Heart failure alters the strength and mechanisms of the muscle metaboreflex. Am. J. Physiol. Heart Circ. Physiol. 278: H818-H828, 2000.-We hypothesized that excessive sympathoactivation observed during strenuous exercise in subjects with heart failure (HF) may result from tonic activation of the muscle metaboreflex (MMR) via hypoperfusion of active skeletal muscle. We studied MMR responses in dogs during treadmill exercise by graded reduction of terminal aortic blood flow (TAQ) before and after induction of HF by rapid ventricular pacing. At a low workload, in both control and HF experiments, large decreases in TAQ were required to elicit the MMR pressor response. During control experiments, this pressor response resulted from increased cardiac output (CO), whereas in HF CO did not increase; thus the pressor response was solely due to peripheral vasoconstriction. In HF, MMR activation also induced higher plasma levels of vasopressin, norepinephrine (NE), and renin. At a higher workload, in control experiments any reduction of TAQ elicited MMR pressor responses. In HF, before any vascular occlusion, TAQ was already below MMR control threshold levels and reductions in TAQ again did not result in higher CO; thus SAP increased via peripheral vasoconstriction. NE rose markedly, indicating intense sympathetic activation. We conclude that in HF, the MMR is likely tonically active at moderate workloads and contributes to the tonic sympathoactivation. dynamic exercise; hormones; dogs; Frank-Starling; rapid ventricular pacing WHEN OXYGEN DELIVERY to active skeletal muscle is insufficient for the ongoing metabolic demands, metabolites accumulate and stimulate afferents within the active skeletal muscle that elicit a powerful pressor response known as the muscle metaboreflex. Activation of the muscle metaboreflex during exercise elicits increases in heart rate, cardiac output, systemic arterial pressure, ventricular performance, central blood volume mobilization, and vasoconstriction in the renal and nonischemic active skeletal muscle vasculatures (9,11,12,14,16,17,22,23,25,33). In addition, metaboreflex activation can also increase the circulating levels of vasoactive hormones (13,18). These marked cardiovascular responses are buffered by arterial (23) and cardiopulmonary (4) baroreflexes. Studies from our laboratory and from others (11, 12, 16-18, 22, 23, 33) have shown that in dogs during mild exercise a clear threshold exists for metaboreflex activation, i.e., initial reductions in blood flow to active skeletal muscle (i.e., hindlimbs) do not elicit any metaboreflex responses. Only when oxygen delivery is reduced below a threshold level do substantial metaboreflex pressor responses occur (25). In contrast, during moderate workloads no clear threshold exists, indicating that the metaboreflex may be tonically active or that the prevailing level of blood flow approximates the threshold for the reflex, and any reduction in perfusion to the active skeletal muscle will engage the muscle metaboreflex (20,22,33).The cardiovas...

When oxygen delivery to active muscle is too low for the ongoing rate of metabolism, metabolites accumulate and stimulate sensory nerves within the muscle leading to sympathetic activation (muscle chemoreflex). To date, studies on this reflex have focused primarily on its ability to increase arterial pressure or on the activity of the nerves that mediate this response. Clearly, a rise in cardiac output (CO) constitutes an important adjustment, because it increases the total blood flow available to be distributed among organs competing for flow. However, increments in heart rate and contractility provide limited means of raising CO because of the inverse relationship that exists between CO and right atrial pressure (RAP) in the intact circulation. Our goal was to test whether muscle chemoreflex activation, achieved via graded reductions in hindlimb blood flow by partial vascular occlusion, elicits peripheral vascular adjustments that raise RAP. In four conscious dogs exercising on a treadmill at 3.2 km/h 0% grade, RAP was well maintained during reflex activation despite increases in CO and arterial pressure that are expected to reduce RAP. Thus peripheral vascular adjustments elicited by the reflex successfully defend RAP in a setting where it would otherwise fall. To isolate the effects of the reflex on RAP, CO was maintained constant by ventricular pacing in conjunction with β1-adrenergic blockade with atenolol. When the reflex was activated by reducing hindlimb blood flow from 0.6 to 0.3 l/min, RAP rose from 5.1 ± 0.8 to 7.4 ± 0.4 mmHg ( P < 0.05) despite continued large (40 mmHg) increases in arterial pressure. During heavier exercise (6.4 km/h 10% grade) in five dogs with normal ventricular function, the reflex raised RAP from 5.7 ± 0.9 to 6.6 ± 0.8 mmHg ( P < 0.05) despite increases in CO and arterial pressure. We conclude that the muscle chemoreflex is capable of eliciting substantial increases in RAP.

