Reductions In Hindlimb Blood Flow Research Articles

Sympathetic Activity and Diastolic Dysfunction in HFrEF: Muscle metaboreflex induced changes in left ventricle passive filling pressure

During exercise, activation of afferents within active skeletal muscle improves cardiovascular performance through reflex increases in cardiac output (CO), ventricular function, and central blood volume mobilization - termed the muscle metaboreflex. In heart failure (HF) ventricular function is depressed and muscle metaboreflex activation (MMA) does little to improve ventricular performance. In HF reflex characteristics shift to from cardio-centric mediated increases in mean arterial pressure via increases in ventricular function and central blood volume mobilization, to profound vasoconstriction of not only the peripheral circulation but also the myocardium which thereby further limits increases in contractility. Impaired increases in CO during MMA in HF are not a result of reductions in preload, but are primarily a result of reduced contractile function via pathology and enhanced negative reflex characteristics. In HF, there are attenuated improvements in the rate of left ventricular relaxation just after the cessation of contraction during MMA vs. that observed in healthy subjects. To what degree MMA also induces alterations in passive left ventricular filling is unknown. We sought to determine if rate of rise in left ventricular passive filling pressure (LVPFR) (an index of ventricular stiffness) during MMA in HF was significantly increased, thus suggesting not only pathological but sympathetically mediated ventricular stiffening. Using conscious, chronically instrumented canines who were observed before and after the induction of HF via rapid ventricular pacing we analyzed 10 ventricular beats in each experiment taken from steady state values at rest, during volitional exercise (3.2 km/hr), and during volitional exercise (3.2 km/hr) with MMA achieved via imposed reductions in hindlimb blood flow by ~ 50%. From these 10 beats the rate of ventricular filling pressure was assessed prior to the atrial kick. We observed in healthy subjects that neither exercise nor MMA significantly altered LVPFR. In HF the LVPFR was significantly increased from rest to exercise (312 ± 54 to 449 ± 76 mmHg/sec) and in response to MMA (449 ± 76 to 726 ± 111 mmHg/sec). The effect of heart failure on LVPFR at rest (217 ± 22 vs 312 ± 54 mmHg/sec P=0.051) and during exercise (288 ± 47 to 449 ± 76 mmHg/sec P=0.059) approached significance, but only reached significance during MMA (385 ± 58 to 726 ± 111 mmHg/sec P= 0.030) when compared to healthy controls. We conclude that in HF, MMA significantly increases the LVPFR thereby indicating reflex mediated increases in ventricular stiffness in addition to those induced as a result of HF. Increases in ventricular stiffness during MMA may be an additional mechanism that limits CO, reducing peripheral perfusion during exercise and potentially leading to sudden cardiac death. This project was funded by NHLBI grant HL-055473. 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.

Hypertension depresses arterial baroreflex control of both heart rate and cardiac output during rest, exercise, and metaboreflex activation.

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach-unilateral reduction in renal blood flow to ∼30% of control values until systolic pressure ≥ 140 mmHg and a diastolic pressure ≥ 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients.

Chronic ablation of TRPV1-sensitive skeletal muscle afferents attenuates the 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 ultrapotent 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 ± 3.1 mmHg 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.

Muscle metaboreflex-induced increases in effective arterial elastance: effect of heart failure.

