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Impaired muscle metaboreflex-induced increases in
ventricular function in heart failure

Donal S. O'Leary, Javier A. Sala-Mercado, Robert A. Augustyniak, Robert L.
Hammond, Noreen F. Rossi and Eric J. Ansorge
Am J Physiol Heart Circ Physiol 287:H2612-H2618, 2004. First published 15 July 2004;
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Am J Physiol Heart Circ Physiol 287: H2612–H2618, 2004.
First published July 15, 2004; doi:10.1152/ajpheart.00604.2004.
Impaired muscle metaboreflex-induced increases in ventricular function in Donal S. O'Leary,1 Javier A. Sala-Mercado,1 Robert A. Augustyniak,1
Robert L. Hammond,1,2 Noreen F. Rossi,3 and Eric J. Ansorge1
1Departments of Physiology 2Surgery, and 3Internal Medicine, Wayne State University School of
Medicine, and John D. Dingell Veterans Administration Medical Center, Detroit, Michigan 48201

Submitted 17 June 2004; accepted in final form 9 July 2004 O'Leary, Donal S., Javier A. Sala-Mercado, Robert A. Au-
blood flow (HBF)], the primary mechanism mediating the gustyniak, Robert L. Hammond, Noreen F. Rossi, and Eric J.
pressor response is the rise in cardiac output (CO). Increases in Ansorge. Impaired muscle metaboreflex-induced increases in ventric-
ventricular performance combined with maintained or in- ular function in heart failure. Am J Physiol Heart Circ Physiol 287: creased filling pressure act to preserve stroke volume during H2612–H2618, 2004. First published July 15, 2004; doi:10.1152/ metaboreflex activation (24, 31, 43). Stroke volume is sus- ajpheart.00604.2004.—We investigated to what extent heart failure tained despite the decrease in ventricular filling time due to the alters the ability of the muscle metaboreflex to improve ventricular function. Dogs were chronically instrumented to monitor mean arte- tachycardia, which, by itself, would decrease stroke volume rial pressure (MAP), cardiac output (CO), heart rate (HR), stroke (42). Thus the maintained stroke volume coupled with the volume (SV), and central venous pressure (CVP) at rest and during tachycardia increases CO. Metaboreflex-mediated increases in mild treadmill exercise (3.2 km/h) before and during reductions in ventricular performance were revealed when the reflex was hindlimb blood flow imposed to activate the muscle metaboreflex.
activated with HR maintained constant via ventricular pacing These control experiments were repeated at constant heart rate (ven- (24). In this setting of metaboreflex activation with constant tricular pacing 225 beats/min) and at constant heart rate coupled with HR, marked increases in CO still occurred but now via sub- a ␤-adrenergic blockade (atenolol, 2 mg/kg iv) in normal animals and stantial increases in stroke volume (24). Inasmuch as no in the same animals after the induction of heart failure (HF, induced significant change in central venous pressure occurred, these via rapid ventricular pacing). In control experiments in normal ani- increases in stroke volume were unlikely a consequence of the mals, metaboreflex activation caused tachycardia with no change inSV, resulting in large increases in CO and MAP. At constant HR, Frank-Starling effect but rather likely reflected increases in large increases in CO still occurred via significant increases in SV.
ventricular performance. In addition, combining ␤-adrenergic Inasmuch as CVP did not change in this setting and that ␤-adrenergic blockade with ventricular pacing in normal dogs abolished the blockade abolished the reflex increase in SV at constant HR, this reflex increase in CO (31) further indicating that the rise in increase in SV likely reflects increased ventricular contractility. In stroke volume with metaboreflex activation at constant HR contrast, after the induction of HF, much smaller increases in CO reflected reflex increases in ventricular performance.
occurred with metaboreflex activation because, although increases in Recently, we observed that the ability of the muscle HR still occurred, SV decreased thereby limiting any increase in CO.
