scholarly journals Muscle metaboreflex-induced vasoconstriction in the ischemic active muscle is exaggerated in heart failure

2018 ◽  
Vol 314 (1) ◽  
pp. H11-H18 ◽  
Author(s):  
Jasdeep Kaur ◽  
Danielle Senador ◽  
Abhinav C. Krishnan ◽  
Hanna W. Hanna ◽  
Alberto Alvarez ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Arterial Pressure ◽  
Exercise Intolerance ◽  
Adrenergic Blockade ◽  
Active Muscle ◽  
Muscle Metaboreflex ◽  
Peripheral Vasoconstriction ◽  
Ischemic Muscle

When oxygen delivery to active muscle is insufficient to meet the metabolic demand during exercise, metabolites accumulate and stimulate skeletal muscle afferents, inducing a reflex increase in blood pressure, termed the muscle metaboreflex. In healthy individuals, muscle metaboreflex activation (MMA) during submaximal exercise increases arterial pressure primarily via an increase in cardiac output (CO), as little peripheral vasoconstriction occurs. This increase in CO partially restores blood flow to ischemic muscle. However, we recently demonstrated that MMA induces sympathetic vasoconstriction in ischemic active muscle, limiting the ability of the metaboreflex to restore blood flow. In heart failure (HF), increases in CO are limited, and metaboreflex-induced pressor responses occur predominantly via peripheral vasoconstriction. In the present study, we tested the hypothesis that vasoconstriction of ischemic active muscle is exaggerated in HF. Changes in hindlimb vascular resistance [femoral arterial pressure ÷ hindlimb blood flow (HLBF)] were observed during MMA (via graded reductions in HLBF) during mild exercise with and without α1-adrenergic blockade (prazosin, 50 µg/kg) before and after induction of HF. In normal animals, initial HLBF reductions caused metabolic vasodilation, while reductions below the metaboreflex threshold elicited reflex vasoconstriction, in ischemic active skeletal muscle, which was abolished after α1-adrenergic blockade. Metaboreflex-induced vasoconstriction of ischemic active muscle was exaggerated after induction of HF. This heightened vasoconstriction impairs the ability of the metaboreflex to restore blood flow to ischemic muscle in HF and may contribute to the exercise intolerance observed in these patients. We conclude that sympathetically mediated vasoconstriction of ischemic active muscle during MMA is exaggerated in HF. NEW & NOTEWORTHY We found that muscle metaboreflex-induced vasoconstriction of the ischemic active skeletal muscle from which the reflex originates is exaggerated in heart failure. This results in heightened metaboreflex activation, which further amplifies the reflex-induced vasoconstriction of the ischemic active skeletal muscle and contributes to exercise intolerance in patients.

scholarly journals Interaction between the muscle metaboreflex and the arterial baroreflex in control of arterial pressure and skeletal muscle blood flow

2016 ◽  
Vol 311 (5) ◽  
pp. H1268-H1276 ◽  
Author(s):  
Jasdeep Kaur ◽  
Alberto Alvarez ◽  
Hanna W. Hanna ◽  
Abhinav C. Krishnan ◽  
Danielle Senador ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Muscle Blood Flow ◽  
Arterial Baroreflex ◽  
Muscle Metaboreflex ◽  
Peripheral Vasoconstriction ◽  
Bilateral Carotid ◽  
Ischemic Muscle

The muscle metaboreflex and arterial baroreflex regulate arterial pressure through distinct mechanisms. During submaximal exercise muscle metaboreflex activation (MMA) elicits a pressor response virtually solely by increasing cardiac output (CO) while baroreceptor unloading increases mean arterial pressure (MAP) primarily through peripheral vasoconstriction. The interaction between the two reflexes when activated simultaneously has not been well established. We activated the muscle metaboreflex in chronically instrumented canines during dynamic exercise (via graded reductions in hindlimb blood flow; HLBF) followed by simultaneous baroreceptor unloading (via bilateral carotid occlusion; BCO). We hypothesized that simultaneous activation of both reflexes would result in an exacerbated pressor response owing to both an increase in CO and vasoconstriction. We observed that coactivation of muscle metaboreflex and arterial baroreflex resulted in additive interaction although the mechanisms for the pressor response were different. MMA increased MAP via increases in CO, heart rate (HR), and ventricular contractility whereas baroreflex unloading during MMA caused further increases in MAP via a large decrease in nonischemic vascular conductance (NIVC; conductance of all vascular beds except the hindlimb vasculature), indicating substantial peripheral vasoconstriction. Moreover, there was significant vasoconstriction within the ischemic muscle itself during coactivation of the two reflexes but the remaining vasculature vasoconstricted to a greater extent, thereby redirecting blood flow to the ischemic muscle. We conclude that baroreceptor unloading during MMA induces preferential peripheral vasoconstriction to improve blood flow to the ischemic active skeletal muscle.

