Cardioaccelerator Responses Research Articles

The stimulant cathine from Khat causes tachycardia indirectly in the rat.

Leaves of the Khat plant are widely consumed in the Horn of Africa, Yemen and the Jazan region of Saudi Arabia. I have investigated the mode of cardiovascular and autonomic actions of the stimulant cathine from Khat in terms of direct or indirect adrenergic actions in anaesthetised male and female rats, and in isolated tissues. Male and female rats were anaesthetised with pentobarbitone and changes in diastolic blood pressure and cardioaccelerator responses were examined in vehicle-treated or chemically sympathectomised rats. Cathine produced marked tachycardia and smaller blood pressure responses in vehicle-treated animals, with significant rises in heart rate occurring at cathine (0.1mg/kg). In sympathectomised rats, cardiac actions were greatly attenuated in both male and female animals, with no differences between male and female rats. Although pressor responses to cathine were relatively small, sympathectomy significantly reduced these responses in female, but not male, rats. In rat aorta and spleen, cathine produced almost no direct contractions. It is concluded that cathine acts predominantly indirectly, presumably by the release of noradrenaline, in both male and female rats to produce cardiovascular actions. This may have implications for adverse cardiovascular actions of consumption of the plant Khat, particularly with dried Khat, in which actions of cathine may predominate over those of cathinone.

Role of ASIC3 in Evoking the Exercise Pressor Reflex in Type 1 Diabetes Mellitus Rats

Previous studies have suggested that the exercise pressor reflex is exaggerated in individuals with type 1 diabetes mellitus (T1DM); however, the mechanisms responsible for this altered reflex are poorly understood. Acid-sensing ion channel 3 (ASIC3) likely contributes to this exaggeration as previous studies found that peripheral blockade, as well as functional knockout (KO) of the ASIC3 gene, prevented the exaggeration of exercise pressor reflex in rats with cardiovascular-related diseases. However, whether ASIC3 plays a similar role in the exaggerated exercise pressor reflex in T1DM is currently unknown. Therefore, the purpose of this study was to determine whether ASIC3 contributes to the exaggerated exercise pressor reflex in T1DM rats. We hypothesized that the exaggerated exercise pressor reflex would be attenuated in ASIC3 KO T1DM rats compared to their wild-type (WT) counterparts. To test this, we used adult, male and female Wistar-Kyoto ASIC3 KO (n=3; body weight: 348 ± 84 g) and WT counterparts (n=5; body weight: 318 ± 112 g) rats. Streptozotocin (50 mg/kg) was injected intraperitoneally in fasted anesthetized rats to induce T1DM, and a random blood glucose over 300 mg/dl was used to diagnose diabetes. One week later, the exercise pressor reflex was evoked in unanesthetized, decerebrated rats by statically contracting the hindlimb muscles for 30 s. Peak mean arterial pressure (MAP) and heart rate (HR) were calculated as the highest change (Δ) during 30 s contraction baseline. We found that the peak pressor and cardioaccelerator responses to static contraction, although is not statistically significant, appear to be lower in ASIC3 KO (ΔMAP: 17 ± 14 mmHg; ΔHR: 13 ± 12 bpm), compared to WT rats (ΔMAP: 23 ± 11 mmHg; P=0.26 ΔHR:23 ± 9 bpm; P=0.11). Furthermore, we found that within female rats, the peak pressor and heart rate responses were lower in ASIC3 KO (n=1) rat (ΔMAP: 7 mmHg; ΔHR: 15 bpm) compared to WT rats (n=3) (ΔMAP: 27 ± 12 mmHg; ΔHR: 27 ± 11 bpm). Our preliminary findings suggest that ASIC3 may play a role in the exaggerated exercise pressor reflex in T1DM rats and that sex differences may also be present. Further studies involving larger sample sizes will reveal if trends from the current results become significant. This project was supported by NIH R01HL 166323-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Inhibiting Cyclooxygenase Activity Attenuates the Exaggerated Exercise Pressor Reflex in Male UCD-Type 2 Diabetes Mellitus Rats