Dynamic exercise elicits robust increases in sympathetic activity in part due to muscle metaboreflex activation (MMA), a pressor response triggered by activation of skeletal muscle afferents. MMA during dynamic exercise increases arterial pressure by increasing cardiac output via increases in heart rate, ventricular contractility, and central blood volume mobilization. In heart failure, ventricular function is compromised, and MMA elicits peripheral vasoconstriction. Ventricular-vascular coupling reflects the efficiency of energy transfer from the left ventricle to the systemic circulation and is calculated as the ratio of effective arterial elastance (Ea) to left ventricular maximal elastance (Emax). The effect of MMA on Ea in normal subjects is unknown. Furthermore, whether muscle metaboreflex control of Ea is altered in heart failure has not been investigated. We utilized two previously published methods of evaluating Ea [end-systolic pressure/stroke volume (EaPV)] and [heart rate × vascular resistance (EaZ)] during rest, mild treadmill exercise, and MMA (induced via partial reductions in hindlimb blood flow imposed during exercise) in chronically instrumented conscious canines before and after induction of heart failure via rapid ventricular pacing. In healthy animals, MMA elicits significant increases in effective arterial elastance and stroke work that likely maintains ventricular-vascular coupling. In heart failure, Ea is high, and MMA-induced increases are exaggerated, which further exacerbates the already uncoupled ventricular-vascular relationship, which likely contributes to the impaired ability to raise stroke work and cardiac output during exercise in heart failure.

Chronic Ablation of Hindlimb Afferents Containing TRPV1 Receptors Attenuates Cardiovascular Responses to Muscle Metaboreflex Activation

Increases in sympathetic nerve activity during exercise occur, in part, due to activation of the muscle metaboreflex – a pressor reflex triggered via stimulation of type III and IV skeletal muscle afferents. Some of these afferents express capsaicin sensitive transient receptor potential vanilloid 1 (TRPV1) channels. Epicardial and intrathecal administration of resiniferatoxin (RTX), an ultra‐potent analog of capsaicin, attenuates responses to cardiac sympathetic afferent activation and provides relief of limb pain due to bone cancer. We investigated whether administration of intrathecal RTX (2μg/kg, L4–L6) would attenuate the muscle metaboreflex (induced by partial reductions in hindlimb blood flow during steady‐state mild exercise; 3.2 km/h). Experiments were performed using conscious, chronically instrumented canines before and 10–42 days after RTX. RTX markedly attenuated metaboreflex‐induced increases in mean arterial pressure (+27.0 ± 5.0 mmHg vs. +5.9 ± 8.2 mmHg) and cardiac output (+1.40 ± 0.20 l/min vs. +0.28 ± 0.12 l/min). Terminal experiments under isoflurane anesthesia performed 78 ± 14 days after RTX showed attenuated pressor responses to hindlimb intra‐arterial infusion of 20μg/kg capsaicin (+45.7 ± 6.5 mmHg pre RTX vs. +19.7 ± 3.1 mmHg post RTX). We conclude that intrathecal RTX chronically attenuates muscle metaboreflex pressor responses. Thus, RTX could be an effective treatment to reduce excessive sympatho‐activation often seen during exercise in patients with heart failure or other diseases when the metaboreflex is overstimulated due to underperfusion of the active skeletal muscle.Support or Funding InformationHL‐55473, HL‐126706, HL‐120822 and GM‐058905

Muscle Metaboreflex Induced Increases in Effective Arterial Elastance

Dynamic exercise elicits robust changes in sympathetic activity in part due to accumulation of metabolites within the active skeletal muscle which activates group III and IV afferents triggering the muscle metaboreflex. This reflex raises cardiac output via tachycardia, increased ventricular contractility, and central blood volume mobilization which improves perfusion to the active skeletal muscle. An important component of maintaining exercise performance is optimal ventricular ‐ vascular coupling which can change with exercise, aging, as well as pathophysiological conditions. The effect of muscle metaboreflex activation (MMA) on ventricular ‐ vascular interactions is unknown. We hypothesized that MMA increases Effective Arterial Elastance (Ea). We utilized two previously published methods of evaluating Ea (End Systolic Pressure / Stroke Volume (M1) and Heart Rate x Vascular Resistance (M2)) at rest, during mild treadmill exercise, and during MMA induced via partial reductions in hindlimb blood flow imposed during exercise. At rest Ea averaged 3.0 ± 0.1 and 3.0 ± 0.2 mmHg/mL for M1 and M2, respectively. With the transition from rest to mild exercise little change in Ea occurred, whereas with subsequent MMA, Ea increased significantly by 33.6% ± 2.7 and 20.5% ± 2.3 for M1 and M2. We conclude that MMA elicits robust increases in Ea which parallel the substantial increases in ventricular performance thereby optimizing ventricular ‐ vascular coupling.Support or Funding InformationSupported by HL‐55473, HL‐126706, HL120822 and R25 GM058905This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Altered arterial baroreflex-muscle metaboreflex interaction in heart failure.

