Acid‐Sensing Ion Channels Blockade Attenuates Pressor and Sympathetic Responses to Skeletal Muscle Metaboreflex Activation in Humans

Abstract

In animals, the blockade of acid‐sensing ion channels (ASICS), cation pore‐forming membrane proteins located in the free nerve endings of group IV afferent fibers that are activated by acidic pH transients, attenuates reflex increases in sympathetic nerve activity (MSNA) and blood pressure (BP) during muscle contraction. These findings indicate that ASICS have an important role in mediating the metabolic component (skeletal muscle metaboreflex) of the exercise pressor reflex in animal models. Nonetheless, it is still unclear whether these findings can be translated to humans. We then tested the hypothesis that ASICS play a role in evoking the skeletal muscle metaboreflex in humans, quantifying beat‐by‐beat mean BP (MBP, Finometer), MSNA (peroneal nerve, microneurography) and heart rate (HR, ECG) in 11 healthy young men (N = 11) during rest, static handgrip exercise (SHE, 2 min at 35% of the MVC) and post‐exercise muscle ischemia (PEMI, 2 min) before (BFA) and after local infusion of amiloride (AFA −0.75 mg/mL), an antagonist of ASICs, in saline (2.5% of total forearm volume) via modified Bier block (regional intravenous anesthesia). In an additional protocol, participants (N = 7) underwent the experimental procedures before (BFS) and after (AFS) venous infusion of a similar amount of saline via modified Bier block. MBP responses were slightly but significantly attenuated during SHE after amiloride infusion (BFA +29.6 ± 6.1 vs. AFA +24.3 ± 7.0 mmHg, p = 0.001). A smaller increase in MSNA (N = 9) was also observed as a consequence of ASICs blockade (BFA +14.5 ± 9.6 vs. AFA +10.7 ± 6.5 bursts/min, p = 0.004). Equivalent SHE‐induced increases in HR were observed before and after ASICs blockade (p > 0.05). Amiloride infusion attenuated the PEMI‐induced increases in both MBP (BFA +25.8 ± 6.9 vs. AFA +16.3 ± 6.4 mmHg, p = 0.0001) and MSNA (BFA +16.2 ± 9.2 vs. AFA +8.4 ± 8.0 bursts/min, p = 0.0001). In the additional protocol, SHE‐evoked increases in MBP (BFS +28.7 ± 12.2 vs. AFS +27.0 ± 9.8 mmHg, p = 0.477), MSNA (N = 5, BFS +10.0 ± 8.6 vs. AFS +13.0 ± 9.4 burst/min, p = 0.208) and HR (BFS +32.0 ± 12.4 vs. AFS +37.2 ± 22.5 bpm/min, p = 0.265) did not differ before and after saline infusion. Similar observations were obtained for MBP (BFS +24.2 ± 14.2 vs. AFS +23.7 ± 10.4 mmHg, p = 0.830) and MSNA (BFS +10.0 ± 8.6 vs. AFS +13.0 ± 9.4 burst/min, p = 0.208) during PEMI. Therefore, these findings indicate that ASICs play a role in evoking pressor and sympathetic responses to both SHE and isolated activation of the skeletal muscle metaboreflex in humans.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.