It is well established that prostaglandins, a product of cyclooxygenase (COX) enzymes contribute to evoking the exercise pressor reflex. Previous studies suggest that COX expression is upregulated in the peripheral nerves of those with type 2 diabetes (T2D), likely due to low grade inflammation associated with the disease. The purpose of this study was to determine if COX activity in the exercising skeletal muscle exaggerates the exercise pressor reflex in T2D. We hypothesized that inhibiting COX activity in the hindlimb would reduce the exaggerated pressor response to muscle contraction in T2D rats. To do this, we evoked the exercise pressor reflex by statically contracting the skeletal muscle for 30s in unanesthetized, decerebrate rats. Experiments were performed on male University of California Davis (UCD)-T2D (n=8; body weight: 526 ± 42g) and Sprague Dawley rats (n=3; body weight: 473 ± 10g). Changes (Δ) in peak mean arterial pressure (MAP) and heart rate (HR) responses to exercise were compared before and after locally injecting indomethacin (1 mg/kg in 0.2 mL of 100 mM sodium carbonate), a COX 1 and 2 inhibitor, or its vehicle (0.2 mL of 100 mM sodium carbonate) into the arterial supply of the ipsilateral (contracting) and contralateral (non-contracting) hindlimb. Data are presented as mean ± SD. We found that local injection of indomethacin into the contracting hindlimb reduced the exaggerated peak pressor (ΔMAP: 30 ± 14 mmHg to 18 ± 8 mmHg; P<0.01) but not cardioaccelerator (ΔHR: 21 ± 8 bpm to 19 ± 11 bpm; P=0.59) responses in T2D rats, but did not reduce these responses in healthy rats (ΔMAP 14 ± 3 mmHg to 14 ± 6 mmHg; P>0.99; ΔHR: 10 ± 5 bpm to 13 ± 7 bpm; P=0.67). Conversely, local injection of indomethacin into the non-contracting hindlimb (n=4), as well as injection of the vehicle in the contracting hindlimb (n=4), did not affect the pressor response to muscle contraction in T2D rats. Developed tensions during muscle contraction were similar for all comparisons. In summary, our findings suggest that COX activity contributes to the exaggerated pressor response to muscle contraction in T2D rats. This project was supported by NIH R01 HL144723. This project was supported by NIH R01 HL144723. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of acute hyperglycemia on the exercise pressor reflex in healthy rats.

The exercise pressor reflex is exaggerated in type 2 diabetes mellitus (T2DM). Hyperglycemia, a main characteristic of T2DM, likely contributes to this exaggerated response. However, the isolated effect of acute hyperglycemia, independent of T2DM, on the exercise pressor reflex is not known. Therefore, the purpose of this study was to determine the effect of acute, local exposure to hyperglycemia on the exercise pressor reflex and its two components, namely the mechanoreflex and the metaboreflex, in healthy rats. To accomplish this, we determined the effect of an acute locol intra-arterial glucose infusion (0.25g/mL) on cardiovascular responses to static contraction (i.e., exercise pressor reflex) and tendon stretch (i.e., mechanoreflex) for 30s, as well as hindlimb intra-arterial lactic acid (24mM) injection (i.e., metaboreflex) in fasted unanesthetized, decerebrated Sprague-Dawley rats. We measured and compared changes in mean arterial pressure (MAP) and heart rate (HR) before and after glucose infusion. We found that acute glucose infusion did not affect the pressor response to static contraction (ΔMAP: before: 15±2mmHg, after: 12±2mmHg; n=8, p>0.05), tendon stretch (ΔMAP: before: 12±1mmHg, after: 12±3mmHg; n=8, p>0.05), or lactic acid injection (ΔMAP: before: 13±2mmHg, after: 17±3mmHg; n=9, p>0.05). Likewise, cardioaccelerator responses were unaffected by glucose infusion, p>0.05 for all. In conclusion, these findings suggest that acute, local exposure to hyperglycemia does not affect the exercise pressor reflex or either of its components.

Acute Effect Of Hyperglycemia On The Mechanoreflex And Metaboreflex

Recent studies in both humans and rodents have shown that the mechanoreflex and metaboreflex are exaggerated in type 2 diabetes mellitus (T2DM). Hyperglycemia is a main characteristic of T2DM and is known to cause damage to both cardiovascular and nervous system structures. However, the effects of the presence of hyperglycemia on the mechanoreflex and metaboreflex are not known. PURPOSE: To determine the acute effect of hyperglycemia on the mechanoreflex and metaboreflex. METHODS: Experiments were conducted after an overnight fast in unanesthetized, decerebrated healthy male and female Sprague-Dawley rats. The mechanoreflex was evoked by stretching the Achilles tendon for 30 s and the metaboreflex was evoked by locally injecting lactic acid (0.2ml, 24mM) into the hindlimb. Time and dosage for glucose infusion were selected based on a preliminary study that showed infusing 250 mg/ml of glucose solution for 15 min into the hindlimb circulation, with blood flow to and from the hindlimb restricted, would elevate local blood glucose concentration to the same degree as that seen in T2DM rats with an exaggerated exercise pressor reflex. To elicit an acute hyperglycemia environment while preventing an endogenous insulin response, somatostatin (3.9 ug/100 ul) was infused systemically and simultaneously along with local glucose infusion. Changes in mean arterial pressure (ΔMAP) and heart rate (ΔHR) in response to tendon stretch and lactic acid injection were measured and compared before and after infusion. RESULTS: We found that the peak pressor and cardioaccelerator responses to tendon stretch were not significantly affected by acute hyperglycemia (ΔMAP before: 12 ± 2 mmHg, after: 12 ± 3 mmHg, n=6, p>0.05; ΔHR before: 10 ± 3 bpm; after: 10 ± 3 bpm, n=6, p>0.05). Likewise, the pressor and cardioaccelerator responses to lactic acid were not significantly affected by acute hyperglycemia (ΔMAP before: 13 ± 2 mmHg, after: 16 ± 3 mmHg, n=10, p>0.05; ΔHR before: 10 ± 2 bpm, after: 12 ± 5 bpm, n=10, p>0.05). CONCLUSIONS: The acute presence of hyperglycemia in the local circulation of the hindlimb does not contribute to the exaggerated mechanoreflex or metaboreflex. This project was supported by NIH R01 HL144723.