Chronic Ablation of TRPV1 Sensitive Skeletal Muscle Afferents Attenuates the Muscle Metaboreflex

2021 ◽  
Author(s):  
Joseph Mannozzi ◽  
Mohamed-Hussein Al-Hassan ◽  
Beruk Lessanework ◽  
Alberto Alvarez ◽  
Danielle Senador ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Skeletal Muscle ◽  
Blood Flow ◽  
Cardiac Output ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Intrathecal Administration ◽  
Exercise Intolerance ◽  
Stroke Work ◽  
Muscle Metaboreflex

Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex- induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express Transient Receptor Potential Vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultra-potent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1 sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 μg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min) and stroke work (2.27 ± 0.2 L*mmHg vs. 1.01 ± 0.2 L*mmHg). Effects were maintained until 78 ± 14 days post RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 μg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre RTX vs +19.7 ± 3.1mmHg post RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.

scholarly journals Altered arterial baroreflex-muscle metaboreflex interaction in heart failure

2018 ◽  
Vol 315 (5) ◽  
pp. H1383-H1392 ◽  
Author(s):  
Jasdeep Kaur ◽  
Abhinav C. Krishnan ◽  
Danielle Senador ◽  
Alberto Alvarez ◽  
Hanna W. Hanna ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Flow ◽  
Ventricular Function ◽  
Pressor Response ◽  
Cardiovascular Responses ◽  
Arterial Baroreflex ◽  
Active Muscle ◽  
Muscle Metaboreflex ◽  
Peripheral Vasoconstriction ◽  
Vascular Beds

Two powerful reflexes controlling cardiovascular function during exercise are the muscle metaboreflex and arterial baroreflex. In heart failure (HF), the strength and mechanisms of these reflexes are altered. Muscle metaboreflex activation (MMA) in normal subjects increases mean arterial pressure (MAP) primarily via increases in cardiac output (CO), whereas in HF the mechanism shifts to peripheral vasoconstriction. Baroreceptor unloading increases MAP via peripheral vasoconstriction, and this pressor response is blunted in HF. Baroreceptor unloading during MMA in normal animals elicits an enormous pressor response via combined increases in CO and peripheral vasoconstriction. The mode of interaction between these reflexes is intimately dependent on the parameter (e.g., MAP and CO) being investigated. The interaction between the two reflexes when activated simultaneously during dynamic exercise in HF is unknown. We activated the muscle metaboreflex in chronically instrumented dogs during mild exercise (via graded reductions in hindlimb blood flow) followed by baroreceptor unloading [via bilateral carotid occlusion (BCO)] before and after induction of HF. We hypothesized that BCO during MMA in HF would cause a smaller increase in MAP and a larger vasoconstriction of ischemic hindlimb vasculature, which would attenuate the restoration of blood flow to ischemic muscle observed in normal dogs. We observed that BCO during MMA in HF increases MAP by substantial vasoconstriction of all vascular beds, including ischemic active muscle, and that all cardiovascular responses, except ventricular function, exhibit occlusive interaction. We conclude that vasoconstriction of ischemic active skeletal muscle in response to baroreceptor unloading during MMA attenuates restoration of hindlimb blood flow. NEW & NOTEWORTHY We found that baroreceptor unloading during the muscle metaboreflex in heart failure results in occlusive interaction (except for ventricular function) with significant vasoconstriction of all vascular beds. In addition, restoration of blood flow to ischemic active muscle, via preferentially larger vasoconstriction of nonischemic beds, is significantly attenuated in heart failure.

Is the muscle metaboreflex important in control of blood flow to ischemic active skeletal muscle in dogs?

1995 ◽  
Vol 268 (3) ◽  
pp. H980-H986 ◽  
Author(s):  
D. S. O'Leary ◽  
D. D. Sheriff
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Arterial Pressure ◽  
Pressor Response ◽  
Muscle Blood Flow ◽  
Vascular Occlusion ◽  
Systemic Arterial Pressure ◽  
Initial Increase ◽  
Aortic Blood Flow ◽  
Muscle Metaboreflex

