Mechanisms mediating muscle metaboreflex control of cardiac output during exercise: Impaired regulation in heart failure.

The ability to increase cardiac output during dynamic exercise is paramount for the ability to maintain workload performance. Reflex control of the cardiovascular system during exercise is complex and multifaceted involving multiple feedforward and feedback systems. One major reflex thought to mediate the autonomic adjustments to exercise is termed the muscle metaboreflex and is activated via afferent neurons within active skeletal muscle which respond to the accumulation of interstitial metabolites during exercise when blood flow and O2 delivery are insufficient to meet metabolic demands. This is one of the most powerful cardiovascular reflexes capable of eliciting profound increases in sympathetic nerve activity, arterial blood pressure, central blood volume mobilization, heart rate and cardiac output. This review summarizes the mechanisms meditating muscle metaboreflex-induced increases in cardiac output. Although much has been learned from studies using anaesthetized and/or decerebrate animals, we focus on studies in conscious animals and humans performing volitional exercise. We discuss the separate and interrelated roles of heart rate, ventricular contractility, ventricular preload and ventricular-vascular coupling as well as the interaction with other cardiovascular reflexes which modify muscle metaboreflex control of cardiac output. We discuss how these mechanisms may be altered in subjects with heart failure with reduced ejection fraction and offer suggestions for future studies.

Altered Autonomic Function in Metabolic Syndrome: Interactive Effects of Multiple Components.

Metabolic syndrome (MetS) describes a set of disorders that collectively influence cardiovascular health, and includes hypertension, obesity, insulin resistance, diabetes, and dyslipidemia. All these components (hypertension, obesity, dyslipidemia, and prediabetes/diabetes) have been shown to modify autonomic function. The major autonomic dysfunction that has been documented with each of these components is in the control of sympathetic outflow to the heart and periphery at rest and during exercise through modulation of the arterial baroreflex and the muscle metaboreflex. Many studies have described MetS components in singularity or in combination with the other major components of metabolic syndrome. However, many studies lack the capability to study all the factors of metabolic syndrome in one model or have not focused on studying the effects of how each component as it arises influences overall autonomic function. The goal of this review is to describe the current understanding of major aspects of metabolic syndrome that most likely contribute to the consequent/associated autonomic alterations during exercise and discuss their effects, as well as bring light to alternative mechanisms of study.

Muscle metaboreflex stimulates the cardiac sympathetic afferent reflex causing positive feedback amplification of sympathetic activity: effect of heart failure.

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O2 delivery and O2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity.NEW & NOTEWORTHY The powerful pressor responses from the CSAR arise via O2 delivery versus O2 demand imbalance. Muscle metaboreflex activation (MMA) simultaneously elicits coronary vasoconstriction (which is augmented in heart failure) and profound increases in cardiac work thereby upsetting oxygen balance. Whether MMA activates the CSAR thereby amplifying MMA responses is unknown. We observed that removal of the CSAR afferents attenuated the strength of the muscle metaboreflex in normal and subjects with heart failure.

Augmented sympathoexcitation slows postexercise heart rate recovery.