Ischemia of active skeletal muscle stimulates neuronal afferents within the muscle, which elicits a reflex increase in systemic arterial pressure (SAP), heart rate (HR), and cardiac output (CO) termed the muscle metaboreflex. We investigated whether activation of the muscle metaboreflex elicits increases in ventricular performance using conscious, chronically instrumented dogs trained to run on a treadmill (3.2 km/h, 0% grade). The muscle metaboreflex was activated via progressive partial vascular occlusion of the terminal aorta during control experiments and with HR maintained constant via a pacemaker connected to ventricular electrodes (225 beats/min). In control experiments, hindlimb ischemia elicited substantial increases in SAP, HR, and CO (+53.9 ± 4.3 mmHg, +32.4 ± 4.5 beats/min, and +1.57 ± 0.22 l/min, respectively; all changes P < 0.05), whereas stroke volume (SV) remained unchanged with reflex activation (control 45.9 ± 2.3 vs. 46.1 ± 2.4 ml, P > 0.05). During metaboreflex activation at constant HR, SV significantly increased such that the increases in CO and SAP were not significantly different from control experiments (+1.77 ± 0.56 l/min and +57.4 ± 3.8 mmHg, P > 0.05 vs. control experiments). No significant change in central venous pressure occurred in either experiment, indicating no Frank-Starling effect on SV. We conclude that muscle metaboreflex-induced increases in ventricular contractility act to sustain SV despite decreases in ventricular filling time due to the tachycardia such that the sustained SV coupled with the tachycardia elicits substantial increases in CO that contribute importantly to the reflex increase in SAP.

Previous studies have shown that in dogs performing mild to moderate treadmill exercise, partial graded reductions in hindlimb blood flow cause active skeletal muscle to become ischemic and metabolites to accumulate thus evoking the muscle metaboreflex. This leads to a substantial reflex increase in mean arterial pressure (MAP) mediated almost solely via a rise in cardiac output (CO). However, during severe exercise CO is likely near maximal and thus metaboreflex-mediated increases in MAP may be attenuated. We therefore evoked the metaboreflex via partial graded reductions in hindlimb blood flow in seven dogs during mild, moderate, and severe treadmill exercise. During mild and moderate exercise there was a large rise in CO (1.5 +/- 0.2 and 2.2 +/- 0.3 l/min, respectively), whereas during severe exercise no significant increase in CO occurred. The rise in CO caused a marked pressor response that was significantly attenuated during severe exercise (26.3 +/- 7.0, 33.2 +/- 5.6, and 12.2 +/- 4.8 mmHg, respectively). We conclude that during severe exercise the metaboreflex pressor response mechanisms are altered such that the ability of this reflex to increase CO is abolished, and reduced pressor response occurs only via peripheral vasoconstriction. This shift in mechanisms likely limits the effectiveness of the metaboreflex to increase blood flow to ischemic active skeletal muscle. Furthermore, because the metaboreflex is a flow-raising reflex and not a pressure-raising reflex, it may be most appropriate to describe the metaboreflex magnitude based on its ability to evoke a rise in CO and not a rise in MAP.

Lumbar (LSNA), renal (RSNA), or adrenal sympathetic nerve activity (ASNA) is most commonly used as an index of sympathetic nerve activity in investigations of arterial baroreflex control in the rat. Although differential regulation of sympathetic outputs to different organs has been extensively studied, no direct and simultaneous comparisons of the full range of baroreflex reactivity have been described for these sympathetic outputs. Therefore, we compared steady-state sigmoidal baroreflex stimulus-response curves (via phenylephrine-nitroprusside infusion) for RSNA recorded simultaneously with LSNA or ASNA in urethan-chloralose-anesthetized male Sprague-Dawley rats. Characteristics of the baroreflex curves differed significantly between all three sympathetic outputs. ASNA exhibited the greatest range of baroreflex regulation, the highest upper level of activity, and the widest distribution of the gain over a broad range of mean arterial pressure (MAP). RSNA exhibited greater gain than LSNA. LSNA showed the smallest range and maximal inhibition in comparison to other sympathetic outputs. However, all three nerves responded similarly to baroreflex stimulation and unloading in the range in MAP close to the operating point. We conclude that baroreflex regulation of sympathetic activity shows wide regional variability in gain, range, and maximal inhibition. Therefore, the entire stimulus-response relationship should be considered in comparing regional sympathetic responses.

