: 330±95g). Streptozotocin (STZ) (50 mg/kg), an antineoplastic agent which causes pancreatic β-cell death, was injected into fasted, anesthetized rats to induce T1DM, and a random blood glucose >300 mg/dL was used to confirm diabetes. Three weeks post injection, the exercise pressor reflex was evoked in unanesthetized decerebrated rats before and after infusion of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) (10mg/kg), a selective P2X antagonist that blocks contractions induced by ATP, into the hindlimb circulation, while blood flow was occluded by a reversible snare around the iliac artery. Peak changes (Δ) in HR, mean arterial pressure (MAP), and BP index (BPi; blood pressure response over time) were recorded during static muscle contraction and tendon stretch before and after PPADS infusion. Using a paired Student’s t-test, we found that peak pressor responses to static contraction were significantly lower following PPADS infusion compared to before in T1DM rats (Δ MAP before: 31±4 mmHg vs. after: 7±1 mmHg; n=4; p=0.027). Peak pressor responses to tendon stretch were also significantly lower following PPADS infusion compared to before in T1DM rats (Δ MAP before: 28±12 mmHg vs. after 13±12 mmHg; n=4; p=0.004). Results also showed that Δ BPi was significantly lower following infusion of PPADS during tendon stretch compared to before in T1DM rats (Δ BPi before: 569±380 mmHg*s vs. after: 108±162 mmHg*s; n=4; p=0.033). These findings suggest that P2X3R play a role in exaggerating both the peak pressor response to muscle contraction and the pressor response throughout the duration of the contraction. Furthermore, P2X3R also play a role in evoking the mechanical component of the exercise pressor reflex in T1DM rats. Future studies are needed to determine if these findings are due to increased sensitivity of P2X3R or upregulation of P2X3R in T1DM rats. This project was supported by NIH R01HL 166323. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.