HIF‐1α inhibition alleviates the exaggerated exercise pressor reflex in rats with peripheral artery disease induced by femoral artery occlusion

The mechanoreflex is exaggerated in patients with peripheral artery disease (PAD) and in a rat model of simulated PAD in which a femoral artery is chronically (~72hrs) ligated. We found recently that, in rats with a ligated femoral artery, blockade of thromboxane A2 (TxA2) receptors on the sensory endings of thin fiber muscle afferents reduced the pressor response to 1 Hz repetitive/dynamic hindlimb skeletal muscle stretch (a model of mechanoreflex activation isolated from contraction-induced metabolite production). Conversely, we found no effect of TxA2 receptor blockade in rats with freely perfused femoral arteries. Here we extended the isolated mechanoreflex findings in "ligated" rats to experiments evoking dynamic hindlimb skeletal muscle contractions. We also investigated the role played by inositol 1-4-5-trisphosphate (IP3) receptors, receptors associated with intracellular signaling linked to TxA2 receptors, in the exaggerated response to dynamic mechanoreflex and exercise pressor reflex activation in ligated rats. Injection of the TxA2 receptor antagonist daltroban into the arterial supply of the hindlimb reduced the pressor response to 1 Hz dynamic contraction in ligated but not "freely perfused" rats. Moreover, injection of the IP3 receptor antagonist xestospongin C into the arterial supply of the hindlimb reduced the pressor response to 1 Hz dynamic stretch and contraction in ligated but not freely perfused rats. These findings demonstrate that, in rats with a ligated femoral artery, sensory neuron TxA2 receptor and IP3 receptor mediated signaling contributes to a chronic sensitization of the mechanically activated channels associated with the mechanoreflex and the exercise pressor reflex.

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Proximal Superficial Femoral Artery Occlusion, Collateral Vessels, and Walking Performance in Peripheral Artery Disease

JACC Cardiovascular Imaging ◽

10.1016/j.jcmg.2012.10.024 ◽

2013 ◽

Vol 6 (6) ◽

pp. 687-694 ◽

Cited By ~ 17

Author(s):

Mary M. McDermott ◽

Timothy J. Carroll ◽

Melina Kibbe ◽

Christopher M. Kramer ◽

Kiang Liu ◽

...

Keyword(s):

Peripheral Artery Disease ◽

Femoral Artery ◽

Superficial Femoral Artery ◽

Artery Occlusion ◽

Peripheral Artery ◽

Femoral Artery Occlusion ◽

Walking Performance ◽

Artery Disease ◽

Collateral Vessels

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Investigation of the mechanisms of cyclooxygenase-mediated mechanoreflex sensitization in a rat model of simulated peripheral artery disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00399.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. H1050-H1061 ◽

Cited By ~ 2

Author(s):

Alec L. E. Butenas ◽

Tyler D. Hopkins ◽

Korynne S. Rollins ◽

Kennedy P. Felice ◽

Steven W. Copp

Keyword(s):

Skeletal Muscle ◽

Peripheral Artery Disease ◽

Femoral Artery ◽

Skeletal Muscles ◽

Pressor Response ◽

Peripheral Artery ◽

Artery Ligation ◽

Exercise Pressor Reflex ◽

Pressor Reflex ◽

Artery Disease

Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in patients with peripheral artery disease (PAD) and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery (“ligated” rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1-Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats ( n = 7), indomethacin reduced the pressor response during stretch (control: 30 ± 4; indomethacin: 12 ± 3 mmHg; P < 0.01), whereas there was no effect in rats with “freely perfused” femoral arteries ( n = 6, control: 18 ± 5; indomethacin: 17 ± 5 mmHg; P = 0.87). In ligated rats ( n = 4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity or concentration of the COX metabolite prostaglandin E2. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A2-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents, which occurs principally as a result of increased expression of COX metabolite receptors. NEW & NOTEWORTHY We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.

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Chronic femoral artery ligation exaggerates the pressor and sympathetic nerve responses during dynamic skeletal muscle stretch in decerebrate rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00498.2017 ◽

2018 ◽

Vol 314 (2) ◽

pp. H246-H254 ◽

Cited By ~ 6

Author(s):

Evan A. Kempf ◽

Korynne S. Rollins ◽

Tyler D. Hopkins ◽

Alec L. Butenas ◽

Joseph M. Santin ◽

...