Slow heart rate recovery following exercise may be influenced by persistent sympathoexcitation. This study examined 1) the effect of muscle metaboreflex activation (MMA) on heart rate recovery following dynamic exercise; and 2) whether the effect of MMA on heart rate recovery is reversible by reducing sympathoexcitation [baroreflex activation via phenylephrine (PE)] in canines. Twenty-two young adults completed control and MMA protocols during cycle ergometry at 110% ventilatory threshold with 5 min recovery. Heart rate recovery kinetics [tau (τ), amplitude, end-exercise, and end-recovery heart rate] and root mean square of successive differences (RMSSD) were measured. Five chronically instrumented canines completed control, MMA (50%-60% imposed reduction in hindlimb blood flow), and MMA with end-exercise PE infusion (MMA + PE) protocols during moderate exercise (6.4 km·h-1) and 3 min recovery. Heart rate recovery kinetics and MAP were measured. MAP increased during MMA versus control in canines (P < 0.001). Heart rate recovery τ was slower during MMA versus control in humans (17% slower; P = 0.011) and canines (150% slower; P = 0.002). Heart rate recovery τ was faster during MMA + PE versus MMA (40% faster; P = 0.034) and was similar to control in canines (P = 0.426). Amplitude, end-exercise, and end-recovery heart rate were similar between conditions in humans (all P ≥ 0.122) and in canines (all P ≥ 0.084). MMA decreased RMSSD in early recovery (P = 0.004). MMA-induced sympathoexcitation slows heart rate recovery and this effect is markedly attenuated with PE. Therefore, elevated sympathoexcitation via MMA impairs heart rate recovery and inhibition of this stimulus normalizes, in part, heart rate recovery.NEW & NOTEWORTHY Augmented sympathoexcitation, via muscle metaboreflex activation, functionally slows heart rate recovery in both young healthy adults and chronically instrumented canines. Furthermore, elevated sympathoexcitation corresponded with lower parasympathetic activity, as assessed by heart rate variability, during the first 3 min of recovery. Finally, sympathoinhibition, via phenylephrine infusion, normalizes heart rate recovery during muscle metaboreflex activation.

Blood flow restriction training activates the muscle metaboreflex during low-intensity sustained exercise.

Blood flow restriction training (BFRT) employs partial vascular occlusion of exercising muscle and has been shown to increase muscle performance while using reduced workload and training time. Numerous studies have demonstrated that BFRT increases muscle hypertrophy, mitochondrial function, and beneficial vascular adaptations. However, changes in cardiovascular hemodynamics during the exercise protocol remain unknown, as most studies measured blood pressure before the onset and after the cessation of exercise. With reduced perfusion to the exercising muscle during BFRT, the resultant accumulation of metabolites within the ischemic muscle could potentially trigger a large reflex increase in blood pressure, termed the muscle metaboreflex. At low workloads, this pressor response occurs primarily via increases in cardiac output. However, when increases in cardiac output are limited (e.g., heart failure or during severe exercise), the reflex shifts to peripheral vasoconstriction as the primary mechanism to increase blood pressure, potentially increasing the risk of a cardiovascular event. Using our chronically instrumented conscious canine model, we utilized a 60% reduction in femoral blood pressure applied to the hindlimbs during steady-state treadmill exercise (3.2 km/h) to reproduce the ischemic environment observed during BFRT. We observed significant increases in heart rate (+19 ± 3 beats/min), stroke volume (+2.52 ± 1.2 mL), cardiac output (+1.21 ± 0.2 L/min), mean arterial pressure (+18.2 ± 2.4 mmHg), stroke work (+1.93 ± 0.2 L/mmHg), and nonischemic vascular conductance (+3.62 ± 1.7 mL/mmHg), indicating activation of the muscle metaboreflex.NEW & NOTEWORTHY Blood flow restriction training (BFRT) increases muscle mass, strength, and endurance. There has been minimal consideration of the reflex cardiovascular responses that could be elicited during BFRT sessions. We showed that during low-intensity exercise BFRT may trigger large reflex increases in blood pressure and sympathetic activity due to muscle metaboreflex activation. Thus, we urge caution when employing BFRT, especially in patients in whom exaggerated cardiovascular responses may occur that could cause sudden, adverse cardiovascular events.

A cross-species validation of single-beat metrics of cardiac contractility.