metaboreflex to increase CO was reduced in animals with mild At constant HR, no increase in CO occurred with metaboreflex to moderate congestive heart failure (HF) (11). In this setting, activation even though CVP increased significantly. After ␤-adrener- activation of the muscle metaboreflex still elicited a significant gic blockade, CO and SV decreased with metaboreflex activation. Weconclude that in HF, the ability of the muscle metaboreflex to increase increase in HR, but little change in CO occurred due to a fall ventricular function via both increases in contractility as well as in stroke volume during metaboreflex activation. HR during increases in filling pressure are markedly impaired.
mild to moderate exercise is significantly increased after in-duction of HF, thus filling time is already reduced in this exercise; arterial pressure; cardiac output; ventricular contractility setting. Substantial metaboreflex-induced tachycardia furtherdecreases ventricular filling time, which could lead to reduc- WHEN OXYGEN DELIVERY to active skeletal muscle is insufficient tions in stroke volume (42). Furthermore, the ventricles may for the prevailing metabolic demands, metabolites accumulate become more afterload sensitive, and the ability of the and stimulate afferents within the active muscle, which elicits metaboreflex to enhance ventricular contractility may be im- a reflex pressor response (termed the muscle metaboreflex).
paired. Thus the mechanisms mediating the reduced ability of Previous studies from our laboratory and others have shown the muscle metaboreflex to increase CO in HF are unclear. The that activation of this reflex causes increases in sympathetic present study was designed to test the hypothesis that in nerve activity, arterial blood pressure, heart rate (HR), cardiac subjects with HF, the ability of the muscle metaboreflex to output (CO), plasma levels of vasoactive hormones, and vaso- increase ventricular function is markedly impaired.
constriction within the kidney and nonischemic active skeletalmuscle (2– 4, 11, 16, 18 –21, 23–26, 29 –32, 41, 43).
Previously, we and others (2– 4, 43) have shown that when Experiments were performed using 10 conscious, chronically in- the muscle metaboreflex is activated during mild to moderate strumented dogs of either gender selected for their willingness to run dynamic exercise in dogs [via partial reductions in hindlimb on a motor-driven treadmill. All procedures were reviewed and Address for reprint requests and other correspondence: D. S. O'Leary, Dept.
The costs of publication of this article were defrayed in part by the payment of Physiology, Wayne State Univ. School of Medicine, 540 East Canfield Ave., of page charges. The article must therefore be hereby marked "advertisement" Detroit, MI 48201 (E-mail:
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
IMPAIRED METABOREFLEX CONTROL OF VENTRICULAR FUNCTION IN HF approved by the institutional animal care and use committee and Data analysis. All data were averaged for 1 min during steady state conformed to National Institutes of Health guidelines.
at rest, free-flow exercise, and with imposed reductions in HBF. Our Surgical preparation. Detailed descriptions of the surgical prepa- objective was that after induction of HF, we would reduce HBF to the ration and postoperative care have been described in several recent same levels as induced before HF within each setting of control previous publications (2– 4, 11). Briefly, in a series of aseptic surgical experiments and experiments at constant HR and constant HR plus sessions, blood flow transducers (Transonic Systems) were implanted ␤-adrenergic blockade. This objective was accomplished in that on the ascending aorta and terminal aorta (immediately proximal to within each experimental setting there were no significant differences the iliac arteries) to monitor CO and hindlimb blood flow (HBF), in the level of HBF during metaboreflex activation.