Keyword(s):

Blood Pressure ◽

Peripheral Artery Disease ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Peripheral Artery ◽

Nerve Activity ◽

Exercise Pressor Reflex ◽

Pressor Reflex ◽

Artery Disease ◽

Dynamic Stretch

Mechanical and metabolic signals arising during skeletal muscle contraction reflexly increase sympathetic nerve activity and blood pressure (i.e., the exercise pressor reflex). In a rat model of simulated peripheral artery disease in which a femoral artery is chronically (~72 h) ligated, the mechanically sensitive component of the exercise pressor reflex during 1-Hz dynamic contraction is exaggerated compared with that found in normal rats. Whether this is due to an enhanced acute sensitization of mechanoreceptors by metabolites produced during contraction or involves a chronic sensitization of mechanoreceptors is unknown. To investigate this issue, in decerebrate, unanesthetized rats, we tested the hypothesis that the increases in mean arterial blood pressure and renal sympathetic nerve activity during 1-Hz dynamic stretch are larger when evoked from a previously “ligated” hindlimb compared with those evoked from the contralateral “freely perfused” hindlimb. Dynamic stretch provided a mechanical stimulus in the absence of contraction-induced metabolite production that closely replicated the pattern of the mechanical stimulus present during dynamic contraction. We found that the increases in mean arterial blood pressure (freely perfused: 14 ± 1 and ligated: 23 ± 3 mmHg, P = 0.02) and renal sympathetic nerve activity were significantly greater during dynamic stretch of the ligated hindlimb compared with the increases during dynamic stretch of the freely perfused hindlimb. These findings suggest that the exaggerated mechanically sensitive component of the exercise pressor reflex found during dynamic muscle contraction in this rat model of simulated peripheral artery disease involves a chronic sensitizing effect of ligation on muscle mechanoreceptors and cannot be attributed solely to acute contraction-induced metabolite sensitization. NEW & NOTEWORTHY We found that the pressor and sympathetic nerve responses during dynamic stretch were exaggerated in rats with a ligated femoral artery (a model of peripheral artery disease). Our findings provide mechanistic insights into the exaggerated exercise pressor reflex in this model and may have important implications for peripheral artery disease patients.

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Activation of peripheral mu‐opioid receptor attenuates the augmented exercise pressor reflex seen in rats with chronic femoral artery occlusion

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.619.4 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Hirotsugu Tsuchimochi ◽

Jennifer L McCord ◽

Marc P Kaufman

Keyword(s):

Opioid Receptor ◽

Femoral Artery ◽

Artery Occlusion ◽

Mu Opioid Receptor ◽

Mu Opioid ◽

Exercise Pressor Reflex ◽

Femoral Artery Occlusion ◽

Pressor Reflex

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Blockade of acid sensing ion channels attenuates the augmented exercise pressor reflex in rats with chronic femoral artery occlusion

The Journal of Physiology ◽

10.1113/jphysiol.2011.217851 ◽

2011 ◽

Vol 589 (24) ◽

pp. 6173-6189 ◽

Cited By ~ 42

Author(s):

Hirotsugu Tsuchimochi ◽

Katsuya Yamauchi ◽

Jennifer L. McCord ◽

Marc P. Kaufman

Keyword(s):

Ion Channels ◽

Femoral Artery ◽

Artery Occlusion ◽

Exercise Pressor Reflex ◽

Femoral Artery Occlusion ◽

Acid Sensing Ion Channels ◽

Pressor Reflex

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Systemic and regional hemodynamic response to activation of the exercise pressor reflex in patients with peripheral artery disease

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00493.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. H916-H924 ◽

Cited By ~ 1

Author(s):

Danielle Jin-Kwang Kim ◽

Marcos Kuroki ◽

Jian Cui ◽

Zhaohui Gao ◽

J. Carter Luck ◽

...

Keyword(s):