The assessment of left ventricular (LV) contractility in animal models is useful in various experimental paradigms, yet obtaining such measures is inherently challenging and surgically invasive. In a cross-species study using small and large animals, we comprehensively tested the agreement and validity of multiple single-beat surrogate metrics of LV contractility against the field-standard metrics derived from inferior vena cava occlusion (IVCO). Fifty-six rats, 27 minipigs and 11 conscious dogs underwent LV and arterial catheterization and were assessed for a range of single-beat metrics of LV contractility. All single-beat metrics were tested for the various underlying assumptions required to be considered a valid metric of cardiac contractility, including load-independency, sensitivity to inotropic stimulation, and ability to diagnose contractile dysfunction in cardiac disease. Of all examined single-beat metrics, only LV maximal pressure normalized to end-diastolic volume (EDV), end-systolic pressure normalized to EDV, and the maximal rate of rise of the LV pressure normalized to EDV showed a moderate-to-excellent agreement with their IVCO-derived reference measure and met all the underlying assumptions required to be considered as a valid cardiac contractile metric in both rodents and large-animal models. Our findings demonstrate that single-beat metrics can be used as a valid, reliable method to quantify cardiac contractile function in basic/preclinical experiments utilizing small- and large-animal models KEY POINTS: Validating and comparing indices of cardiac contractility that avoid caval occlusion would offer considerable advantages for the field of cardiovascular physiology. We comprehensively test the underlying assumptions of multiple single-beat indices of cardiac contractility in rodents and translate these findings to pigs and conscious dogs. We show that when performing caval occlusion is unfeasible, single-beat metrics can be utilized to accurately quantify cardiac inotropic function in basic and preclinical research employing various small and large animal species. We report that maximal left-ventricular (LV)-pressure normalized to end-diastolic volume (EDV), LV end-systolic pressure normalized to EDV and the maximal rate of rise of the LV pressure waveform normalized to EDV are the best three single-beat metrics to measure cardiac inotropic function in both small- and large-animal models.

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.

Ventricular-Vascular Uncoupling in Heart Failure: Effects of Arterial Baroreflex-Induced Sympathoexcitation at Rest and During Exercise.

Autonomic alterations in blood pressure are primarily a result of arterial baroreflex modulation of systemic vascular resistance and cardiac output on a beat-by-beat basis. The combined central and peripheral control by the baroreflex likely acts to maintain efficient energy transfer from the heart to the systemic vasculature; termed ventricular-vascular coupling. This level of control is maintained whether at rest or during exercise in healthy subjects. During heart failure, the ventricular-vascular relationship is uncoupled and baroreflex dysfunction is apparent. We investigated if baroreflex dysfunction in heart failure exacerbated ventricular-vascular uncoupling at rest, and during exercise in response to baroreceptor unloading by performing bilateral carotid occlusions in chronically instrumented conscious canines. We observed in healthy subjects that baroreceptor unloading caused significant increases in effective arterial elastance (Ea) at rest (1.2 ± 0.3 mmHg/ml) and during exercise (1.3 ± 0.2 mmHg/ml) that coincided with significant increases in stroke work (SW) (1.5 ± 0.2 mmHg/ml) and (1.6 ± 0.2 mmHg/ml) suggesting maintained ventricular-vascular coupling. Heart Failure significantly increased the effect of baroreceptor unloading on Ea at rest (3.1 ± 0.7 mmHg/ml) and during exercise (2.3 ± 0.5 mmHg/ml) whereas no significant increases in stroke work occurred, thus signifying further ventricular-vascular uncoupling. We believe that the enhanced ventricular-vascular uncoupling observed during baroreceptor unloading only worsens the already challenged orthostatic and exercise tolerance and thereby contributes to poor exercise performance and quality of life for heart failure patients.

Arterial Baroreflex Inhibits Muscle Metaboreflex Induced Increases in Effective Arterial Elastance: Implications for Ventricular-Vascular Coupling.

