Temporal changes in the exercise pressor reflex in type 1 diabetic rats

Grotle, Ann-Katrin; García, Elena Gómez; Huo, Yu; Stone, Audrey J.

doi:10.1152/ajpheart.00399.2017

Cited by 20 publications

(31 citation statements)

References 33 publications

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“… 29 Moreover, Grotle et al indicated that at 6 weeks after STZ treatment, the pressor and cardioaccelerator responses to contraction were significantly attenuated in diabetic rats, suggesting that afferent activity decreases to some extent. 30 Our experiments show that these diabetic rats exhibit mechanical allodynia at 6 weeks after induction ( Figure 2A , 4 weeks: P <0.05; 2, 4, and 6 weeks: P <0.01). This result is in agreement with the previous observation that Paulson et al reported.…”

Section: Resultsmentioning

confidence: 54%

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Zhou

Liu

et al. 2018

JPR

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ObjectiveThe dorsal horn P2Y13 receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1β and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y13 receptor in rats with diabetic neuropathic pain (DNP).MethodsA rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y13 receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr1336, and pTyr1472 NR2B in rat spinal dorsal horn.ResultsCompared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y13 receptor, Iba-1, IL-1β, and IL-6 in the dorsal spinal cord that was continued for 6 weeks in DNP rats. The data obtained indicated that, in DNP rats, administration of MRS2211 significantly attenuated mechanical allodynia. Compared with DNP rats, after MRS2211 treatment, expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y13 receptor, Iba-1, IL-1β, and IL-6 at 6 weeks after the STZ injection. MRS2211 suppressed JAK2 and STAT3 expression in the early stage, but not in the later stage. Moreover, pTyr1336 NR2B was significantly decreased, whereas pTyr1472 NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats.ConclusionIntrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y13 receptor downregulates levels of IL-1β and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y13 receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.

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Section: Resultsmentioning

confidence: 54%

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Zhou

Liu

et al. 2018

JPR

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“…Both animal and human studies have shown that, in chronic diseases such as heart failure (20), hypertension (39), type 2 diabetes (29), and peripheral artery disease (14,55), blood pressure responses to exercise are exaggerated. We recently extended these findings to include the early stages of type 1 diabetes mellitus (T1DM) in rats (23). However, the underlying mechanisms contributing to the exercise pressor reflex dysfunction in T1DM are not known.…”

Section: Introductionmentioning

confidence: 99%

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

Grotle

García

Harrison

et al. 2019

American Journal of Physiology-Regulatory, Integrative and Comp

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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.

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“…Metabolic stimuli evoke the metaboreflex by stimulating primarily group IV afferent endings, whereas mechanical stimuli evoke the mechanoreflex by stimulating primarily group III afferent endings (26,35). Previous studies have shown that the exercise pressor reflex is exaggerated in cardiovascular-related diseases such as heart failure (36,50), peripheral artery disease (3,47), hypertension (2,32) and type-1 diabetes (16). Type-2 diabetes mellitus (T2DM) is also considered a cardiovascular-related disease, as individuals with T2DM are two-to fourfold more likely to die from a cardiovascular-related event than those without T2DM, an effect that, in turn, is associated with disease duration and severity (17,51).…”

Section: Introductionmentioning

confidence: 99%

Exaggerated cardiovascular responses to muscle contraction and tendon stretch in UCD type-2 diabetes mellitus rats

Grotle

Crawford

Huo

et al. 2019

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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Temporal changes in the exercise pressor reflex in type 1 diabetic rats

Cited by 20 publications

References 33 publications

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

Exaggerated cardiovascular responses to muscle contraction and tendon stretch in UCD type-2 diabetes mellitus rats

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Temporal changes in the exercise pressor reflex in type 1 diabetic rats

Cited by 20 publications

References 33 publications

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1&beta; and IL-6 in rats with diabetic neuropathic pain

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1&beta; and IL-6 in rats with diabetic neuropathic pain

Exaggerated mechanoreflex in early-stage type 1 diabetic rats: role of Piezo channels

Exaggerated cardiovascular responses to muscle contraction and tendon stretch in UCD type-2 diabetes mellitus rats

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Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain

Activation of spinal dorsal horn P2Y<sub>13</sub> receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic pain