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.

Muscle Metaboreflex Control of Left Ventricular Filling Pressure

When oxygen delivery to active skeletal muscle is limited, afferent signals from the muscle elicit reflex increases in cardiac output (CO) and mean arterial pressure (MAP) in order to increase perfusion to the ischemic muscle ‐ termed the muscle metaboreflex (MMR). Previous studies have shown that in normal subjects, CO is increased predominantly through increases in heart rate (HR) while maintaining stroke volume (SV) essentially constant. However, increases in HR alone have limited ability to raise CO because as HR increases, SV falls due to decreased filling time. Increases in ventricular contractility can limit the falls in SV, however with sustained increases in CO, blood is translocated from the venous to the arterial circulation and ventricular filling pressure falls which limits the ability to maintain elevated CO. To sustain increases in CO, central blood volume mobilization must also occur to maintain ventricular filling pressure. We previously showed that MMR activation does increase central venous pressure (Sheriff, Augustyniak and O'Leary, Am. J. Physiol., 1998), but whether this translates into increases in left ventricular end‐diastolic pressure (LVEDP) is unknown. MMR was activated via reductions in hindlimb blood flow during mild treadmill exercise in chronically instrumented canines before and after induction of heart failure (HF, rapid ventricular pacing, 220–240 bpm, ~30 days). In normal animals, MMR activation induced a rise in LVEDP from 14.4 ± 1.8 to 18.2 ± 1.8 mmHg (p<0.05) despite substantial increases in HR (Δ 26 ± 4 bpm), CO (Δ 1.45 ± 0.16 l/min) and MAP (Δ 42.3 ± 2.6 mmHg). After induction of HF, MMA activation increased LVEDP from 28.6 ± 2.5 to 38.7 ± 2.6 mmHg (p<0.05) which was a significantly larger rise than observed in normal animals. In HF, the attenuated rise in CO (Δ 0.20 ± 0.08 l/min) with MMR activation likely contributes to the exaggerated increase in LVEDP. We conclude that MMR activation elicits significant blood volume mobilization which increases cardiac filling pressure which thereby likely helps sustain SV despite shortened filling time. In HF, the limited ability to raise CO is not due to reduced filling pressures.Support or Funding InformationNIH RO1 Grants HL055473 and HL126706This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

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

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.

Role of endothelial nitric oxide in control of peripheral vascular conductance during muscle metaboreflex activation.

The muscle metaboreflex is a powerful pressor reflex induced by the activation of chemically sensitive muscle afferents as a result of metabolite accumulation. During submaximal dynamic exercise, the rise in arterial pressure is primarily due to increases in cardiac output, since there is little systemic vasoconstriction. Indeed, in normal animals, we have often shown a small, but significant, peripheral vasodilation during metaboreflex activation, which is mediated, at least in part, by release of epinephrine and activation of vascular β2-receptors. We tested whether this vasodilation is in part due to increased release of nitric oxide caused by the rise in cardiac output eliciting endothelium-dependent flow-mediated vasodilation. The muscle metaboreflex was activated via graded reductions in hindlimb blood flow during mild exercise with and without nitric oxide synthesis blockade [NG-nitro-l-arginine methyl ester (l-NAME); 5 mg/kg]. We assessed the role of increased cardiac output in mediating peripheral vasodilation via the slope of the relationship between the rise in nonischemic vascular conductance (conductance of all vascular beds excluding hindlimbs) vs. the rise in cardiac output. l-NAME increased mean arterial pressure at rest and during exercise. The metaboreflex-induced increases in mean arterial pressure were unaltered by l-NAME, whereas the increases in cardiac output and nonischemic vascular conductance were attenuated. However, the slope of the relationship between nonischemic vascular conductance and cardiac output was not affected by l-NAME, indicating that the rise in cardiac output did not elicit vasodilation via increased release of nitric oxide. Thus, although nitric oxide is intrinsic to the vascular tonus, endothelial-dependent flow-mediated vasodilation plays little role in the small peripheral vasodilation observed during muscle metaboreflex activation.