The ventricular-vascular relationship assesses the efficacy of energy transferred from the left ventricle to the systemic circulation and is quantified as the ratio of effective arterial elastance to maximal left ventricular elastance. This relationship is maintained during exercise via reflex increases in cardiovascular performance raising both arterial and ventricular elastance in parallel. These changes are, in part, due to reflexes engendered by activation of metabosensitive skeletal muscle afferents-termed the muscle metaboreflex. However, in heart failure, ventricular-vascular uncoupling is apparent and muscle metaboreflex activation worsens this relationship through enhanced systemic vasoconstriction markedly increasing effective arterial elastance which is unaccompanied by substantial increases in ventricular function. This enhanced arterial vasoconstriction is, in part, due to significant reductions in cardiac performance induced by heart failure causing over-stimulation of the metaboreflex due to under perfusion of active skeletal muscle, but also as a result of reduced baroreflex buffering of the muscle metaboreflex-induced peripheral sympatho-activation. To what extent the arterial baroreflex modifies the metaboreflex-induced changes in effective arterial elastance is unknown. We investigated in chronically instrumented conscious canines if removal of baroreflex input via sino-aortic baroreceptor denervation (SAD) would significantly enhance effective arterial elastance in normal animals and whether this would be amplified after induction of heart failure. We observed that effective arterial elastance (Ea), was significantly increased during muscle metaboreflex activation after SAD (0.4 ± 0.1 mmHg/mL to 1.4 ± 0.3 mmHg/mL). In heart failure, metaboreflex activation caused exaggerated increases in Ea and in this setting, SAD significantly increased the rise in Ea elicited by muscle metaboreflex activation (1.3 ± 0.3 mmHg/mL to 2.3 ± 0.3 mmHg/mL). Thus, we conclude that the arterial baroreflex does buffer muscle metaboreflex induced increases in Ea and this buffering likely has effects on the ventricular-vascular coupling.

Flowering time advances since the 1970s in a sagebrush steppe community: Implications for management and restoration.

Climate change is widely known to affect plant phenology, but little is known about how these impacts manifest in the widespread sagebrush ecosystem of the Western United States, which supports a number of wildlife species of concern. Shifts in plant phenology can trigger consequences for the plants themselves as well as the communities of consumers that depend upon them. We assembled historical observations of first-flowering dates for 51 species collected in the 1970s and 1980s in a montane sagebrush community in the Greater Yellowstone Ecosystem and compared these to contemporary phenological observations targeting the same species and locations (2016-2019). We also assembled regional climate data (average spring temperature, day of spring snowmelt, and growing degree days) and tested the relationship between first-flowering time and these variables for each species. We observed the largest change in phenology in early-spring flowers, which, as a group, bloomed on average 17 days earlier, and as much as 36 days earlier, in the contemporary data set. Mid-summer flowers bloomed on average 10 days earlier, nonnative species 15 days earlier, and berry-producing shrubs 5 days earlier, while late summer flowering plants did not shift. The greatest correlates of early-spring and mid-summer flowering were average spring temperature and day of snowmelt, which was 21 days earlier, on average, in 2016-2019 relative to the 1973-1978 observations. The shifts in flowering phenology that we observed could indicate developing asynchronies or novel synchronies of these plant resources and wildlife species of conservation concern, including Greater Sage-grouse, whose nesting success is tied to availability of spring forbs; grizzly bears, which rely heavily on berries for their fall diet; and pollinators. This underscores the importance of maintaining a diverse portfolio of native plants in terms of species composition, genetics, phenological responsiveness to climatic cues, and ecological importance to key wildlife and pollinator species. Redundancy within ecological niches may also be important considering that species roles in the community may shift as climate change affects them differently. These considerations are particularly relevant to restoration and habitat-enhancement projects in sagebrush communities across western North America.

Spinal Reflex Control of Arterial Blood Pressure: The Role of TRP Channels and Their Endogenous Eicosanoid Modulators.