Contribution of TRPC channels in evoking the exercise pressor reflex and mechanoreflex in healthy and type 1 diabetic rats

The exercise pressor reflex and the mechanoreflex are exaggerated in type 1 diabetes mellitus (T1DM) rats. Studies using GsMTx‐4, which has high potency for Piezo channels, have suggested that Piezo channels play a significant role in evoking this exaggerated response. However, studies have also reported that GsMTx‐4 may block TRPC1 and TRPC6 channels at similar concentrations. Therefore, to account for the possible effects of GsMTx‐4 on TRPC1 and TRPC6 channels, the purpose of this study was to determine whether TRPC channels contribute to the exercise pressor reflex and the mechanoreflex in both healthy and T1DM rats.MethodsStudies were conducted in adult unanesthetized, decerebrated T1DM (STZ; Streptozotocin 50 mg/kg i.p) and healthy control (CTL) Sprague Dawley rats. The exercise pressor reflex was evoked by intermittently contracting the hindlimb for 30 s and the mechanoreflex was evoked by stretching the Achilles tendon for 30 s. Changes in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were continuously measured and compared before and after injecting a TRPC channel antagonist, namely SKF 96365 (0.1ml, 10μM or 100μM).ResultsSKF 96365 (100μM) had no effect on the peak pressor response to muscle contraction in either STZ rats (ΔMAP before: 37 ± 9 mmHg, ΔMAP after: 32 ± 12 mmHg, n=2, p>0.05) or CTL rats (before: 16 ± 3 mmHg, after: 5 ± 2 mmHg, n=3, p>0.05). The cardioaccelerator response to muscle contraction was unaffected by SKF 96365 in STZ rats (before: 25 ± 1 bpm, after: 21 ± 6 bpm, n=2, p>0.05), whereas it was attenuated in CTL rats (before: 13 ± 4 bpm, after: 4 ± 4 bpm, n=3, p<0.05). The sympathetic response to muscle contraction was unaffected by SKF 96365 in CTL rats (%ΔRSNA before: 138 ± 108 %, %ΔRSNA after: 181 ± 41 %, n=2, p>0.05). The peak pressor response to tendon stretch was unaffected by SKF 96365 in STZ (before: 42 ± 9 mmHg, after: 34 ± 10 mmHg, n=3, p>0.05) and CTL rats (before: 16 ± 3 mmHg, after: 16 ± 2 mmHg, n=4, p>0.05). Likewise, the cardioaccelerator response to tendon stretch was unaffected by SKF 96365 in STZ (before: 25 ± 4 bpm, after: 36 ± 12 bpm, n=3, p>0.05) and CTL rats (before: 13 ± 2 bpm, after: 14 ± 2 bpm, n=4, p>0.05). The sympathetic response to tendon stretch was unaffected by SKF 96365 in CTL rats (%ΔRSNA before: 98 ± 94 %, %ΔRSNA after: 94 ± 104 %, n=2, p>0.05). Furthermore, a lower concentration of SKF 96365 (10μM) had no effect on the peak pressor (before: 33 ± 20 mmHg, after: 31 ± 18 mmHg, n=2, p>0.05) or cardioaccelerator (before: 23 ± 9 bpm, after: 22 ± 6 bpm, p>0.05) responses to muscle contraction in STZ rats. Similarly, the peak pressor (before: 29 ± 15 mmHg, after: 16 ± 3 mmHg, n=2, p>0.05) and cardioaccelerator (before: 29 ± 15 bpm, after: 16 ± 3 bpm, n=2, p>0.05) responses to tendon stretch were unaffected by SKF 96365 (10μM) in STZ rats.ConclusionThese preliminary findings suggest that TRPC channels do not play a role in evoking the exercise pressor reflex or the mechanoreflex in T1DM and healthy rats. Thus, it is unlikely that the attenuating effect of GsMTx‐4 on the exercise pressor reflex is due to its effect on TRPC channels.

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

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.

Cyclooxygenase inhibition does not impact the pressor response during static or dynamic mechanoreflex activation in healthy decerebrate rats.

Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex independent of contraction-induced metabolite production. Cyclooxygenase (COX) metabolites, however, are produced by skeletal muscle stretch in vitro and have been found to impact various models of mechanoreflex activation. Whether COX metabolites influence the decerebrate rat triceps surae muscle stretch mechanoreflex model remains unknown. We examined the effect of rat triceps surae muscle stretch on the interstitial concentration of the COX metabolite prostaglandin E2 (PGE2). Interstitial PGE2 concentration was increased above baseline values by 4 min of both static (38% increase, P = 0.01) and dynamic (56% increase, P < 0.01) triceps surae muscle stretch (n = 10). The 4-min protocol was required to collect enough microdialysis fluid for PGE2 detection. The finding that skeletal muscle stretch in vivo was capable of producing COX metabolites prompted the hypothesis that intra-arterial administration of the COX inhibitor indomethacin (1 mg/kg) would reduce the pressor and cardioaccelerator responses evoked during 30 s (the duration most commonly used in the rat mechanoreflex model) of static and dynamic rat triceps surae muscle stretch. We found that indomethacin had no effect (P > 0.05, n = 9) on the pressor or cardioaccelerator response during 30 s of either static or dynamic stretch. We conclude that, despite the possibility of increased COX metabolite concentration, COX metabolites do not activate or sensitize thin-fiber muscle afferents stimulated during 30 s of static or dynamic hindlimb skeletal muscle stretch in healthy rats.

The Acute Effect of Hyperglycemia on the Exercise Pressor Reflex

Previous work has shown that the exercise pressor reflex is exaggerated in type 2 diabetic rats that present with hyperglycemia. Although it is likely that chronic hyperglycemia plays a role, no studies have isolated the acute effects of high blood glucose levels on this reflex. Therefore, the purpose of the current study was to determine the acute effects of hyperglycemia on the exercise pressor reflex. We first determined the glucose concentration needed to increase local blood glucose level in the hindlimb vasculature to a similar level seen in our type 2 diabetic rats that had an exaggerated exercise pressor reflex. To do this, healthy Sprague‐Dawley rats were infused over 20 min with one of two different concentrations of glucose (125 mg/ml, male n=3 or 250 mg/ml, male n=3) into the arterial supply of the left hindlimb with blood flow to and from the hindlimb restricted. At the same time somatostatin (3.9 ug/100 ul) was infused systemically in order to prevent an endogenous insulin response. Blood glucose was measured every two minutes from both hindlimbs to determine how long it would take to bring blood glucose concentration up to the desired level. We then determined the acute effect of glucose on the pressor and cardioaccelerator responses during static contraction of the hindlimb. The exercise pressor reflex was evoked in healthy, unanesthetized, decerebrated Sprague‐Dawley rats by statically contracting the hindlimb muscle for 30 seconds before and after 15 minutes of either glucose (250 mg/ml) or saline infusion, while mean arterial pressure and heart rate were recorded. We found that infusing 250 mg/ml of glucose significantly raised blood glucose levels to 486 ± 84 mg/dl by the 3rd minute compare to the control leg. However, infusing 125 mg/ml of glucose did not raise blood glucose concentration to 546 ± 33 mg/dl until the 11th minute compare to the control leg (p&lt;0.05). Therefore, we decided to use 250 mg/ml glucose for the exercise pressor experiment. We then found that acutely infusing 250 mg/ml of glucose into the arterial supply of the hindlimb did not significantly affect the pressor (ΔMAP before glucose: 13 ± 0.4 mmHg; after glucose: 12 ± 0.8 mmHg, n=4; before saline: 11 ± 2 mmHg; after saline: 10 ± 2 mmHg, n=3; p&gt;0.05) or cardioaccelerator (ΔHR before glucose: 14 ± 1 bpm; after glucose: 12 ± 2 bpm, n=4; before saline: 14 ± 3 bpm; after saline: 12 ± 4 bpm, n=3; p&gt;0.05) responses to static contraction. We conclude that the acute presence of glucose in the circulation of the hindlimb muscles plays no role in exaggerating the exercise pressor reflex.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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

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 anesthetized, 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.

Methylhexaneamine causes tachycardia and pressor responses indirectly by releasing noradrenaline in the rat

We have investigated the mode of cardiovascular action of the stimulant methylhexaneamine (MHA) in terms of direct or indirect adrenergic actions in anaesthetised rats. Male and female rats were anaesthetised with pentobarbitone and pressor (changes in diastolic blood pressure) and cardioaccelerator responses to MHA were examined in vehicle treated or chemically sympathectomised rats. MHA produced pressor and cardioaccelerator responses over the same dose range in vehicle treated animals, with significant cardioaccelerator and pressor responses occurring at MHA (0.1 mg/kg). However, tachycardia was more marked than pressor responses. In sympathectomised rats, cardiac and pressor actions of MHA were greatly attenuated. MHA was also studied in isolated tissues. In rat vas deferens, MHA produced small tonic contractions, but these were virtually abolished by sympathectomy In rat aorta, MHA produced almost no contractions. These results are also consistent with largely indirect actions. There were no differences between male and female rats. It is concluded that MHA acts predominantly indirectly in both male and female rats causing noradrenaline release to produce cardiovascular actions and that as a result pressor and cardiac responses occur at similar doses. This propensity for MHA to cause tachycardia and rises in blood pressure at similar doses range may have implications for adverse cardiovascular actions.