Altered Arterial Baroreflex ‐ Muscle Metaboreflex Interaction in Heart Failure

Previous studies have shown that heart failure (HF) alters the strength and mechanisms of both the muscle metaboreflex and the arterial baroreflex during dynamic exercise. Muscle metaboreflex activation (MMA) in normal individuals increases mean arterial pressure (MAP) virtually solely by an increase in cardiac output (CO) whereas in HF, the mechanisms of this pressor response shift to peripheral vasoconstriction. In contrast, the pressor response evoked by baroreceptor unloading in normal subjects occurs primarily through peripheral vasoconstriction which is blunted in HF. How HF alters the interaction between these two powerful reflexes when activated simultaneously is unknown. We hypothesized that co‐activation of both reflexes in HF would cause a smaller increase in MAP and a larger vasoconstriction of the ischemic hindlimb vasculature, resulting in an attenuated restoration of blood flow to the ischemic muscle than that observed prior to HF. We activated the muscle metaboreflex in chronically instrumented canines during mild exercise (via graded reductions in hindlimb blood flow; HLBF) followed by baroreceptor unloading (via bilateral carotid occlusion; BCO) before and after induction of HF in the same animals. We observed that interaction between the two reflexes in normal animals is intimately dependent on the hemodynamic parameter investigated; MAP, conductance of all vascular beds except hindlimbs, and ventricular function all exhibited additive interaction, CO and renal conductance demonstrated occlusive interaction while HR exhibited facilitative interaction. Furthermore, BCO during MMA caused a preferentially larger vasoconstriction in non‐ischemic vascular beds, thereby redirecting blood flow to the ischemic vascular bed. However, after induction of HF, all cardiovascular responses except ventricular function exhibited occlusive interaction in response to baroreceptor unloading during MMA. The pressor response during co‐activation of reflexes occurred via substantial vasoconstriction of all vascular beds including the ischemic active muscle and there is no significant restoration of blood flow to the ischemic vascular bed. We conclude that larger vasoconstriction of ischemic active skeletal muscle during co‐activation of both reflexes in HF attenuates the restoration of blood flow to ischemic muscle.Support or Funding InformationHL‐55473 and HL‐126706

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

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.

Role of endothelial nitric oxide in control of peripheral vascular conductance during muscle metaboreflex activation

The muscle metaboreflex is a powerful pressor reflex induced by the activation of chemically sensitive muscle afferents as a result of metabolite accumulation. During submaximal dynamic exercise, the rise in arterial pressure is primarily due to increases in cardiac output as there is little systemic vasoconstriction. Indeed, in normal animals we have shown a small, but significant, peripheral vasodilation during metaboreflex activation which is mediated at least in part by release of epinephrine and activation of vascular β2 receptors (Kaur et al., Am. J. Physiol. Heart Circ., 2015). We tested whether this vasodilation is in part due to increased release of nitric oxide caused by the rise in cardiac output eliciting endothelium‐dependent flow‐mediated vasodilation. The muscle metaboreflex was activated via graded reductions in hindlimb blood flow during mild exercise with and without nitric oxide synthesis blockade (L‐nitroarginine methyl ester (L‐NAME); 5mg/kg). We accessed the role of increased cardiac output in mediating peripheral vasodilation via the slope of the relationship between the rise in non‐ischemic vascular conductance (conductance of all vascular beds excluding hindlimbs) vs. the rise in cardiac output. L‐NAME increased mean arterial pressure at rest and during exercise. The metaboreflex‐induced increases in mean arterial pressure were unaltered by L‐NAME; whereas, the increases in cardiac output and non‐ischemic vascular conductance were attenuated. However, the slope of the relationship between non‐ischemic vascular conductance and cardiac output was not affected by L‐NAME indicating that the rise in cardiac output did not elicit vasodilation via increased release of nitric oxide. Thus, although nitric oxide is intrinsic to the vascular tonus, endothelial‐dependent flow‐mediated vasodilation plays little role in the small peripheral vasodilation observed during muscle metaboreflex activation.Support or Funding Information(NIH HL55473)

Muscle metaboreflex activation during dynamic exercise vasoconstricts ischemic active skeletal muscle.

