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J Appl Physiol 103: 190-194, 2007. First published May 3, 2007; doi:10.1152/japplphysiol.00139.2007
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Muscle metaboreflex-induced increases in cardiac sympathetic activity vasoconstrict the coronary vasculature

Donal S. O'Leary,1 Javier A. Sala-Mercado,1 Robert L. Hammond,1,2 Eric J. Ansorge,1 Jong-Kyung Kim,1 Jaime Rodriguez,1 Dominic Fano,1 and Masashi Ichinose1,3

Departments of 1Physiology and 2Surgery, Wayne State University School of Medicine, Detroit, Michigan; and 3Laboratory for Applied Human Physiology, Faculty of Human Development, Kobe University, Kobe, Japan

Submitted 1 February 2007 ; accepted in final form 23 April 2007


   ABSTRACT
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Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after {alpha}1-receptor blockade (prazosin, 100 µg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 ± 3.7 ml/min; P < 0.05), CVC did not change (0.45 ± 0.05 vs. 0.47 ± 0.06 ml·min–1·mmHg–1, exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 ± 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 ± 0.08 vs. 0.81 ± 0.17 ml·min–1·mmHg–1, exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 ± 0.1 vs. +3.27 ± 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.

exercise pressor response; coronary blood flow; ventricular function; prazosin; {alpha}-adrenergic receptors

THE MUSCLE METABOREFLEX IS a powerful blood pressure-raising reflex that is activated when oxygen delivery to active skeletal muscle falls below a critical level. During submaximal dynamic exercise in conscious dogs, this reflex acts to increase arterial pressure primarily via reflex increases in cardiac output (CO) (20). These increases in CO stem from increased ventricular performance (1, 13, 15) coupled with central blood volume mobilization (16), which maintains or increases ventricular filling pressure despite the increase in CO, which, by itself, would lower filling pressure (17), and despite the tachycardia, which reduces ventricular filling time. The sustained or slightly increased stroke volume (SV) coupled with the tachycardia elicit substantial increases in CO, which increases perfusion pressure and thereby blood flow to the ischemic active skeletal muscle (14).

The large increases in ventricular performance, heart rate (HR), CO, and ventricular afterload (arterial pressure), which occur with muscle metaboreflex activation, are strong stimuli for increased myocardial oxygen demand and thus metabolic vasodilation in the coronary vasculature (3, 12, 19). However, increases in sympathetic activity to the heart can also activate coronary vascular {alpha}-adrenergic receptors. Previous studies have shown that during normal dynamic exercise, the increases in coronary blood flow (CBF) are limited by the coronary vasoconstrictor effects of the increased cardiac sympathetic tone (5, 7, 8, 18). This restriction in coronary vasodilation functionally limits increases in ventricular performance that otherwise may occur via activation of myocardial beta-adrenergic receptors. To what extent this balance between the direct vasoconstrictor effects of increased cardiac sympathetic tone vs. indirect vasodilator effects (via increases in myocardial oxygen demand) occurs during strong reflex stimulation such as occurs with muscle metaboreflex activation is not well understood. In the present study, we investigated the effects of {alpha}-adrenergic receptor blockade on the coronary vascular responses to muscle metaboreflex activation. We hypothesized that after {alpha}-adrenergic blockade, a substantial vasodilation will occur in the coronary vasculature with muscle metaboreflex activation and that this increased perfusion would result in increased ventricular function.


   METHODS
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All experiments were performed using six conscious dogs (20–25 kg) of either sex selected for their willingness to run on a motor-driven treadmill. All procedures were reviewed and approved by the Wayne State Animal Investigation Committee and conformed to National Institutes of Health guidelines.

Specific details of the surgical preparation and postoperative care have been described in previous studies (1, 2). Briefly, through two surgical procedures (left thoracotomy and left retroperitoneal, separated by at least 14 days), the animals were instrumented to measure left circumflex CBF and CO via placement of ultrasonic blood flow transducers (Transonic) on the left circumflex artery and ascending aorta, respectively. Mean arterial and central venous pressures (MAP and CVP, respectively) were measured via catheters implanted in the abdominal aorta and at the right atrial-vena caval junction (via the right external jugular vein), respectively. Hindlimb blood flow (HLBF) was measured via placement of an ultrasonic blood flow transducer (Transonic) on the terminal aorta just proximal to the iliac arteries. Distal to this flow probe, a vascular occluder was implanted to elicit reductions in HLBF to activate the muscle metaboreflex. The thoracotomy was performed first with at least 2 wk allowed for recovery. At least 1 wk was allowed for recovery before the first experiment. For studies unrelated to the present investigation, ventricular pacing leads (O-Flexon, Ethicon) were installed on the left ventricle and in three animals a catheter was placed in the left ventricle, and an additional blood flow transducer (Transonic) was placed on the left renal artery.