respectively. A vascular occluder (InVivo Metrics) was placed distal Reductions in HBF via vascular occlusion will also increase arterial to the terminal aortic flow probe to activate the muscle metaboreflex pressure independent of the muscle metaboreflex due to the passive, via partial reductions in HBF. Mean arterial pressure (MAP) and mechanical effect of decreasing vascular conductance to a bed that central venous pressure (CVP) were measured via catheters implanted receives a substantial fraction of CO (4, 22). Because we simul- in the abdominal aorta and atrial-caval junction via the right jugular taneously measured both CO and HBF, the passive, mechanical vein, respectively. In addition, two stainless steel ventricular pacing effect of vascular occlusion on MAP can be directly calculated as electrodes were attached to the apex of the left ventricle for subse- MAPpassive ⫽ COcontrol/(TVCcontrol ⫺ ⌬HVC) where the subscript quent ventricular pacing. All cables and catheters were tunneled control refers to the value during exercise before occlusion, TVC subcutaneously and exteriorized between the scapulae. The animals equals total vascular conductance (TVC ⫽ CO/MAP ⫺ CVP), and were allowed to recover at least 1 wk between surgical procedures and ⌬HVC equals the decrease in hindlimb vascular conductance between the last procedure and the first experiment.
(HVC ⫽ HBF/MAP ⫺ CVP) imparted by inflation of the vascular Experimental protocols. All experiments were performed after the occluder. This passive, mechanical effect of vascular occlusion animals had completely recovered from the surgical preparation, were was subtracted from the observed level of MAP to reveal the active, afebrile, and had a good appetite. The animal was brought to metaboreflex-mediated increase in MAP caused by increases in CO the laboratory and directed to the treadmill. The blood flow transduc- and peripheral vasoconstriction (MAPactive). The extent of periph- ers were connected to flowmeters (Transonic systems) to monitor CO eral vasoconstriction was estimated by calculating vascular con- and HBF, and the catheters were connected to pressure transducers ductance in all vascular beds except the hindlimbs, termed nonis- (Transpac IV, Abbott Laboratories) to monitor MAP and CVP. HR chemic vascular conductance (NIVC), which was calculated as was monitored via a cardiotachometer triggered by the CO signal.
NIVC ⫽ (CO ⫺ HBF)/(MAP ⫺ CVP). All data are reported as Data were displayed on a physiograph (Gould 3800) and were col- means ⫾ SE. Statistical analysis was made via two-way ANOVA lected on a laboratory computer at 1,000 Hz. Beat-by-beat mean for repeated measures, and individual means were compared via values were saved to hard disk for subsequent analysis.
the test for simple effects using SYSTAT software (version 8.0).
The muscle metaboreflex was activated via partial reductions in Statistical significance was concluded if P ⬍ 0.05.
HBF during mild exercise (3.2 km/h, 0% grade). The treadmill wasstarted, and after 3–5 min, HBF was partially decreased via the inflation of the vascular occluder implanted below the blood flowtransducer on the terminal aorta. HBF was decreased to the lowest Table 1 shows the effect of HF on resting hemodynamics.
level at which we felt that animals could maintain the workload for Rapid ventricular pacing caused modest HF characterized by sufficient time to allow the responses to achieve steady state for 60 s increased resting HR, CO, depressed MAP, high CVP, and (usually 3–5 min). Experiments were conducted as described above decreased HBF.
(control) and repeated on a separate day after the ventricular pacing Figures 1, 2, and 3 show the effects of muscle metaboreflex electrodes were connected to a pacemaker (set at 225 beats/min) activation via imposed decreases in HBF on CO, HR, SV, immediately before the experiment to examine the responses to MAP, CVP, and nonischemic vascular conductance in control muscle metaboreflex activation at constant HR. This pacing rate was experiments (Fig. 1), during constant HR (Fig. 2), and during above any level of HR observed in the control experiments. Thepacemaker was disconnected at the end of the experiment. On an constant HR after ␤-adrenergic blockade (Fig. 3) before (nor- additional separate day, the experiment with constant HR was re- mal) and after the induction of HF.
peated coupled with ␤-adrenergic blockade via atenolol (2 mg/kg iv) In normal animals during control experiments (Fig. 1), administered ⬃15 min before the experiment.