We hypothesized that performance of exercise during heart failure (HF) would lead to hypoperfusion of active skeletal muscles, causing sympathoactivation at lower workloads and alteration of the normal hemodynamic and hormonal responses. We measured cardiac output, mean aortic and right atrial pressures, hindlimb and renal blood flow (RBF), arterial plasma norepinephrine (NE), plasma renin activity (PRA), and plasma arginine vasopressin (AVP) in seven dogs during graded treadmill exercises and at rest. In control experiments, sympathetic activation at the higher workloads resulted in increased cardiac performance that matched the increased muscle vascular conductance. There were also increases in NE, PRA, and AVP. Renal vascular conductance decreased during exercise, such that RBF remained at resting levels. After control experiments, HF was induced by rapid ventricular pacing, and the exercise protocols were repeated. At rest in HF, cardiac performance was significantly depressed and caused lower mean arterial pressure, despite increased HR. Neurohumoral activation was evidenced by renal and hindlimb vasoconstriction and by elevated NE, PRA, and AVP levels, but it did not increase at the mildest workload. Beyond mild exercise, sympathoactivation increased, accompanied by progressive renal vasoconstriction, a fall in RBF, and very large increases of NE, PRA, and AVP. As exercise intensity increased, peripheral vasoconstriction increased, causing arterial pressure to rise to near normal levels, despite depressed cardiac output. However, combined with redirection of RBF, this did not correct the perfusion deficit to the hindlimbs. We conclude that, in dogs with HF, the elevated sympathetic activity observed at rest is not exacerbated by mild exercise. However, with heavier workloads, sympathoactivation begins at lower workloads and becomes progressively exaggerated at higher workloads, thus altering distribution of blood flow.

The arterial baroreflex mediates changes in arterial pressure via reflex changes in cardiac output (CO) and regional vascular conductance, and the relative roles may change between rest and exercise and across workloads. Therefore, we quantified the contribution of CO and regional vascular conductances to carotid baroreflex-mediated increases in mean arterial pressure (MAP) at rest and during mild to heavy treadmill exercise (3.2 kph; 6.4 kph, 10% grade; and 8 kph, 15% grade). Dogs (n = 8) were chronically instrumented to measure changes in MAP, CO, hindlimb vascular conductance, and renal vascular conductance in response to bilateral carotid occlusion (BCO). At rest and at each workload, BCO caused similar increases in MAP (average 35 +/- 2 mmHg). In response to BCO, neither at rest nor at any workload were there significant increases in CO; therefore, the pressor response occurred via peripheral vasoconstriction. At rest, 10.7 +/- 1.4% of the rise in MAP was due to vasoconstriction in the hindlimb, whereas 4.0 +/- 0.7% was due to renal vasoconstriction. Linear regression analysis revealed that, with increasing workloads, relative contributions of the hindlimb increased and those of the kidney decreased. At the highest workload, the decrease in hindlimb vascular conductance contributed 24.3 +/- 3.4% to the pressor response, whereas the renal contribution decreased to only 1.6 +/- 0.3%. We conclude that the pressor response during BCO was mediated solely by peripheral vasoconstriction. As workload increases, a progressively larger fraction of the pressor response is mediated via vasoconstriction in active skeletal muscle and the contribution of vasoconstriction in inactive beds (e.g., renal) becomes progressively smaller.

We investigated to what extent heart failure alters the ability of the muscle metaboreflex to improve ventricular function. Dogs were chronically instrumented to monitor mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), stroke volume (SV), and central venous pressure (CVP) at rest and during mild treadmill exercise (3.2 km/h) before and during reductions in hindlimb blood flow imposed to activate the muscle metaboreflex. These control experiments were repeated at constant heart rate (ventricular pacing 225 beats/min) and at constant heart rate coupled with a beta-adrenergic blockade (atenolol, 2 mg/kg iv) in normal animals and in the same animals after the induction of heart failure (HF, induced via rapid ventricular pacing). In control experiments in normal animals, metaboreflex activation caused tachycardia with no change in SV, resulting in large increases in CO and MAP. At constant HR, large increases in CO still occurred via significant increases in SV. Inasmuch as CVP did not change in this setting and that beta-adrenergic blockade abolished the reflex increase in SV at constant HR, this increase in SV likely reflects increased ventricular contractility. In contrast, after the induction of HF, much smaller increases in CO occurred with metaboreflex activation because, although increases in HR still occurred, SV decreased thereby limiting any increase in CO. At constant HR, no increase in CO occurred with metaboreflex activation even though CVP increased significantly. After beta-adrenergic blockade, CO and SV decreased with metaboreflex activation. We conclude that in HF, the ability of the muscle metaboreflex to increase ventricular function via both increases in contractility as well as increases in filling pressure are markedly impaired.