Ischemia of active skeletal muscle induces a reflex increase in sympathetic activity, heart rate, cardiac output, and arterial pressure, termed the muscle metaboreflex. Whether this pressor response contributes importantly in the regulation of blood flow to the ischemic active skeletal muscle is not well understood. If the pressor response is achieved without substantial vasoconstriction in the ischemic muscle, this increase in arterial pressure would act to improve muscle blood flow. Dogs performed treadmill exercise at mild (3.2 km/h, 0% grade) and moderate (6.4 km/h, 10% grade) workloads. During each workload, resistance to blood flow in the hindlimbs (Rh) was increased via graded partial inflation of a vascular occluder implanted on the terminal aorta. The closed-loop gain of the muscle metaboreflex (Gcl) was calculated, based on the steady-state changes in terminal aortic blood flow (TAQ). If no pressor response occurred, then TAQ should decrease in proportion to the increase in total Rh (the sum of resistance due to partial vascular occlusion and hindlimb vascular resistance); i.e., no reflex restoration of hindlimb blood flow would occur. However, with a reflex increase in systemic arterial pressure, TAQ could rise above the level predicted on the basis of the increase in Rh. We observed that with the initial increase in Rh during mild exercise, Gcl was not significantly different from zero (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Participation of alpha 2-adrenergic receptors in neural vascular tone of canine skeletal muscle

1992 ◽  
Vol 262 (6) ◽  
pp. H1705-H1710 ◽  
Author(s):  
P. Kubes ◽  
M. Melinyshyn ◽  
K. Nesbitt ◽  
S. M. Cain ◽  
C. K. Chapler
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Mean Arterial Pressure ◽  
Sciatic Nerve ◽  
Arterial Pressure ◽  
Adrenergic Receptors ◽  
Receptor Agonist ◽  
Vascular Tone ◽  
Adrenergic Blockade ◽  
Adrenergic Blockers

Studies were carried out in anesthetized, paralyzed, and ventilated dogs to determine whether postsynaptic alpha 2-adrenergic receptors participated in neurally mediated vascular tone in skeletal muscle. Hindlimb skeletal muscle resistance (RL) and blood flow (QL) were determined before, during, and after reversible cold block of the sciatic nerve. This sequence of observations was repeated 30 min after blockade of alpha 1-adrenergic receptors with prazosin. Then the alpha 2-adrenergic receptors were blocked with yohimbine, and the nerve cold block was repeated. When the sciatic nerve was cold blocked before alpha 1-adrenergic blockade, RL decreased approximately 50% and QL increased 75% (P less than 0.05) and then returned to control when the nerve was rewarmed. After alpha 1-block 76% of neural tone remained as assessed by nerve cooling (P less than 0.05). This phenomenon occurred despite effective alpha 1-adrenergic blockade as assessed by the alpha 1-receptor agonist methoxamine. With alpha 1- plus alpha 2-block no change in RL or QL was seen with nerve cold block. The same protocol was repeated in a second series of animals, but mean arterial pressure, which fell after alpha 1-block in the group above, was maintained by dextran infusion at normotensive levels. In these animals, 40% of neural tone remained after alpha 1-block. Both alpha 1- and alpha 2-adrenergic blockers were again needed to abolish the QL and RL response to nerve cold block. In another series of animals, yohimbine was administered before prazosin. In this series, alpha 2-adrenergic blockade greatly reduced neural tone as assessed by nerve cooling.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle

2015 ◽  
Vol 309 (12) ◽  
pp. H2145-H2151 ◽  
Author(s):  
Jasdeep Kaur ◽  
Tiago M. Machado ◽  
Alberto Alvarez ◽  
Abhinav C. Krishnan ◽  
Hanna W. Hanna ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Threshold Level ◽  
Dynamic Exercise ◽  
Adrenergic Blockade ◽  
Muscle Metaboreflex ◽  
Group Iii ◽  
Arterial Blood ◽  
Sympathetic Vasoconstriction ◽  
Before And After

Metabolite accumulation due to ischemia of active skeletal muscle stimulates group III/IV chemosensitive afferents eliciting reflex increases in arterial blood pressure and sympathetic activity, termed the muscle metaboreflex. We and others have previously demonstrated sympathetically mediated vasoconstriction of coronary, renal, and forelimb vasculatures with muscle metaboreflex activation (MMA). Whether MMA elicits vasoconstriction of the ischemic muscle from which it originates is unknown. We hypothesized that the vasodilation in active skeletal muscle with imposed ischemia becomes progressively restrained by the increasing sympathetic vasoconstriction during MMA. We activated the metaboreflex during mild dynamic exercise in chronically instrumented canines via graded reductions in hindlimb blood flow (HLBF) before and after α1-adrenergic blockade [prazosin (50 μg/kg)], β-adrenergic blockade [propranolol (2 mg/kg)], and α1 + β-blockade. Hindlimb resistance was calculated as femoral arterial pressure/HLBF. During mild exercise, HLBF must be reduced below a threshold level before the reflex is activated. With initial reductions in HLBF, vasodilation occurred with the imposed ischemia. Once the muscle metaboreflex was elicited, hindlimb resistance increased. This increase in hindlimb resistance was abolished by α1-adrenergic blockade and exacerbated after β-adrenergic blockade. We conclude that metaboreflex activation during submaximal dynamic exercise causes sympathetically mediated α-adrenergic vasoconstriction in ischemic skeletal muscle. This limits the ability of the reflex to improve blood flow to the muscle.