muscle metaboreflex activation caused a substantial increase in Induction of HF. After the above experiments were completed, CO. In the same animals after induction of modest HF, the congestive HF was induced via rapid ventricular pacing. The ventric- baseline levels of CO, SV, and HBF during exercise were ular pacing electrodes were connected to a pacemaker set at 225 significantly decreased. HBF was decreased to a similar level beats/min for ⬃30 days. After induction of HF, the experiments were as in the normal setting (483 ⫾ 83 vs. 572 ⫾ 137 ml/min, P ⬎ repeated. The pacemaker was disconnected for the initial control 0.05). CO did rise somewhat with hindlimb ischemia after experiment after the induction of HF and, on separate days, the induction of HF, but the change was less than one-third of that experiments during constant HR (225 beats/min) and constant HRplus ␤-adrenergic blockade were repeated. Thus each animal served as observed in normal animals (⫹1.58 ⫾ 0.34 vs. ⫹0.48 ⫾ 0.10 its own control in each setting of control experiments, constant HR, l/min, P ⬍ 0.05). In both settings, metaboreflex activation and constant HR plus ␤-adrenergic blockade, before and after the caused substantial tachycardia; however, in normal animals induction of congestive HF.
stroke volume was maintained, whereas after HF, metaboreflex Table 1. Effect of heart failure on hemodynamic values at rest Values are means ⫾ SE at rest in animals before and after the induction of heart failure. MAP, mean arterial pressure; CO, cardiac output; HR, heart rate; SV, stroke volume; CVP, central venous pressure; HBF, hindlimb blood flow. * Significantly different from normal.
AJP-Heart Circ Physiol • VOL 287 • DECEMBER 2004 • IMPAIRED METABOREFLEX CONTROL OF VENTRICULAR FUNCTION IN HF Fig. 1. Levels of cardiac output (CO), heart rate (HR), stroke volume (SV),mean arterial pressure (MAP), central venous pressure (CVP), nonischemicvascular conductance (NIVC), and HBF during mild exercise during control(C) and metaboreflex activation (MR) in normal animals and in the sameanimals after induction of heart failure from control experiments. The level ofMAP during MR reflects only MAPactive. *Significantly different from respec- Fig. 2. Levels of CO, HR, SV, MAP, CVP, NIVC, and HBF with HR tive control levels; #control values in heart failure significantly different from maintained constant during mild exercise before (C) and after muscle MR in control values in normal animals. Horizontal brackets with * indicate a normal animals and in the same animals after induction of heart failure.
significant effect of heart failure was detected; vertical brackets with * indicate Abbreviations and symbol definitions as in Fig. 1.
a significant effect of metaboreflex activation was detected; in these settings nosignificant interaction term was detected so pairwise comparisons of individualmeans could not be performed.
AJP-Heart Circ Physiol • VOL 287 • DECEMBER 2004 • IMPAIRED METABOREFLEX CONTROL OF VENTRICULAR FUNCTION IN HF activation caused a significant decrease. In normal animals nochange in nonischemic vascular conductance occurred withmetaboreflex activation, whereas after induction of HF, asignificant decrease was observed with hindlimb ischemia.
ANOVA revealed significant effects of both HF and metabore-flex activation on MAPactive, but no significant interaction termwas detected, indicating that HF decreases MAP, but the reflexincrease in MAPactive was similar in both groups. In normalanimals no change in CVP occurred with metaboreflex activa-tion. After induction of HF, CVP was markedly elevatedduring mild exercise and increased further with metaboreflexactivation.