Type 2 Diabetic Rats Develop Exercise Pressor Reflex Dysfunction Over Time: New Insight Into Aging With Diabetes

Type 2 diabetes Mellitus (T2DM) patients have an augmented sympathetic activity and cardiovascular response to exercise. The exercise pressor reflex, which is evoked by mechanical and metabolic stimuli arising from contracting muscle, and results in an increase in mean arterial pressure and heart rate, may contribute to this augmented response. Studies have shown that the exercise pressor reflex is augmented in several cardiovascular related diseases including T2DM; however, it is not known how the exercise pressor reflex is expressed in aging T2DM rats. Therefore, the purpose of this study was to determine the expression of the exercise pressor reflex with aging in T2DM rats. We measured the exercise pressor reflex in unanaesthetized, decerebrated UC Davis T2DM rats and healthy (CTL) Sprague Dawley rats by statically contracting the hindlimb for 30 s while mean arterial pressure (MAP) and heart rate (HR) were continuously measured. Young (4 mo old) adult T2DM rats (BW: 594±15 g, glucose: 337±73 mg/dl, HbA1c: 7.4±0.3%) and older (12 mo old) adult T2DM rats (BW: 546±26 g, glucose: 549±28 mg/dl, HbA1c: 12.82±0.18%), were compared to adult CTL rats (BW:465±18 g, glucose: 200±14 mg/dl, HbA1c: 4.73±0.1%). We found that the pressor (younger T2DM: ΔMAP=21±5 mmHg, n=4; older T2DM: ΔMAP=39±5 mmHg, n=5; CTL: ΔMAP=17±2 mmHg, n=8; p&lt;0.05) but not cardioaccelerator (younger T2DM: ΔHR=16±4 bpm, n=4; older T2DM: ΔHR=19±7 bpm, n=5; CTL: ΔHR=14±1 bpm, n=8; p&gt;0.05) responses to static contraction were significantly greater in the older adult T2DM, but not in the younger T2DM rats compared to the CTL rats. Developed tension was similar for all group comparisons, p&gt;0.05. We conclude that older T2DM rats develop an augmented exercise pressor reflex to static contraction of the hindlimb, but this hyper‐reactivity is not present in younger T2DM rats. In a population where exercise is typically prescribed as a treatment modality, an augmented exercise pressor reflex can put these individuals at a higher risk for experiencing cardiovascular events while exercising.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Development and Progression of Mechanical Allodynia in UC, Davis Type 2 Diabetic Rats

Type 2 diabetes (T2DM) is a metabolic disorder that can lead to many neuropathic complications such as mechanical allodynia, which is perceived pain caused by a normally non‐painful stimulus. T2DM is also associated with exaggerated pressor and cardioaccelerator responses to skeletal muscle contraction, namely the exercise pressor reflex. The mechanisms by which diabetes elicits these effects are not fully understood; however, both mechanical allodynia and the exercise pressor reflex are evoked by thin‐fiber afferent activity. The purpose of this study was to utilize noninvasive techniques to monitor the development and progression of diabetes‐induced neuropathy in thin‐fiber afferents. We used male UC Davis T2DM (n=9) rats from the age of 4 to 7 months to model the progression of T2DM. We took monthly measurements of blood glucose, HbA1c, and body weight. We also measured changes in mechanical sensitivity using von Frey filaments. Filaments were applied to the L5 dermatome on the plantar side of the left and right hind paws, between the footpads; the lowest force eliciting an abrupt paw withdrawal was measured and averaged between paws. We found that blood glucose (4mo: 255±28 mg/dl, 5mo: 366±50 mg/dl, 6mo: 417±58 mg/dl, 7mo: 453±49 mg/dl) and HbA1c (4mo: 5.7±0.2%, 5mo: 6.6±0.4%, 6mo: 9.3±1.2%, 7mo: 10.3±1.2%) were above the diabetic threshold (300 mg/dl, 6.5%) at 5, 6, and 7 months of age; they were significantly higher at 6 and 7 months, compared to 4 months, p&lt;0.05. Body weight was significantly higher at 5, 6, and 7 months compared to 4 months (4mo: 525±4g, 5mo: 609±3g, 6mo: 620±21g, 7mo: 610±31g; p&lt;0.05). Sensitivity to von Frey filaments was significantly greater, indicating mechanical allodynia, at 6 and 7 months compared to 4 months (4mo: 29±3.2 g, 5mo: 26.3±4.5 g, 6mo: 14.1±3.3 g, 7mo: 9.7±1.7 g; p&lt;0.05). We conclude that mechanical allodynia progresses in severity as the rats develop and progress with T2DM. Moreover, these observations may provide insight to diabetes‐induced changes in thin‐fiber dependent reflexes, such as the exercise pressor reflex.Support or Funding InformationN/AThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