scholarly journals Muscle metaboreflex improves O2delivery to ischemic active skeletal muscle

1999 ◽  
Vol 276 (4) ◽  
pp. H1399-H1403 ◽  
Author(s):  
Donal S. O’Leary ◽  
Robert A. Augustyniak ◽  
Eric J. Ansorge ◽  
Heidi L. Collins
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Pressor Response ◽  
Systemic Arterial Pressure ◽  
Integrative Approach ◽  
Muscle Metaboreflex ◽  
Arterial Blood ◽  
Per Se ◽  
Hb Concentration ◽  
Ischemic Muscle

Ischemia of active skeletal muscle elicits a powerful pressor response, termed the muscle metaboreflex. We recently reported that the muscle metaboreflex pressor response acts to partially restore blood flow to the ischemic active skeletal muscle. However, because this reflex is activated by reductions in O2 delivery rather than blood flow per se, gain of the muscle metaboreflex as analyzed on the basis of blood flow alone may underestimate its true strength if this reflex also acts to increase arterial O2content. In conscious dogs chronically instrumented to measure systemic arterial pressure, cardiac output, and hindlimb blood flow, we activated the muscle metaboreflex via graded, partial reductions in hindlimb blood flow during mild (3.2 km/h) and moderate (6.4 km/h, 10% grade) workloads. At rest, during free-flow exercise, and with metaboreflex activation, we analyzed arterial blood samples for Hb concentration and O2 content and compared muscle metaboreflex gain calculations based on the ability to partially restore flow with those based on the ability to partially restore O2 delivery (blood flow × arterial O2 content). During both mild and moderate exercise, metaboreflex activation caused significant increases in arterial Hb concentration and O2 content. Metaboreflex gain quantified on the ability to partially restore O2 delivery was significantly greater than that based on restoration of blood flow during both mild and moderate workloads (0.52 ± 0.10 vs. 0.39 ± 0.08, P < 0.05, and 0.61 ± 0.05 vs. 0.46 ± 0.04, P < 0.05, respectively). We conclude that the muscle metaboreflex acts to increase both arterial O2 content and blood flow to ischemic muscle such that when combined, O2 delivery is substantially increased and metaboreflex gain is greater when analyzed with a more integrative approach.

Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure

2005 ◽  
Vol 288 (3) ◽  
pp. H1381-H1388 ◽  
Author(s):  
Eric J. Ansorge ◽  
Robert A. Augustyniak ◽  
Mariana L. Perinot ◽  
Robert L. Hammond ◽  
Jong-Kyung Kim ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Blood Flow ◽  
Cardiac Output ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Coronary Blood Flow ◽  
Moderate Exercise ◽  
Muscle Metaboreflex ◽  
Significant Change

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF), coronary vascular conductance (CVC), and regional left ventricular performance in conscious, chronically instrumented dogs during treadmill exercise before and after the induction of heart failure (HF). In control experiments, muscle metaboreflex activation during mild exercise elicited significant reflex increases in mean arterial pressure, heart rate, and cardiac output. CBF increased significantly, whereas no significant change in CVC occurred. There was no significant change in the minimal rate of myocardial shortening (−d l/d tmin) with muscle metaboreflex activation during mild exercise (15.5 ± 1.3 to 16.8 ± 2.4 mm/s, P > 0.05); however, the maximal rate of myocardial relaxation (+d l/d tmax) increased (from 26.3 ± 4.0 to 33.7 ± 5.7 mm/s, P < 0.05). Similar hemodynamic responses were observed with metaboreflex activation during moderate exercise, except there were significant changes in both −d l/d tmin and d l/d tmax. In contrast, during mild exercise with metaboreflex activation during HF, no significant increase in cardiac output occurred, despite a significant increase in heart rate, inasmuch as a significant decrease in stroke volume occurred as well. The increases in mean arterial pressure and CBF were attenuated, and a significant reduction in CVC was observed (0.74 ± 0.14 vs. 0.62 ± 0.12 ml·min−1·mmHg−1; P < 0.05). Similar results were observed during moderate exercise in HF. Muscle metaboreflex activation did not elicit significant changes in either −d l/d tmin or +d l/d tmax during mild exercise in HF. We conclude that during HF the elevated muscle metaboreflex-induced increases in sympathetic tone to the heart functionally vasoconstrict the coronary vasculature, which may limit increases in myocardial performance.

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