Metaboreflex activation at constant HR in normal animals induced similar hemodynamic responses as in control experi-ments (Fig. 2). A substantial increase in CO was again ob-served; however, the mechanism of this increase was reversedfrom control experiments in that instead of a tachycardia withsustained stroke volume, HR was experimentally held constant, and the increase in CO occurred due to a significant increase instroke volume. In contrast, after induction of HF, both CO andstroke volume were significantly lower than in normal animalsduring mild exercise, and no significant change occurred ineither variable with metaboreflex activation. HBF was againlower than normal during mild exercise in HF and was de-creased to a similar level as in normal animals for metaboreflex activation (P ⬎ 0.05). As in control experiments, in normalanimals no change in nonischemic vascular conductance wasobserved with metaboreflex activation, whereas after inductionof HF, a significant decrease occurred during metaboreflexactivation. ANOVA also revealed significant effects of HF andmetaboreflex activation on MAPactive, but no significant inter-action term was observed, similar to that observed in controlexperiments. Again similar to control experiments, no reflex change in CVP was observed in normal animals, and afterinduction of HF, CVP was markedly elevated during exerciseand increased further with metaboreflex activation.
Maintaining HR constant plus pretreatment with the ␤-ad- renergic antagonist atenolol altered the hemodynamic re-sponses to mild exercise and metaboreflex activation in bothgroups (Fig. 3). CO and stroke volume were depressed fromcontrol values during mild exercise in both groups but mark-edly so after induction of HF. Indeed stroke volume in thissetting was only ⬃20% of normal levels. ANOVA revealedsignificant effects of HF and metaboreflex activation on bothCO and stroke volume, but in neither case were significantinteraction terms detected. HBF was reduced by nearly 50%during mild exercise after induction of HF, but the levels ofHBF with metaboreflex activation were not significantly dif-ferent. In normal animals, nonischemic vascular conductancedecreased from control levels during exercise by ⬃30% andmore so after induction of HF. ANOVA revealed significanteffects of both HF and metaboreflex activation, but no signif-icant interaction term was detected, indicating that both HF andmetaboreflex activation lowered nonischemic vascular conduc-tance. ANOVA revealed significant effects of HF and Fig. 3. Levels of CO, HR, SV, MAP, CVP, NIVC, and HBF with HR metaboreflex activation as well as a significant interaction term maintained constant plus pretreatment with the ␤-adrenergic receptor antago- for MAPactive, indicating that the reflex increase in MAPactive nist atenolol during mild exercise before (C) and after muscle MR in normal was significantly smaller after induction of HF. CVP was animals and in the same animals after induction of heart failure. Abbreviations substantially higher during mild exercise after induction of HF, and symbol definitions as in Fig. 1.
and in contrast to control experiments, CVP increased similarlyin both groups with metaboreflex activation (e.g., significant AJP-Heart Circ Physiol • VOL 287 • DECEMBER 2004 • IMPAIRED METABOREFLEX CONTROL OF VENTRICULAR FUNCTION IN HF ANOVA HF and metaboreflex effects and no significant inter- metaboreflex activation causes functional increases in ventric- action effect).
ular performance, in part, via increases in sympathetic activity.
Table 2 shows the absolute observed increases in MAP in In contrast, after the induction of HF, only small if any increase each setting (active ⫹ passive changes). In control experiments in CO is observed with metaboreflex activation (see Ref. 11, similar increases in the observed level of MAP occurred with Fig. 1). Although a substantial metaboreflex tachycardia is still metaboreflex activation in normal animals and after induction observed, stroke volume is not maintained but decreases, of HF. However, at constant HR and at constant HR plus which limits any rise in CO. This occurs despite an increase in atenolol smaller increases were observed after induction of HF.
