Patients with type-2 diabetes mellitus (T2DM) have exaggerated sympathetic activity and blood pressure responses to exercise. However, the underlying mechanisms for these responses, as well as how these responses change throughout disease progression, are not completely understood. For this study, we examined the effect of the progression of T2DM on the exercise pressor reflex, a critical neurocardiovascular mechanism that functions to increase sympathetic activity and blood pressure during exercise. We also aimed to examine the effect of T2DM on reflexive cardiovascular responses to static contraction, as well as those responses to tendon stretch when an exaggerated exercise pressor reflex was present. We evoked the exercise pressor reflex and mechanoreflex by statically contracting the hindlimb muscles and stretching the Achilles tendon, respectively, for 30 s. We then compared pressor and cardioaccelerator responses in unanesthetized, decerebrated University of California Davis (UCD)-T2DM rats at 21 and 31 wk following the onset of T2DM to responses in healthy nondiabetic rats. We found that the pressor response to static contraction was greater in the 31-wk T2DM [change in mean arterial pressure (∆MAP) = 39 ± 5 mmHg] but not in the 21-wk T2DM (∆MAP = 24 ± 5 mmHg) rats compared with nondiabetic rats (∆MAP = 18 ± 2 mmHg; P < 0.05). Similarly, the pressor and the cardioaccelerator responses to tendon stretch were significantly greater in the 31-wk T2DM rats [∆MAP = 69 ± 6 mmHg; change in heart rate (∆HR) = 28 ± 4 beats/min] compared with nondiabetic rats (∆MAP = 14 ± 2 mmHg; ∆HR = 5 ± 3 beats/min; P < 0.05). These findings suggest that the exercise pressor reflex changes as T2DM progresses and that a sensitized mechanoreflex may play a role in exaggerating these cardiovascular responses. NEW & NOTEWORTHY This is the first study to provide evidence that as type-2 diabetes mellitus (T2DM) progresses, the exercise pressor reflex becomes exaggerated, an effect that may be due to a sensitized mechanoreflex. Moreover, these findings provide compelling evidence suggesting that impairments in the reflexive control of circulation contribute to exaggerated blood pressure responses to exercise in T2DM.

Recent findings have shown that muscle contraction evokes an exaggerated pressor response in type 1 diabetes mellitus (T1DM) rats; however, it is not known whether the mechanoreflex, which is commonly stimulated by stretching the Achilles tendon, contributes to this abnormal response. Furthermore, the role of mechano-gated Piezo channels, found on thin-fiber afferent endings, in evoking the mechanoreflex in T1DM is also unknown. Therefore, in male and female streptozotocin (STZ, 50 mg/kg)-induced T1DM and healthy control (CTL) rats, we examined the pressor and cardioaccelerator responses to tendon stretch during the early stage of the disease. To determine the role of Piezo channels, GsMTx-4, a selective Piezo channel inhibitor, was injected into the arterial supply of the hindlimb. At 1 wk after STZ injection in unanesthetized, decerebrate rats, we stretched the Achilles tendon for 30 s and measured pressor and cardioaccelerator responses. We then compared pressor and cardioaccelerator responses to tendon stretch before and after GsMTx-4 injection (10 µg/100 ml). We found that the pressor (change in mean arterial pressure) response [41 ± 5 mmHg ( n = 15) for STZ and 18 ± 3 mmHg ( n = 11) for CTL ( P < 0.01)] and cardioaccelerator (change in heart rate) response [18 ± 4 beats/min for STZ ( n = 15) and 8 ± 2 beats/min ( n = 11) for CTL ( P < 0.05)] to tendon stretch were exaggerated in STZ rats. Local injection of GsMTx-4 attenuated the pressor [55 ± 7 mmHg ( n = 6) before and 27 ± 9 mmHg ( n = 6) after GsMTx-4 ( P < 0.01)], but not the cardioaccelerator, response to tendon stretch in STZ rats and had no effect on either response in CTL rats. These data suggest that T1DM exaggerates the mechanoreflex response to tendon stretch and that Piezo channels play a role in this exaggeration.

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, as 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 unanesthetized decerebrate rats, we compared the pressor and cardioaccelerator responses to intermittent muscle contraction before and after locally injecting grammostola spatulata mechanotoxin 4 (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 transient receptor potential cation (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 streptozotocin (STZ) rats (n = 8). GsMTx-4 attenuated the exaggerated early onset pressor and 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. NEW & NOTEWORTHY This is the first study to demonstrate that blocking Piezo channels is effective in ameliorating the exaggerated exercise pressor reflex evoked by intermittent muscle contraction, commonly occurring during physical activity, in T1DM. Thus, these findings suggest Piezo channels may serve as an effective therapeutic target to reduce the acute and prolonged cardiovascular strain that may occur during dynamic exercise in T1DM.

This is the first study to provide evidence that early-stage type 1 diabetes mellitus (T1DM) leads to an exaggerated exercise pressor reflex evoked by intermittent muscle contraction, resulting in substantially higher cardiovascular strain. These findings are significant as they indicate that interventions targeting the exercise pressor reflex may work to alleviate the increased cardiovascular strain and overall burden during exercise in T1DM.