Experimental procedures.   All experiments were performed after the animals had fully recovered from the last surgery and were active, afebrile, and of good appetite. On separate days, experiments were performed in the same animals before and after {alpha}1-adrenergic blockade (prazosin 100 µg/kg iv); thus each animal served as its own control. Each animal was taken to the laboratory and allowed to roam freely for 15–30 min. The animals were then taken to the treadmill, and the blood flow transducers were connected to the flowmeters (Transonic System). The MAP and CVP catheters were connected to pressure transducers (Transpac IV, Abbott Laboratories). All flow and pressure transducers were coupled to both a Gould recording system (model RS 3800) and a computer data acquisition system. HR was monitored via a cardiotachometer triggered by the CO signal. A laboratory computer sampled all data at 1,000 Hz, and mean values for each cardiac cycle were saved on hard disk for subsequent data analysis.

The muscle metaboreflex was activated as described previously (1, 2). Briefly, after steady-state data were obtained with the animal at rest standing on the treadmill, the treadmill was started and advanced to 3.2 km/h, 0% grade (mild exercise). After all parameters had reached steady state (~5 min), the muscle metaboreflex was activated via partial inflation of the vascular occluder placed on the terminal aorta. Our objective was to reduce HLBF to ~50% of the free-flow level during mild exercise. The occlusion was maintained until all parameters achieved at least 60 s of steady state. Data were averaged over 60 s at rest, during mild exercise, and during mild exercise with muscle metaboreflex activation. On a separate day, the experiment was repeated after {alpha}1-adrenergic blockade using prazosin (100 µg/kg iv). The metaboreflex was activated as described above with the objective being to reduce HLBF to the same level as in the control experiment for that animal. One previous study concluded that the vast majority of {alpha}-mediated vasoconstriction in the coronary circulation is via {alpha}1-adrenergic receptors (18). This dose of prazosin was sufficient to abolish the ~20- to 40-mmHg increase in MAP induced by intravenous bolus infusion of phenylephrine (4 µg/kg) for at least the duration of the experiment. Approximately 5–10 min were allowed after infusion of prazosin before the experiment was begun.

Statistical analysis.   Each animal served as its own control. Steady-state values at rest, during mild exercise, and during mild exercise plus muscle metaboreflex activation during control and after {alpha}1-adrenergic blockade were compared using two-way ANOVA for repeated measures. If a significant interaction term was revealed, then pairwise comparisons of individual means was performed using the test for simple effects. All analysis was performed using Systat software (version 11.0).


   RESULTS
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Figure 1 shows the steady-state mean values of MAP, CO, CBF, coronary vascular conductance (CVC), and HLBF at rest, during mild exercise, and during mild exercise plus muscle metaboreflex activation during control experiments and after administration of the {alpha}1-adrenergic receptor antagonist prazosin. There was a larger increase in HLBF in response to mild exercise after prazosin, but the HLBF was reduced to the same level as in control experiments to activate the muscle metaboreflex (P > 0.05 control vs. prazosin). In control experiments, muscle metaboreflex activation caused large increases in MAP, CO, and CBF; however, no significant change in CVC occurred. After {alpha}1-blockade, both CBF and CVC were significantly higher during mild exercise vs. control, and in response to muscle metaboreflex activation both increased even further. In addition, the reflex increase in CO with muscle metaboreflex activation was significantly larger after {alpha}1-receptor blockade. However, despite this larger increase in CO, the increase in MAP was significantly smaller due to substantial peripheral vasodilation with muscle metaboreflex activation. Vascular conductance to all nonischemic vascular beds [calculated as (CO – HLBF)/(MAP – CVP)] did not change significantly with metaboreflex activation in control experiments (55.5 ± 8.2 vs. 53.4 ± 7.5 ml·min–1·mmHg–1, exercise vs. exercise with metaboreflex activation, respectively; P > 0.05). In contrast, after {alpha}1-receptor blockade, metaboreflex activation caused a significant peripheral vasodilation (60.9 ± 7.5 vs. 73.4 ± 8.0 ml·min–1·mmHg–1, exercise vs. exercise with metaboreflex activation, respectively; P < 0.05).


