Asic3 In Skeletal Muscle Contributes To The Exaggerated Exercise Pressor Reflex In Type 1 Diabetic Rats

Individuals with type 1 diabetes (T1D) experience exaggerated blood pressure responses during exercise. Acid-sensing ion channel 3 (ASIC3), expressed on thinly myelinated afferents, contributes to the exercise pressor reflex under healthy conditions and is implicated in T1D-related neuropathy. Although it has been shown that pharmacological blockade of ASIC3 attenuates the exercise pressor reflex in cardiovascular disease, its role in T1D remains unknown. PURPOSE:Investigate the role of ASIC3 in the exercise pressor reflex in T1D rats. We hypothesized that local blockade of ASIC3 in skeletal muscle would normalize the exaggerated reflex cardiovascular responses to static muscle contraction. METHODS: Adult male (n=5) and female (n=3) Wistar-Kyoto T1D rats (n=8; body weight: 349 ± 82 g; blood glucose: 485 ± 55 mg/dl) were studied. T1D was induced with streptozotocin (50 mg/kg) in fasted rats and confirmed by random blood glucose levels >300 mg/dl. Following decerebration, the exercise pressor reflex was evoked in unanesthetized rats by statically contracting the hindlimb muscles for 30 s. Peak changes in mean arterial pressure (MAP) and heart rate (HR) were measured before and after injecting APETx2 (ASIC3 antagonist) into the superficial epigastric artery with both the iliac artery and vein occluded. ASIC3 protein expression in L4–L5 dorsal root ganglia (DRG) was assessed by Western blot analysis in both T1D and healthy rats. Paired t-tests were performed to compare ΔMAP and ΔHR responses to static contraction before and after APETx2 injection. Data are presented as mean ± SD. RESULTS: Peak MAP and HR responses to static contraction were significantly reduced following local ASIC3 blockade with APETx2 in T1D rats compared with before injection (ΔMAP: before 26 ± 7 vs. after 13 ± 5 mmHg, P < 0.001; ΔHR: before 18 ± 9 vs. after 11 ± 5 bpm, P = 0.04). However, there was no significant difference in ASIC3 protein expression in DRGs between T1D and healthy rats (STZ 329 ± 290 vs. healthy 241 ± 162 AU, p=0.78). CONCLUSION: These findings indicate that ASIC3 may play an important role in evoking an exaggerated exercise pressor reflex in T1D, but this is independent of channel protein expression. This work was supported by NIH R01HL166323.