GsMTx-4 normalizes the exercise pressor reflex evoked by intermittent muscle contraction in early-stage type 1 diabetic rats.

Emerging evidence suggests the exercise pressor reflex is exaggerated in early-stage type 1 diabetes mellitus (T1DM). Piezo channels may play a role in this exaggeration since blocking these channels attenuates the exaggerated pressor response to tendon stretch in T1DM rats. However, tendon stretch constitutes a different mechanical and physiological stimuli than that occurring during muscle contraction. Therefore, the purpose of this study was to determine the contribution of Piezo channels in evoking the pressor reflex during an intermittent muscle contraction in T1DM. In unanaesthetized, decerebrate rats we compared the pressor and cardioaccelerator responses to intermittent muscle contraction before and after locally injecting GsMTx-4 (0.25 µM) into the hindlimb vasculature. Although GsMTx-4 has a high potency for Piezo channels, it has also been suggested to block TRPC channels. We, therefore, performed additional experiments to control for this possibility by also injecting SKF 96365 (10 µM), a TRPC channel blocker. We found that local injection of GsMTx-4, but not SKF 96365, attenuated the exaggerated peak pressor (ΔMAP before: 33±3 mmHg, after: 22±3 mmHg, p=0.007) and pressor index (ΔBPi before: 668±91 mmHg·s, after: 418±81 mmHg·s, p=0.021) response in STZ rats (n=8). GsMTx-4 attenuated the exaggerated early-onset pressor as well as the pressor response over time, which eliminated peak differences as well as those over time between T1DM and healthy controls. These data suggest that Piezo channels are an effective target to normalize the exercise pressor reflex in T1DM.