Figure 1
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  		Fig. 1. Mean arterial pressure (MAP), cardiac output (CO), coronary blood flow (CBF), coronary vascular conductance (CVC), and hindlimb blood flow (HLBF) at rest, during mild exercise (EX), and during mild exercise with muscle metaboreflex activation (EX+MMR) during control experiments and after {alpha}1-adrenergic receptor blockade with prazosin. *P < 0.05 rest vs. EX. #P < 0.05 EX vs. EX+MMR. {dagger}P < 0.05 vs. control experiments.

 
Table 1 shows the values of HR, SV, and double product (DP; calculated as HR·MAP, which is useful as an index of left ventricular work). ANOVA revealed both significant setting and drug effects on HR with no significant interaction between the two, indicating that whereas HR was higher after prazosin, the increases with exercise and metaboreflex activation occurred with a similar pattern. ANOVA showed only a significant effect of setting on SV with no significant effect of prazosin or any significant interaction. Similar results were obtained for DP, indicating that prazosin did not affect the amount of work performed by the left ventricle at rest, during exercise, or during exercise with muscle metaboreflex activation. Thus the differences observed in the CBF and CVC responses were likely not due to differences in myocardial work or oxygen demand.


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  		Table 1. Effect of exercise and muscle metaboreflex activation on heart rate, stroke volume, and double product in control experiments and after administration of prazosin

 

   DISCUSSION
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The major new finding in the present study is that muscle metaboreflex activation during dynamic exercise elicits reflex increases in cardiac sympathetic activity and subsequent activation of coronary vascular {alpha}-adrenergic receptors, which restrains coronary vasodilation. This restraint of coronary vasodilation may limit increases in ventricular function with metaboreflex activation.

Previous studies have shown in conscious dogs that the increase in cardiac sympathetic activity during moderate-to-heavy dynamic exercise limits increases in coronary vasodilation, which thereby limits increases in ventricular function. Gwirtz and colleagues (4, 5, 8) observed that coronary {alpha}-adrenergic receptor blockade during dynamic exercise increased coronary blood flow, indexes of cardiac contractility, and CO. These results strongly support the hypothesis that the normal increases in cardiac sympathetic tone and subsequent activation of cardiac vascular {alpha}-adrenergic receptors during dynamic exercise functionally restrain coronary vasodilation. This restraint of coronary flow subsequently limits increases in ventricular performance, likely via limiting coronary oxygen delivery and thereby myocardial oxygen consumption and thus the capacity of the heart to perform work. Thus the increase in cardiac sympathetic nerve activity that occurs during exercise likely both augments cardiac pumping, via activation of beta-adrenergic receptors causing tachycardia and increased ventricular contractility, and also restrains coronary vasodilation, via activation of coronary vascular {alpha} adrenergic receptors, thereby limiting the ability to improve ventricular performance. Huang and Feigl (7) further showed that this sympathetically mediated {alpha}-adrenergic functional coronary vasoconstriction affects the epicardium more than the endocardium. Thus, whereas total flow is limited by the increased cardiac sympathetic drive, this increased coronary vasoconstrictor tone does act to preserve perfusion to the endocardium (increased ratio of endocardial to epicardial blood flow), which may be more at risk of functional ischemia during heavy cardiac work (3). These effects of {alpha}-receptor activation are most likely due to increased sympathetic tone to the heart inasmuch as in normal dogs, plasma levels of norepinephrine do not increase substantially at these workloads (6).