The spinal cord is an important integrative center for blood pressure control. Spinal sensory fibers send projections to sympathetic preganglionic neurons of the thoracic spinal cord and drive sympathetically-mediated increases in blood pressure. While these reflexes responses occur in able-bodied individuals, they are exaggerated following interruption of descending control - such as occurs following spinal cord injury. Similar reflex control of blood pressure may exist in disease states, other than spinal cord injury, where there is altered input to sympathetic preganglionic neurons. This review primarily focuses on mechanisms wherein visceral afferent information traveling via spinal nerves influences sympathetic nerve activity and blood pressure. There is an abundance of evidence for the widespread presence of this spinal reflex arch originating from virtually every visceral organ and thus having a substantial role in blood pressure control. Additionally, this review highlights specific endogenous eicosanoid species, which modulate the activity of afferent fibers involved in this reflex, through their interactions with transient receptor potential (TRP) cation channels.

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.

Purinergic receptor antagonism: A viable strategy for the management of autonomic dysreflexia?

The purinergic receptor ligand, ATP, may participate in reflex induced vasoconstriction through sympathetic efferent and sensory afferent mechanisms. However, the role of the purinergic system in contributing to autonomic dysreflexia following spinal cord injury is unclear. The present study investigates the involvement of P2X receptors in contributing to pressor responses during autonomic dysreflexia. Twenty rats were subjected to spinal cord injury and 24 h later hemodynamic responses to colorectal distension were recorded. Animals were randomized to receive intravenous administration of the P2X receptor antagonist, NF023, or vehicle control. The data indicate that NF023 attenuates pressor responses to colorectal distension.

Ventricular contraction and relaxation rates during muscle metaboreflex activation in heart failure: are they coupled?

NEW FINDINGS: What is the central question of this study? Does the muscle metaboreflex affect the ratio of left ventricular contraction/relaxation rates and does heart failure impact this relationship. What is the main finding and its importance? The effect of muscle metaboreflex activation on the ventricular relaxation rate was significantly attenuated in heart failure. Heart failure attenuates the exercise and muscle metaboreflex-induced changes in the contraction/relaxation ratio. In heart failure, the reduced ability to raise cardiac output during muscle metaboreflex activation may not solely be due to attenuation of ventricular contraction but also alterations in ventricular relaxation and diastolic function. ABSTRACT: The relationship between contraction and relaxation rates of the left ventricle varies with exercise. In in vitro models, this ratio was shown to be relatively unaltered by changes in sarcomere length, frequency of stimulation, and ß-adrenergic stimulation. We investigated whether the ratio of contraction to relaxation rate is maintained in the whole heart during exercise and muscle metaboreflex activation and whether heart failure alters these relationships. We observed that in healthy subjects the ratio of contraction to relaxation increases from rest to exercise as a result of a higher increase in contraction relative to relaxation. During muscle metaboreflex activation the ratio of contraction to relaxation is significantly reduced towards 1.0 due to a large increase in relaxation rate matching contraction rate. In heart failure, contraction and relaxation rates are significantly reduced, and increases during exercise are attenuated. A significant increase in the ratio was observed from rest to exercise although baseline ratio values were significantly reduced close to 1.0 when compared to healthy subjects. There was no significant change observed between exercise and muscle metaboreflex activation nor was the ratio during muscle metaboreflex activation significantly different between heart failure and control. We conclude that heart failure reduces the muscle metaboreflex gain and contraction and relaxation rates. Furthermore, we observed that the ratio of the contraction and relaxation rates during muscle metaboreflex activation is not significantly different between control and heart failure, but significant changes in the ratio in healthy subjects due to increased relaxation rate were abolished in heart failure.

Recent advances in exercise pressor reflex function in health and disease.