Blood Pressure ◽

Blood Flow ◽

Peripheral Artery Disease ◽

Plantar Flexion ◽

Peripheral Artery ◽

Exercise Pressor Reflex ◽

Femoral Blood Flow ◽

Femoral Blood ◽

Pressor Reflex ◽

Artery Disease

Patients with peripheral artery disease (PAD) have an accentuated exercise pressor reflex (EPR) during exercise of the affected limb. The underlying hemodynamic changes responsible for this, and its effect on blood flow to the exercising extremity, are unclear. We tested the hypothesis that the exaggerated EPR in PAD is mediated by an increase in total peripheral resistance (TPR), which augments redistribution of blood flow to the exercising limb. Twelve patients with PAD and 12 age- and sex-matched subjects without PAD performed dynamic plantar flexion (PF) using the most symptomatic leg at progressive workloads of 2–12 kg (increased by 1 kg/min until onset of fatigue). We measured heart rate, beat-by-beat blood pressure, femoral blood flow velocity (FBV), and muscle oxygen saturation ([Formula: see text]) continuously during the exercise. Femoral blood flow (FBF) was calculated from FBV and baseline femoral artery diameter. Stroke volume (SV), cardiac output (CO), and TPR were derived from the blood pressure tracings. Mean arterial blood pressure and TPR were significantly augmented in PAD compared with control during PF. FBF increased during exercise to an equal extent in both groups. However, [Formula: see text] of the exercising limb remained significantly lower in PAD compared with control. We conclude that the exaggerated pressor response in PAD is mediated by an abnormal TPR response, which augments redistribution of blood flow to the exercising extremity, leading to an equal rise in FBF compared with controls. However, this increase in FBF is not sufficient to normalize the SmO2 response during exercise in patients with PAD. NEW & NOTEWORTHY In this study, peripheral artery disease (PAD) patients and healthy control subjects performed graded, dynamic plantar flexion exercise. Data from this study suggest that previously reported exaggerated exercise pressor reflex in patients with PAD is driven by greater vasoconstriction in nonexercising vascular territories which also results in a redistribution of blood flow to the exercising extremity. However, this rise in femoral blood flow does not fully correct the oxygen deficit due to changes in other mechanisms that require further investigation.

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One-Time Acute Heat Treatment Is Effective for Attenuation of the Exaggerated Exercise Pressor Reflex in Rats With Femoral Artery Occlusion

Frontiers in Physiology ◽

10.3389/fphys.2020.00942 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lu Qin ◽

Jianhua Li

Keyword(s):

Heat Treatment ◽

Femoral Artery ◽

Artery Occlusion ◽

Exercise Pressor Reflex ◽

Femoral Artery Occlusion ◽

Pressor Reflex

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Tempol attenuates the exercise pressor reflex independently of neutralizing reactive oxygen species in femoral artery ligated rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00535.2011 ◽

2011 ◽

Vol 111 (4) ◽

pp. 971-979 ◽

Cited By ~ 17

Author(s):

Jennifer L. McCord ◽

Hirotsugu Tsuchimochi ◽

Katsuya Yamauchi ◽

Anna Leal ◽

Marc P. Kaufman

Keyword(s):

Reactive Oxygen Species ◽

Superoxide Dismutase ◽

Femoral Artery ◽

Reactive Oxygen ◽

Artery Occlusion ◽

Arterial Supply ◽

Oxygen Species ◽

Exercise Pressor Reflex ◽

Femoral Artery Occlusion ◽

Pressor Reflex

In decerebrate rats, we reported previously that the exercise pressor reflex arising from a limb whose femoral artery was occluded for 72 h before the experiment was significantly higher than the exercise pressor reflex arising from a contralateral freely perfused limb. These findings prompted us to examine whether reactive oxygen species contributed to the augmented pressor reflex in rats with femoral artery occlusion. We found that the pressor reflex arising from the limb whose femoral artery was occluded for 72 h before the experiment (31 ± 5 mmHg) was attenuated by tempol (10 mg), a superoxide dismutase (SOD) mimetic (18 ± 5 mmHg, n = 9, P < 0.05), that was injected into the arterial supply of the hindlimb. In contrast, the pressor reflex arising from a freely perfused hindlimb (20 ± 3 mmHg) was not attenuated by tempol (17 ± 4 mmHg, n = 10, P = 0.49). Nevertheless, we found no difference in the increase in 8-isoprostaglandin F2α levels, an index of reactive oxygen species, in response to contraction between freely perfused (3.76 ± 0.82 pg/ml, n = 19) and 72-h occluded (3.51 ± 0.92 pg/ml, n = 22, P = 0.90) hindlimbs. Moreover, tempol did not reduce the 8-isoprostaglandin F2α levels during contraction in either group ( P > 0.30). A second SOD mimetic, tiron (200 mg/kg), had no effect on the exercise pressor reflex in either the rats with freely perfused hindlimbs or in those with occluded femoral arteries. These findings suggest that tempol attenuated the exercise pressor reflex in the femoral artery-occluded hindlimb by a mechanism that was independent of its ability to scavenge reactive oxygen species.

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