µ-Opioid receptors inhibit the exercise pressor reflex by closing N-type calcium channels but not by opening GIRK channels in rats.

µ-Opioid G protein-coupled receptors (MOR) interact with ion channels to decrease neuronal excitability. In humans, intrathecal administration of the MOR agonist fentanyl inhibits the exercise pressor reflex, an effect that can be attributed to either the opening of inward rectifying potassium channels (GIRK) or the closing of N-type calcium channels. The purpose of this study was to determine if the highly selective MOR agonist [d-Ala2, N-MePhe4,Gly-ol]-enkephalin (DAMGO) attenuates the exercise pressor reflex and which of these two channels are responsible for this effect. In decerebrate rats, we determined the effect of intrathecal injection of either tertiapin-LQ, which blocks the GIRK channel or ω-conotoxin-GVIA, which blocks the N-type calcium channel on the exercise pressor reflex, which was evoked by contracting the triceps surae muscles. Initially, we established that intrathecal injection of DAMGO inhibited the exercise pressor reflex relative to no intrathecal injection or intrathecal saline injection ( P < 0.001, n = 5). We then found that intrathecal injection of two doses of tertiapin-LQ (1 and 10 µg) had no effect on the exercise pressor reflex ( n = 6 and n = 7, respectively; P > 0.05). Importantly, neither dose of tertiapin-LQ prevented the DAMGO-induced inhibition of the exercise pressor reflex. Last, we found that intrathecal injection of ω-conotoxin-GVIA markedly attenuated the exercise pressor reflex ( P < 0.001, n = 7). The cardioaccelerator response to contraction did not appear to be effected in any of the experiments. We conclude that N-type voltage-gated calcium channel inhibition appears to be the mechanism by which MOR activation inhibits the exercise pressor reflex in decerebrate rats.

Exaggerated cardiovascular responses to treadmill running in rats with peripheral arterial insufficiency.

Patients with atherosclerotic peripheral artery disease have an augmented pressor response to treadmill walking, but the underlying mechanisms remain poorly understood and difficult to isolate because of the confounding presence of numerous cardiovascular risk factors. In the present study, we tested the hypothesis that a chronic deficit in muscle blood flow capacity would be sufficient to trigger an exaggerated pressor response to dynamic exercise. Sprague-Dawley rats (5 male and 5 female) were instrumented with radiotelemetry devices to measure the cardiovascular responses to treadmill running before and after bilateral femoral artery ligation, which has been previously shown to reduce the blood flow capacity of distal hindlimb muscles by >60%. Treadmill running evoked reproducible increases in mean arterial pressure (MAP) and heart rate (HR), which were significantly augmented 3 days after femoral artery ligation in both male rats [ΔMAP: +10 ± 1 (SE) vs. +18 ± 3 mmHg and ΔHR: +94 ± 12 vs. +148 ± 15 beats/min, P < 0.05] and female rats (ΔMAP: +16 ± 3 vs. +30 ± 5 mmHg and ΔHR: +128 ± 20 vs. +178 ± 19 beats/min, P < 0.05). Similar exaggerated MAP and HR responses were observed at repeated intervals between 3 and 65 days postligation. These findings indicate that a chronic deficit in muscle blood flow capacity is an important, persistent cause of the abnormal pressor and cardioaccelerator responses to dynamic exercise in both male and female rats with peripheral arterial insufficiency. NEW & NOTEWORTHY Using radiotelemetry to assess cardiovascular effects of exercise, we showed that femoral artery obstruction in male and female rats is an important, persistent cause of exaggerated pressor and cardioaccelerator responses to treadmill running. This translational model reproduces the abnormal cardiovascular response to exercise seen in patients with peripheral artery disease. Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/treadmill-bp-in-simulated-peripheral-artery-disease/ .