CVP (mechanisms and consequences of this discussed below),which would be expected to raise stroke volume via the Frank-Starling effect. However, Komamura et al. (15) con- The muscle metaboreflex is one of the most powerful car- cluded that the Frank-Starling mechanism is exhausted in HF; diovascular reflexes and is capable of eliciting large increases thus increases in ventricular filling pressure will have little in arterial pressure, HR, CO, CVP, central blood volume impact on stroke volume. The substantial effect of the muscle mobilization, and vasoconstriction in peripheral vascular beds metaboreflex on ventricular function revealed in normal dogs (2– 4, 11, 16, 18 –21, 23–26, 29 –32, 41, 43). In conscious dogs by the large increase in stroke volume when the reflex was during submaximal workloads, the primary mechanism of this activated at constant HR was abolished in HF. In this setting no reflex is to increase CO thereby increasing the total amount of significant metaboreflex-induced increases in stroke volume or blood flow available to the active skeletal muscle (2, 4, 25, 27, CO occurred. The addition of ␤-adrenergic blockade to con- 31, 43). This increase in CO in normal animals likely stems stant HR markedly depressed stroke volume and CO during from several mechanisms (discussed below). In conscious dogs mild exercise in animals after induction of HF and small with HF, the ability of the muscle metaboreflex to increase CO decreases in both occurred with metaboreflex activation likely is severely impaired (11). In the present study, we demon- due to the increase in ventricular afterload. Thus the ability of strated that this impairment is, in part, due to decreased ability the metaboreflex to raise ventricular performance via both to improve ventricular function.
increases in contractility as well as the Frank-Starling mecha- Control of stroke volume. Previously, O'Leary (23) demon- nism are markedly impaired in HF. Several studies have strated that during mild exercise the majority of the metabore- demonstrated a downregulation and desensitization of ␤-ad- flex-induced tachycardia occurs via activation of the sympa- renergic receptors in the ventricular myocardium after induc- thetic nerves to the heart, inasmuch as muscarinic blockade had tion of HF, which likely contributes to this impairment (1, 17).
little effect on the reflex rise in HR, whereas most of the Central blood volume mobilization. During dynamic exer- tachycardia was abolished by ␤-adrenergic blockade (23). In cise when sufficient cardiac reserve exists, muscle metabore- addition, during ␤-adrenergic blockade the reflex rise in MAP flex activation causes substantial increases in CO (2, 4, 43).
was also significantly reduced leading to the conclusion that However, increasing HR or ventricular contractility will have the tachycardia is an important component of the pressor limited sustained effect on CO due to the reciprocal relation- response. However, the results of a subsequent study (24), ship between CO and ventricular filling pressure (31, 33). Thus which were also confirmed in the present study, indicate that increases in CO will decrease CVP thereby decreasing ventric- increases in ventricular performance are likely more important ular preload, which will lower stroke volume due to the than the tachycardia per se. When HR was maintained constant Frank-Starling effect. Therefore, increases in CO by increasing via ventricular pacing, substantial increases in CO still oc- ventricular function become self limiting. Recently, Sheriff et curred with metaboreflex activation, but the mechanism of this al. (31) demonstrated that the muscle metaboreflex is one of the increase shifted from tachycardia with sustained stroke volume most powerful reflexes in the ability to increase central blood to constant HR (experimentally controlled) with significantly volume mobilization. This was indirectly shown by the fact increased stroke volume. Inasmuch as no significant change in that large increases in CO occur with metaboreflex activation, CVP occurred, this increase in stroke volume was unlikely a but no decrease in CVP is observed (see Ref. 31 and Fig. 1). A consequence of the Frank-Starling effect but likely reflected more direct demonstration of a large reflex increase in central increased ventricular contractility. In addition, in a separate blood volume mobilization was the observation that when the study, we (31) subsequently showed that the combination of reflex was activated with CO maintained essentially constant, ventricular pacing coupled with ␤-adrenergic blockade abol- large increases in CVP were observed (31). Similar results ished the increase in CO. Similar results were observed in the were observed in the present study in both normal animals and present study (Fig. 3). These results support the concept that after the induction of HF. In normal animals the combinationof ventricular pacing plus ␤-adrenergic blockade abolishedboth the chronotropic and inotropic changes, little change in Table 2. Absolute observed increases in mean arterial CO occurred, and significant increases in CVP were observed.
pressure with hindlimb occlusion in each setting In the animals after induction of HF, even in the controlexperiments a significant increase in CVP occurred despite a small rise in CO [this rise in CO would be expected to cause less than a 1-mmHg fall in CVP due to the fundamental hydraulic relationship between CO and CVP (31, 33)]. Fur- Constant heart rate thermore, when HR was held constant in the subjects with HF Constant heart rate ⫹ atenolol with or without ␤-adrenergic blockade, little change in COoccurred and CVP increased by Values are means ⫾ SE. * P ⬍ 0.05 vs. normal animal; †P ⬍ 0.05 vs.