Recently, our laboratory demonstrated during submaximal exercise that despite the large increases in myocardial oxygen demand with muscle metaboreflex activation, no significant coronary vasodilation occurred (2). Although CBF increased, this increase in flow was solely due to the increase in perfusion pressure inasmuch as coronary vascular conductance remained unchanged. These results indicate that the large increases in myocardial oxygen demand induced by muscle metaboreflex activation (large increases in HR, ventricular performance, and CO pumped against a higher afterload) which would be expected to elicit coronary vasodilation, were balanced by the vasoconstrictor effects of the increased cardiac sympathetic activity. Momen et al. (11) also observed little change in coronary vascular resistance in humans (measured in the areas perfused by left internal mammary artery bypass grafts) during fatiguing handgrip exercise and postexercise circulatory occlusion. In that study, with high-intensity forearm static contractions, coronary vasoconstriction was observed. Our laboratory previously observed in dogs that the vasoconstrictor effects were revealed by lessening the rise in myocardial oxygen demand via pacing the heart (to block the reflex tachycardia) combined with beta1-adrenergic blockade (to block the reflex increases in ventricular contractility). In this setting, significant coronary vasoconstriction (decreased coronary vascular conductance) occurred with muscle metaboreflex activation (2). During severe exercise (maximal volitional exercise) in dogs, when CO was already at or near maximal levels, imposed hindlimb ischemia caused no further increase in CO, and significant coronary vasoconstriction occurred (2). Furthermore, muscle metaboreflex activation during mild exercise in dogs with induced heart failure also caused significant decreases in coronary vascular conductance (1). To what extent this enhanced coronary vasoconstriction with metaboreflex activation in heart failure contributes to the markedly attenuated ability to reflexly raise ventricular performance is unknown.

A limitation to the study was that prazosin was administered systemically rather than via intracoronary infusion. A somewhat surprising observation was that, although CO rose significantly more with metaboreflex activation after {alpha}-adrenergic blockade vs. control experiments, and the rise in CO is virtually the sole mechanism of the pressor response during submaximal exercise in normal animals, the increase in MAP was significantly smaller in this setting. This is the result of a significant vasodilation in the nonischemic beds. This observed vasodilation was unexpected. Although the mechanism(s) of this vasodilation are unclear, release of epinephrine from the adrenal gland and subsequent activation of vascular beta2-adrenergic receptors is a distinct possibility. In one animal, we repeated the experiment with prazosin plus the nonspecific beta-receptor antagonist propranolol, and no increase in nonischemic vascular conductance occurred with metaboreflex activation. Thus it is possible that metaboreflex activation stimulates preganglionic adrenal sympathetic nerve activity, inducing the release of epinephrine, activation of vascular beta2-adrenergic receptors, and vasodilation, as has been shown to occur via other stimuli (9). Although we did not measure individual systemic regional vascular conductances, it is likely that at least a portion of the increase in nonischemic vascular conductance with metaboreflex activation after prazosin reflected vasodilation in skeletal muscle, which contains a rich supply of beta2-adrenergic receptors. A portion of the coronary vasodilation could also be due to increases in circulating epinephrine and activation of coronary vascular beta2-adrenergic receptors. Because MAP did not increase to the same extent with metaboreflex activation after {alpha}-adrenergic blockade, we cannot discount that the larger rise in CO was the result of a smaller increase in ventricular afterload vs. that due to higher coronary blood flow and oxygen delivery engendering greater increases in ventricular performance. Furthermore, with the smaller rise in MAP with metaboreflex activation after prazosin, we also cannot discount a reduced myogenic vasoconstriction in the coronary circulation as has been shown to occur in skeletal muscle (10). However, in our laboratory's previous study with metaboreflex activation during acute ventricular pacing plus beta1-receptor blockade (2), the rise in MAP was attenuated to a similar extent and significant coronary vasoconstriction occurred. This observation, coupled with the present study, would argue that the primary mechanisms mediating coronary vascular tone in these settings are changes in sympathetic activity and local metabolism.

In summary, muscle metaboreflex activation increases cardiac sympathetic nerve activity, which elicits activation of coronary {alpha}-adrenergic receptors. Activation of these receptors limits increases in coronary blood flow due to the increases in ventricular work and myocardial oxygen demand as well as possible increases in circulating epinephrine activating vascular beta2-adrenergic receptors. This functional vasoconstriction of the coronary circulation may limit the ability to increase ventricular function.


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This work was supported by National Heart, Lung, and Blood Institute Grant HL-55743.


   ACKNOWLEDGMENTS
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The authors thank Sue Harris and Erin Welsh for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: D. S. O'Leary, Dept. of Physiology, Wayne State Univ. School of Medicine, 540 E. Canfield Ave, Detroit, MI 48201 (e-mail: doleary{at}med.wayne.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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  1. Ansorge EJ, Augustyniak RA, Perinot RL, Hammond RL, Kim JK, Sala-Mercado JA, Rodriguez J, Rossi NF, O'Leary DS. Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure. Am J Physiol Heart Circ Physiol 288: H1381–H1388, 2005.[Abstract/Free Full Text]
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