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

Previous studies have shown that diabetic peripheral neuropathy affects both unmyelinated and myelinated afferents, similar to those evoking the exercise pressor reflex. However, the effect of type 1 diabetes (T1DM) on this reflex is not known. We examined, in decerebrate male and female T1DM [streptozotocin (STZ)] and healthy control (CTL) rats, pressor and cardioaccelerator responses to isometric contraction of the hindlimb muscles during the early and late stages of the disease. STZ (50 mg/kg) was injected to induce diabetes, and experiments were conducted at 1, 3, and 6 wk after injection. On the day of the experiment, we statically contracted the hindlimb muscles by stimulating the sciatic nerve and measured changes in mean arterial pressure and heart rate. We found that the pressor but not cardioaccelerator response was exaggerated in STZ rats at 1 wk (STZ: 21 ± 3 mmHg, n = 10, and CTL: 14 ± 2 mmHg, n = 10, P < 0.05) and at 3 wk (STZ: 26 ± 5 mmHg, n = 10, and CTL: 17 ± 3 mmHg, n = 11, P < 0.05) after injection. However, at 6 wk, and only in male rats, both the pressor (STZ: 13 ± 3 mmHg, n = 12, and CTL: 17 ± 3 mmHg, n = 13, P < 0.05) and cardioaccelerator responses (STZ: 7 ± 3 beats/min, n = 12, and CTL: 10 ± 3 beats/min, n = 13, P < 0.05) to contraction were significantly attenuated in STZ rats compared with CTL rats. These data indicate that T1DM exaggerates the exercise pressor reflex during the early stages of the disease in both male and female rats. Conversely, T1DM attenuates this reflex in the late stage of the disease in male but not female rats.NEW & NOTEWORTHY This is the first study to provide evidence that the pressor and cardioaccelerator responses to skeletal muscle contraction vary depending on the duration of type 1 diabetes.

Effects of Type 1 Diabetes on the Exercise Pressor Reflex in Rats

Type 1 diabetes (T1DM) is known to cause both peripheral and autonomic neuropathy through mechanisms affecting thinly myelinated afferents. These same afferents may also play a role in the exercise pressor reflex suggesting that T1DM could alter this reflex as well. The purpose of this study was to establish the effects of type 1 diabetes on the pressor and cardioaccelerator responses evoked by statically contracting the hindlimb muscles at different time points of the disease and identify possible mechanisms responsible for these changes. We injected (i.p.) 50 mg/kg of Streptozotocin (STZ) or the vehicle (CTL) in either sex and waited 1wk (STZ: BW=267±12 g, glucose=438±24 mg/dL, HbA1C=6.5±0.3%; CTL: BW=328±16 g, glucose=167±10 mg/dL, HbA1C=4.4±0.1%), 3wks (STZ: BW=293±10 g, glucose=465±22 mg/dL, HbA1C=10±0.3%; CTL: BW=329±22 g, glucose=212±26 mg/dL, HbA1C=4.8±0.4%), or 6wks (STZ: BW=380±16 g, glucose=546±35 mg/dL, HbA1C=12±0.4%) before performing experiments. In unanaesthetized, decerebrate rats, we statically contracted the hindlimb muscles for 30s and measured changes in mean arterial pressure (MAP) and heart rate (HR). We then injected either α,β‐methylene ATP (20μg/kg; 200μl), a P2X receptor agonist, or lactic acid (24mM; 200μl), an ASIC3 channel agonist, into the arterial supply of the hindlimb and measured the evoked pressor and cardioaccelerator responses for each group. We found that the pressor (STZ: ΔMAP=25±5 mmHg, n=4; CTL: ΔMAP=13±2 mmHg, n=7; p=0.01) but not cardioaccelerator (STZ: ΔHR=23±9 bpm, n=4; CTL: ΔHR=13±3 bpm, n=7; p=0.10) response to static contraction was exaggerated 1wk after injecting STZ. Likewise, the pressor (STZ: ΔMAP=32±5 mmHg, n=8; CTL: ΔMAP=17±3 mmHg, n=6; p=0.02) but not cardioaccelerator (STZ: ΔHR=22±5 bpm, n=8; CTL: ΔHR=15±2 bpm, n=6; p=0.27) response to static contraction was exaggerated 3wks after injecting STZ. Conversely, both the pressor (6wks STZ: ΔMAP=5±2 mmHg, n=7) and cardioaccelerator (6wks STZ: ΔHR=1±2 bpm, n=7) responses to static contraction were significantly attenuated 6wks after injecting STZ compared to 1wk (MAP: p=0.02; HR: p=0.01) and 3wks after injecting STZ (MAP: p&lt;0.01; HR: p&lt;0.01). The developed tensions from contraction were similar within each comparison. Furthermore, we found that injecting lactic acid, but not α,β‐methylene ATP, into the arterial supply of the hindlimb evoked a greater pressor (STZ: ΔMAP=31±5 mmHg, n=9; CTL: ΔMAP=20±3 mmHg, n=13; p=0.04) and cardioaccelerator (STZ: ΔHR=13±3 bpm, n=9; CTL: ΔHR=3±2 bpm, n=13; p&lt;0.01) response 1wk after STZ injection compared to CTL. We conclude that the exercise pressor reflex is exaggerated in the early stages of T1DM but attenuated in the late stages of this disease. Additionally, ASIC3 channels but not P2X receptors may play a role in this exaggerated reflex 1wk after STZ injection.