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.

Muscle Metaboreflex‐Induced Vasoconstriction of Ischemic Active Skeletal Muscle

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 the 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). Hindlimb resistance (Rh) was calculated as hindlimb arterial pressure / HLBF. During mild exercise HLBF must be reduced below a threshold level before MMA occurs. With initial reductions in HLBF, vasodilation occurred with the imposed ischemia. Once muscle metaboreflex was elicited, Rh increased. This increase in Rh was abolished by α1‐adrenergic blockade. We conclude that metaboreflex activation during submaximal dynamic exercise causes sympathetically‐mediated α‐adrenergic vasoconstriction of the ischemic skeletal muscle. HL‐55473

Baroreflex Sympatho‐activation During Muscle Metaboreflex Activation Improves Blood Flow to the Ischemic Muscle

Muscle metaboreflex and arterial baroreflex regulate arterial pressure through distinct mechanisms. 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. 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 the reflexes would result in an exacerbated pressor response owing to both an increase in CO and vasoconstriction. We observed that MMA caused a significant increase in MAP, heart rate (HR), CO, and non‐ischemic vascular conductance (NIVC; conductance of all vascular beds except the hindlimb vasculature). When followed by BCO, there were further increases in MAP and HR however, NIVC decreased by 25% indicating substantial peripheral vasoconstriction. Although the hindlimb resistance in this setting also increased indicating vasoconstriction of the ischemic muscle, the remaining vasculature vasoconstricted more, 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. HL‐55473

Spontaneous baroreflex control of cardiac output during dynamic exercise, muscle metaboreflex activation, and heart failure

We have previously shown that spontaneous baroreflex-induced changes in heart rate (HR) do not always translate into changes in cardiac output (CO) at rest. We have also shown that heart failure (HF) decreases this linkage between changes in HR and CO. Whether dynamic exercise and muscle metaboreflex activation (via imposed reductions in hindlimb blood flow) further alter this translation in normal and HF conditions is unknown. We examined these questions using conscious, chronically instrumented dogs before and after pacing-induced HF during mild and moderate dynamic exercise with and without muscle metaboreflex activation. We measured left ventricular systolic pressure (LVSP), CO, and HR and analyzed the spontaneous HR-LVSP and CO-LVSP relationships. In normal animals, mild exercise significantly decreased HR-LVSP (-3.08 +/- 0.5 vs. -5.14 +/- 0.6 beats.min(-1).mmHg(-1); P < 0.05) and CO-LVSP (-134.74 +/- 24.5 vs. -208.6 +/- 22.2 ml.min(-1).mmHg(-1); P < 0.05). Moderate exercise further decreased both and, in addition, significantly reduced HR-CO translation (25.9 +/- 2.8% vs. 52.3 +/- 4.2%; P < 0.05). Muscle metaboreflex activation at both workloads decreased HR-LVSP, whereas it had no significant effect on CO-LVSP and the HR-CO translation. HF significantly decreased HR-LVSP, CO-LVSP, and the HR-CO translation in all situations. We conclude that spontaneous baroreflex HR responses do not always cause changes in CO during exercise. Moreover, muscle metaboreflex activation during mild and moderate dynamic exercise reduces this coupling. In addition, in HF the HR-CO translation also significantly decreases during both workloads and decreases even further with muscle metaboreflex activation.