⬃2 mmHg. Similar increases control experiment.
were observed in normal dogs when the reflex was activated AJP-Heart Circ Physiol • VOL 287 • DECEMBER 2004 • IMPAIRED METABOREFLEX CONTROL OF VENTRICULAR FUNCTION IN HF with constant HR and ␤-adrenergic blockade in which little We used increases in stroke volume observed in normal (Fig. 3), if any (31), significant change in CO occurred. By animals with metaboreflex activation at constant HR as an comparison of this response to those from other strong cardio- indirect indicator of reflex increases in ventricular perfor- vascular reflexes, unloading of carotid baroreceptors in con- mance. We feel that this is a reasonable estimate of changes in scious dogs with CO held constant results in less than a ventricular contractility, because no change in CVP occurred 1-mmHg rise in CVP (5). Thus the muscle metaboreflex is one and this increase in stroke volume was seen despite marked of the most powerful reflexes in the ability to raise ventricular increases in ventricular afterload. Furthermore, this increase in filling pressure, and this ability is sustained even in HF, stroke volume was abolished by ␤-adrenergic blockade. In wherein baseline levels of CVP are markedly elevated. How- animals after induction of HF, metaboreflex activation at con- ever, in HF this may have little impact on stroke volume due to stant HR caused no change in stroke volume despite significant a reduction in the Frank-Starling mechanism (15).
increases in CVP. Although it should be noted that afterload Mechanisms of metaboreflex pressor responses. In normal was elevated (albeit to a significantly smaller extent in HF, dogs during submaximal dynamic exercise, increases in arterial Table 2) and increased afterload sensitivity in HF may have pressure with metaboreflex activation occur via the increases in obscured any effect of increased ventricular contractility that CO in that little, if any, change in nonischemic vascular could raise stroke volume. Further studies with more direct conductance occurs (see Refs. 2, 4, 11, 43, and Fig. 1). This indexes of ventricular contractility may be warranted.
mechanism is markedly changed in HF. In this setting, little We conclude that HF markedly attenuates the ability of the increase in CO occurs, and significant decreases in nonische- muscle metaboreflex to increase ventricular performance via mic vascular conductance were observed. Indeed, we (11) either the Frank-Starling mechanism or via ␤-adrenergic re- previously reported that virtually complete vasoconstriction of ceptor mediated increases in ventricular contractility. This the kidney was often observed with metaboreflex activation decrease in the ability to raise CO causes a functional shift in after induction of HF. Even in normal dogs a shift in the the mechanisms of muscle metaboreflex-induced increases in mechanism of metaboreflex-induced increases in arterial pres- arterial pressure.
sure, from increases in CO to peripheral vasoconstriction, can also occur. When exercise intensity approaches maximal levelsand little if any further increase in CO is possible, imposed We thank Sue Harris for expert care of the animals.
reductions in HBF still produce a pressor response, but this increase in arterial pressure occurs solely via peripheral vaso-constriction (4). In addition, even during mild exercise, if little This research was supported by National Heart, Lung, and Blood Institute Grant HL-55473 and a joint award from the Departments of Defense and or any increase in CO can occur (e.g., via ventricular pacing Veterans Affairs.
coupled with ␤-adrenergic blockade), a metaboreflex pressorresponse still occurs but now via peripheral vasoconstriction (see Ref. 31, Fig. 3). What causes this marked shift in the 1. Ahmed A. Myocardial ␤-1 adrenoceptor down-regulation in aging and
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