Role of NaV 1.7 channels on skeletal muscle afferents in evoking the exercise pressor reflex

Voltage gated sodium channels (NaV) 1.7 can be blocked by tetrodotoxin (TTX) in concentrations of 300nM or less. Moreover, NaV 1.7 channels are highly expressed in sensory neurons and are thought to play a role in inflammatory pain. These findings prompted us to determine in decerebrated, unanesthetized rats, the role played by NaV 1.7 channels on the axons of thin fiber muscle afferents in evoking the exercise pressor reflex. We first showed that application of 50nM tetrodotoxin to the L3‐L5 dorsal roots attenuated the exercise pressor reflex evoked by statically contracting the hindlimb muscles. The peak pressor responses to static contraction were significantly attenuated by TTX and were restored by replacing the TTX solution with Lactated Ringer's solution (control: 21±1 mmHg, TTX: 8±2 mmHg, restored: 21±3 mmHg; n=6; p&lt;0.01). Likewise, the peak cardioaccelerator responses to contraction were significantly attenuated by TTX (control: 12±3 bpm, TTX: 5±2 bpm, restored: 8±2 bpm; n=6; p&lt;0.05). Similar tensions were developed for each contraction. We next applied the specific NaV 1.7 channel inhibitor, Ssm6a (100nM), to the L3‐L5 dorsal roots to attenuate the reflex. We found that the peak pressor responses to contraction were significantly attenuated by Ssm6a and were restored by replacing the Ssm6a solution with Lactated Ringer's solution (control: 19±3 mmHg, Ssm6a: 10±1 mmHg, recovery: 19±4 mmHg; n=6; p&lt;0.05). In contrast, the peak cardioaccelerator responses to contraction were not attenuated by Ssm6a. Similar tensions were developed for each contraction. We conclude that NaV 1.7 channels, which are TTX‐sensitive, play a role in the afferent pathway evoking the exercise pressor reflex. Funding: NIH AR‐059397

A psychophysiological investigation of emotion regulation in chronic severe posttraumatic stress disorder

There have been few direct examinations of the volitional control of emotional responses to provocative stimuli in PTSD. To address this gap, an emotion regulation task was administered to 27 Operation Enduring Freedom/Operation Iraqi Freedom combat veterans and 23 healthy controls. Neutral and aversive photographs were presented to participants who did or did not employ emotion regulation strategies. Objective indices included corrugator electromyogram, the late positive potential, and the electrocardiogram. On uninstructed trials, participants with PTSD exhibited blunted cardiac reactivity rather than the exaggerated cardioacceleratory responses seen in trauma cue reactivity studies. On interleaved regulation trials, no measure evidenced group differences in voluntary emotion regulation. Persons with PTSD may not differ from normals in their capacity to voluntarily regulate normative emotional responses to provocative stimuli in the laboratory, though they may nevertheless respond differentially on uninstructed trials and endorse symptoms of dyscontrol pathognomonic of the disorder outside of the laboratory.

Increased dietary salt intake enhances the exercise pressor reflex

Increased dietary salt in rats has been shown to sensitize central sympathetic circuits and enhance sympathetic responses to several stressors, including hyperinsulinemia, intracerebroventricular injection of angiotensin, and electrical stimulation of sciatic nerve afferents. These findings prompted us to test the hypothesis that increased dietary salt enhanced the exercise pressor reflex. Male Sprague-Dawley rats were fed 0.1% (low) or 4.0% (high) NaCl chow for 2 to 3 wk. On the day of the experiment, the rats were decerebrated, and the hind limb muscles were statically contracted for 30 s by electrically stimulating the cut peripheral ends of the L4 and L5 ventral roots. We found that contraction produced a significantly greater increase in mean arterial pressure of rats fed 4.0% (n = 26) vs. 0.1% (n = 22) NaCl (24 ± 2 vs. 15 ± 2 mmHg, respectively; P < 0.05). Baseline mean arterial pressure was not different between groups (0.1%, 77 ± 4 vs. 4.0% NaCl, 80 ± 3 mmHg). Likewise, the tension time indexes were not different between the two groups (P = 0.42). Section of the L4 and L5 dorsal roots greatly attenuated both the pressor and cardioaccelerator responses to contraction in both groups of rats, an effect showing that the responses were reflex in origin. Finally, electrical stimulation of the lumbar sympathetic chain produced similar increases in mean arterial pressure and decreases in femoral arterial blood flow and conductance between rats fed 0.1% vs. 4.0% NaCl diets. We conclude that increased dietary salt enhances the exercise pressor reflex.