Autonomic alterations at the onset of exercise are critical to redistribute cardiac output towards the contracting muscles while preventing a fall in arterial pressure due to excessive vasodilation within the contracting muscles. Neural mechanisms responsible for these adjustments include central command, the exercise pressor reflex, and arterial and cardiopulmonary baroreflexes. The exercise pressor reflex evokes reflex increases in sympathetic activity to the heart and systemic vessels and decreases in parasympathetic activity to the heart, which increases blood pressure (BP), heart rate, and total peripheral resistance through vasoconstriction of systemic vessels. In this review, we discuss recent advancements in our understanding of exercise pressor reflex function in health and disease. Specifically, we discuss emerging evidence suggesting that sympathetic vasoconstrictor drive to the contracting and non-contracting skeletal muscle is differentially controlled by central command and the metaboreflex in healthy conditions. Further, we discuss evidence from animal and human studies showing that cardiovascular diseases, including hypertension, diabetes, and heart failure, lead to an altered exercise pressor reflex function. We also provide an update on the mechanisms thought to underlie this altered exercise pressor reflex function in each of these diseases. Although these mechanisms are complex, multifactorial, and dependent on the etiology of the disease, there is a clear consensus that several mechanisms are involved. Ultimately, approaches targeting these mechanisms are clinically significant as they provide alternative therapeutic strategies to prevent adverse cardiovascular events while also reducing symptoms of exercise intolerance.

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.

Guidelines for animal exercise and training protocols for cardiovascular studies.

Whole body exercise tolerance is the consummate example of integrative physiological function among the metabolic, neuromuscular, cardiovascular, and respiratory systems. Depending on the animal selected, the energetic demands and flux through the oxygen transport system can increase two orders of magnitude from rest to maximal exercise. Thus, animal models in health and disease present the scientist with flexible, powerful, and, in some instances, purpose-built tools to explore the mechanistic bases for physiological function and help unveil the causes for pathological or age-related exercise intolerance. Elegant experimental designs and analyses of kinetic parameters and steady-state responses permit acute and chronic exercise paradigms to identify therapeutic targets for drug development in disease and also present the opportunity to test the efficacy of pharmacological and behavioral countermeasures during aging, for example. However, for this promise to be fully realized, the correct or optimal animal model must be selected in conjunction with reproducible tests of physiological function (e.g., exercise capacity and maximal oxygen uptake) that can be compared equitably across laboratories, clinics, and other proving grounds. Rigorously controlled animal exercise and training studies constitute the foundation of translational research. This review presents the most commonly selected animal models with guidelines for their use and obtaining reproducible results and, crucially, translates state-of-the-art techniques and procedures developed on humans to those animal models.

Clinical safety of blood flow-restricted training? A comprehensive review of altered muscle metaboreflex in cardiovascular disease during ischemic exercise.

Blood flow restriction training (BFRT) is an increasingly widespread method of exercise that involves imposed restriction of blood flow to the exercising muscle. Blood flow restriction is achieved by inflating a pneumatic pressure cuff (or a tourniquet) positioned proximal to the exercising muscle before, and during, the bout of exercise (i.e., ischemic exercise). Low-intensity BFRT with resistance training promotes comparable increases in muscle mass and strength observed during high-intensity exercise without blood flow restriction. BFRT has expanded into the clinical research setting as a potential therapeutic approach to treat functionally impaired individuals, such as the elderly, and patients with orthopedic and cardiovascular disease/conditions. However, questions regarding the safety of BFRT must be fully examined and addressed before the implementation of this exercise methodology in the clinical setting. In this respect, there is a general concern that BFRT may generate abnormal reflex-mediated cardiovascular responses. Indeed, the muscle metaboreflex is an ischemia-induced, sympathoexcitatory pressor reflex originating in skeletal muscle, and the present review synthesizes evidence that BFRT may elicit abnormal cardiovascular responses resulting from increased metaboreflex activation. Importantly, abnormal cardiovascular responses are more clearly evidenced in populations with increased cardiovascular risk (e.g., elderly and individuals with cardiovascular disease). The evidence provided in the present review draws into question the cardiovascular safety of BFRT, which clearly needs to be further investigated in future studies. This information will be paramount for the consideration of BFRT exercise implementation in clinical populations.

Development of a decerebrate model for investigating mechanisms mediating viscero-sympathetic reflexes in the spinalized rat.

