Effects of ASIC3 Functional Knockout on the Exaggerated Exercise Pressor Reflex in Type 1 Diabetes Mellitus Rats

Research suggests that individuals with type 1 diabetes mellitus (T1DM) experience exaggerated blood pressure responses during exercise, although the mechanisms for this response are unknown. Activation of acid-sensing ion channel 3 (ASIC3) on the peripheral ends of thinly myelinated and unmyelinated afferents evokes the exercise pressor reflex in healthy conditions and contributes to peripheral neuropathy in those with T1DM. Furthermore, peripheral blockade and functional knockout (KO) of the ASIC3 attenuates the exercise pressor reflex in rats with cardiovascular diseases. However, it remains to be determined if ASIC3 also contributes to the exaggerated exercise pressor reflex in those with T1DM. Therefore, the purpose of this study was to determine the role of ASIC3 in exaggerating the exercise pressor reflex in T1DM rats. We hypothesized that functional KO of ASIC3 would normalize the exercise pressor reflex evoked by static muscle contraction. To test this, we used adult, male (n=42) and female (n=30) Wistar-Kyoto ASIC3 KO T1DM (n=27; body weight: 349 ± 82 g, blood glucose: 484 ± 60 mg/dl), ASIC3 KO healthy (n=21; body weight: 365 ± 97 g, blood glucose: 110 ± 10 mg/dl), Wild Type (WT) T1DM (n=14; body weight: 291 ± 88 g, blood glucose: 489 ±17 mg/dl), and WT healthy (n=7; body weight: 312 ± 72 g, blood glucose: 106 ± 12 mg/dl) rats. Streptozotocin (50 mg/kg) was injected intraperitoneally in fasted, anesthetized rats to induce T1DM, and a random blood glucose over 300 mg/dl was used to diagnose diabetes. One week later, the exercise pressor reflex was evoked in unanesthetized, decerebrated rats by statically contracting the hindlimb muscles for 30 s. Peak changes (Δ) in mean arterial pressure (MAP) and heart rate (HR) were calculated by subtracting 30 s of baseline activity. One-way ANOVA with Tukey post hoc was used to compare means among groups. Data is represented as mean ± SD. We found that peak pressor and cardioaccelerator responses to static contraction were significantly lower in KO T1DM compared with WT T1DM. (Δ MAP KO T1DM: 14 ± 6 mmHg vs. WT T1DM: 27 ± 10 mmHg; p<0.001, and ΔHR KO T1DM: 11 ± 8 bpm vs. WT T1DM: 20 ± 10 bpm; P=0.005). However, KO T1DM responses to static contraction were similar to healthy KO and healthy WT rats. (Δ MAP KO T1DM: 14 ± 6 mmHg vs. KO healthy: 14 ± 4 mmHg; p>0.99, KO T1DM: 14 ± 6 mmHg vs. WT healthy: 16 ± 6 mmHg; P=0.99, and ΔHR KO T1DM: 11 ± 8 bpm vs. KO healthy: 11 ± 5 bpm; p>0.99, KO T1DM: 11 ± 8 mmHg vs. WT healthy: 14 ± 8 bpm; P=0.98). Our findings suggest that ASIC3 play a significant role in exaggerating the exercise pressor reflex in T1DM rats. This project was supported by NIH R01HL 166323. This abstract was presented at the American Physiology Summit 2025 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.