Cardiovascular responses to exercise and muscle metaboreflex activation during the recovery from pacing-induced heart failure

Rapid recovery of resting hemodynamics from tachycardia- or arrhythmia-induced heart failure (HF) has been demonstrated in both humans and animals. However, little is known about cardiovascular responses to exercise in animals or about reflex control of the cardiovascular system during exercise while recovering from HF. Inasmuch as the reduced cardiac output (CO) during exercise in HF has been shown to lead to underperfusion of active skeletal muscle and tonic activation of the muscle metaboreflex, an improved CO during exercise in subjects recovering from HF may lead to higher skeletal muscle blood flows and to relief of this metabolic stimulus. We investigated cardiovascular responses to graded treadmill exercise and metaboreflex activation [evoked by imposed graded reductions in hindlimb blood flow (HLBF) during mild and moderate exercise] in chronically instrumented dogs during control, mild to moderate HF (induced by rapid ventricular pacing), and recovery from HF. Most hemodynamic responses to graded exercise returned to control within 24 h of disconnecting the pacemaker. After 2 wk of recovery, CO and HLBF at each workload were significantly higher than control. In addition, whereas the increase in CO that normally occurs with metaboreflex activation was markedly attenuated in HF, it completely returned in the recovery experiments. We conclude that cardiovascular responses to graded exercise during the recovery from pacing-induced HF return rapidly to near or above control and that the increased CO and HLBF in recovery likely relieved the metabolic stimulus and tonic metaboreflex activation that may have occurred during moderate exercise in HF.

Muscle Metaboreflex (MMR) Responses During Recovery From Pacing‐Induced Heart Failure

We studied MMR responses in eight chronically instrumented dogs before and after modest pacing-induced heart failure (HF; 225 bpm for ~30 days; ~Class II HF) and during recovery from HF. The MMR was activated during mild and moderate exercise via imposed graded reductions in hindlimb blood flow (HLBF). In control experiments, decreases in HLBF were necessary to evoke the MMR suggesting that it is not tonically active. MMR activation led to a rise mean arterial pressure (MAP) that was mediated almost solely via a large increase in cardiac output (CO). During HF, the levels of HLBF at both workloads were at or near the threshold for the MMR determined during control experiments, which suggests that the MMR may already have been tonically active. Even small reductions in HLBF induced a pressor response; however, CO remained largely unchanged and the rise in MAP was mediated via peripheral vasoconstriction. With recovery from HF ( 18 days after disconnecting the pacemaker), during free-flow dynamic exercise at both workloads, CO and HLBF tended to be higher than during control experiments. Reductions in HLBF were necessary to evoke the MMR (i.e., there was again a clear threshold) and the mechanisms of the pressor response reverted back to CO, as observed in control experiments. In conclusion, dynamic exercise during recovery from pacing induced HF was accompanied by increased CO and HLBF which likely relieved the metabolic stimulus that led to tonic MMR activation during HF. Supported by NIH HL55473 and VA-DoD Grant.

Altered reflex cardiovascular control during exercise in heart failure: animal studies

This brief review summarizes recent studies describing the potential role of the muscle metaboreflex in mediating the altered cardiovascular responses to dynamic exercise in heart failure and the interaction between the muscle metaboreflex and the arterial baroreflex in these responses. In normal dogs, activation of the muscle metaboreflex (via partial reductions in hindlimb blood flow) during submaximal exercise, elicits a powerful pressor response. This increase in arterial pressure is mediated by an increase in cardiac output with little, if any, peripheral vasoconstriction. The metaboreflex pressor response is buffered by the arterial baroreflex via baroreflex-mediated inhibition of metaboreflex-induced peripheral vasoconstriction. In contrast, after induction of heart failure, the mechanisms involved in the muscle metaboreflex are shifted to vasoconstriction with little, if any, increase in cardiac output. The loss of the cardiac output response of the metaboreflex in heart failure probably stems from inability to improve ventricular function. The shift towards vasoconstriction in this setting may be due to depressed ability of the arterial baroreflex to buffer metaboreflex-induced peripheral vasoconstriction. The relative underperfusion of active skeletal muscle in heart failure may tonically activate the metaboreflex and this probably contributes to the enhanced sympatho-excitation seen during exercise in heart failure.