Autonomic dysreflexia (AD) often occurs in individuals living with spinal cord injury (SCI) and is characterized by uncontrolled hypertension in response to otherwise innocuous stimuli originating below the level of the spinal lesion. Visceral stimulation is a predominant cause of AD in humans and effectively replicates the phenotype in rodent models of SCI. Direct assessment of sympathetic responses to viscerosensory stimulation in spinalized animals is challenging and requires invasive surgical procedures necessitating the use of anesthesia. However, administration of anesthesia markedly affects viscerosensory reactivity, and the effects are exacerbated following spinal cord injury (SCI). Therefore, the major goal of the present study was to develop a decerebrate rodent preparation to facilitate quantification of sympathetic responses to visceral stimulation in the spinalized rat. Such a preparation enables the confounding effect of anesthesia to be eliminated. Sprague-Dawley rats were subjected to SCI at the fourth thoracic segment. Four weeks later, renal sympathetic nerve activity (RSNA) responses to visceral stimuli were quantified in urethane/chloralose-anesthetized and decerebrate preparations. Visceral stimulation was elicited via colorectal distension (CRD) for 1 min. In the decerebrate preparation, CRD produced dose-dependent increases in mean arterial pressure (MAP) and RSNA and dose-dependent decreases in heart rate (HR). These responses were significantly greater in magnitude among decerebrate animals when compared with urethane/chloralose-anesthetized controls and were markedly attenuated by the administration of urethane/chloralose anesthesia after decerebration. We conclude that the decerebrate preparation enables high-fidelity quantification of neuronal reactivity to visceral stimulation in spinalized rats. NEW & NOTEWORTHY In animal models commonly used to study spinal cord injury, quantification of sympathetic responses is particularly challenging due to the increased susceptibility of spinal reflex circuits to the anesthetic agents generally required for experimentation. This constitutes a major limitation to understanding the mechanisms mediating regionally specific neuronal responses to visceral activation in chronically spinalized animals. In the present study, we describe a spinalized, decerebrate rodent preparation that facilitates quantification of sympathetic reactivity in response to visceral stimuli following spinal cord injury. This preparation enables reliable and reproducible quantification of viscero-sympathetic reflex responses resembling those elicited in conscious animals and may provide added utility for preclinical evaluation of neuropharmacological agents for the management of autonomic dysreflexia.

Muscle metaboreflex-induced central blood volume mobilization in heart failure.

Underperfusion of active skeletal muscle causes metabolites to accumulate and stimulate group III and IV skeletal muscle afferents, which triggers a powerful pressor response termed the muscle metaboreflex. Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in healthy individuals increases arterial pressure mainly via substantial increases in cardiac output (CO). The increases in CO occur via the combination of tachycardia and increased ventricular contractility. Importantly, MMA also elicits substantial central blood volume mobilization, which allows the ventricular responses to sustain the increases in CO. Otherwise preload would fall and the increases in CO could not be maintained. In subjects with systolic heart failure (HF), the ability to increase CO during exercise and MMA is markedly reduced, which has been attributed to impaired ventricular contractility. Whether the ability to maintain preload during MMA in HF is preserved is unknown. Using a conscious chronically instrumented canine model, we observed that MMA in HF is able to raise central blood volume similarly as in normal subjects. Therefore, the loss of the ability to raise CO during MMA in HF is not because of the loss of the ability to mobilize blood volume centrally. NEW & NOTEWORTHY In normal subjects during dynamic exercise muscle metaboreflex activation elicits large increases in cardiac output that occur via increases in heart rate, ventricular contractility, and, importantly, marked central blood volume mobilization that acts to maintain ventricular preload, thereby allowing the changes in cardiac function to maintain the increases in cardiac output. In subjects with heart failure, the ability to raise cardiac output during muscle metaboreflex activation is impaired. We investigated whether this is because of the inability to maintain ventricular preload. We found that this reflex is still able to elicit large increases in central blood volume, and therefore the limited ability to raise cardiac output likely stems from ventricular dysfunction and not the ability to maintain preload.