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Muscle metaboreflex control of ventricular contractility during dynamic exercise

Departments of ¹Physiology and ²Surgery, Wayne State University School of Medicine, Detroit, Michigan

Submitted 12 August 2005 ; accepted in final form 19 September 2005

	ABSTRACT

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When oxygen delivery to active skeletal muscle is insufficient for the metabolic demands, afferent nerves within muscles are activated, which elicit reflex increases in heart rate (HR), cardiac output (CO), and arterial pressure (AP), termed the muscle metaboreflex (MMR). To what extent the increases in CO are the result of increased ventricular contractility is unclear. A widely accepted index of contractility is maximal left ventricular elastance (E_max), the slope of the end-systolic pressure-volume relationship, such as during rapidly imposed reductions in preload. The objective of the present study was to determine whether MMR activation elicits increases in E_max. Experiments were performed using conscious dogs chronically instrumented to measure left ventricular pressure and volume at rest and during mild or moderate treadmill exercise with and without partial hindlimb ischemia to elicit MMR responses. At both workloads, MMR activation significantly increased CO, HR, AP, and maximum rate of change of left ventricular pressure. During both mild and moderate exercise, MMR activation increased E_max to 159.6 ± 8.83 and 155.8 ± 6.32% of the exercise value under free-flow conditions, respectively. We conclude that the increase of ventricular elastance associated with MMR activation indicates that a substantial increase in ventricular contractility contributes to the rise in CO during dynamic exercise.

elastance; pressor response; cardiac function

Previous studies have shown in anesthetized cats that electrically induced static muscle contraction induces an increase in the maximal first derivative of left ventricular pressure (LV dP/dt_max) (20, 39). Furthermore Mitchell et al. (20) showed that the increase in the derivative of left ventricular pressure at 25 mmHg developed pressure was abolished by -receptor blockade, suggesting that reflexes arising from skeletal muscle afferents can cause considerable increases in ventricular contractility via increased sympathetic tone. One dilemma with understanding the effects of static muscle contraction is that it is not easy to differentiate the relative roles of mechanosensitive vs. metabosensitive afferents in mediating the pressor responses (13). Also, anesthesia and acute surgical trauma may affect cardiovascular reflexes. Furthermore, traditional measures of ventricular function, such as LV dP/dt_max, SV, and ejection fraction, are affected not only by the contractile state but also by loading conditions (7, 17, 34). Thus an accurate evaluation of LV contractile function has been a long-standing problem. To overcome these limitations, LV contractility has been studied with the pressure-volume technique. The maximal elastance (E_max), measured as LV end-systolic pressure-volume relationship (ESPVR) obtained under different loading conditions, has been validated by several investigators as a model to evaluate LV contraction and is useful for quantifying inotropic state independent of preload and afterload under physiological conditions (7, 10, 11, 15, 17, 40, 41). Employing the pressure-volume analysis technique, we conducted this investigation in an effort to clarify how the MMR modifies LV contractility during mild and moderate dynamic exercise. We hypothesized that the reflex would cause a significant increase in LV contractility at both workloads.

	MATERIALS AND METHODS

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All experiments were performed on six healthy adult mongrel dogs (weight 20–25 kg) of either gender selected for their willingness to run on a motor-driven treadmill. The protocols were reviewed and approved by the Wayne State University Animal Investigation Committee.

Surgical preparation. All animals were surgically instrumented under sterile conditions in the same manner, allowing the same animal to be used for multiple studies. Before the surgical procedures, all animals were accustomed to human handling and trained to run freely on a treadmill. The animals were prepared in a series of two surgical sessions with at least 10–14 days between surgeries and at least 1 wk between the last surgery and the first experiment. Every animal received acepromazine (0.2 mg/kg im) 30 min before anesthetic induction for preoperative sedation. For all surgical procedures, the animals were anesthetized with intravenous thiopental sodium (25 mg/kg), maintained with isoflurane gas anesthesia (1–3%), and treated for postoperative discomfort with a transdermal fentanyl patch (Duragesic; Janssen Pharmaceutica), which delivered a dose of 125–150 µg/h for 3 days. Immediately before and after each surgery, cefazolin (500 mg iv) was given, and then cephalexin (30 mg/kg by mouth, 2 times/day) was given to avoid postoperative infection. During recovery from surgery, intravenous buprenorphine (0.015 mg/kg) and maleate acepromazine (0.1 mg/kg) and oral etorolac (10–15 mg·kg^–1·day^–1) also were administered for discomfort control and sedation as needed.

In the first surgical session, a midline sternotomy was performed. Hydraulic vascular occluders (16 or 14 mm; In Vivo Metrics) were placed on the superior and inferior vena cavae, respectively, to manipulate the venous return necessary to construct a set of pressure-volume (P-V) loops. The pericardium was then widely opened, and a 20- or 24-mm blood flow transducer (Transonic Systems) was positioned around the ascending aorta to measure CO. Two pairs of sonomicrometry crystals (Sonometrics) were implanted in the endocardium of the left ventricle to measure the anterior-to-posterior (short axis) and base-to-apex (long axis) dimensions. Three stainless steel ventricular pacing electrodes (O-Flexon; Ethicon) were sutured to the right ventricular free wall for studies unrelated to the present investigation. A fully implantable telemetered blood pressure transducer (model PAD-70; Data Sciences International) was placed subcutaneously on the left side of the chest. Its catheter was tunneled into the thoracic cavity and located inside the left ventricle for measuring LV pressure (LVP). The pericardium was reapproximated loosely, and the chest was closed in layers.

After a 10- to 14-day recovery period, dogs underwent a second surgical session. Through a left abdominal retroperitoneal approach, a 10-mm blood flow probe (Transonic Systems) was placed on the terminal aorta to measure hindlimb blood flow (HLBF). A 10-mm hydraulic vascular occluder (In Vivo Metrics) was placed on the terminal aorta just distal to the flow probe. All arteries branching from the aorta between the iliac arteries and the HLBF probe were ligated and severed, and a catheter was placed through a lumbar artery proximal to the HLBF probe and occluder to measure MAP. All cables, wires, occluder tubing, and the aortic catheter were tunneled subcutaneously and exteriorized between the scapulas at the end of each surgery.

Experimental procedures. All experiments were performed after the animals had fully recovered from instrumentation (i.e., active, afebrile, and of good appetite). Before the experimental sessions, each animal was transported to the laboratory, allowed to roam freely for 15–30 min, and then led to the treadmill. The blood flow transducers were connected to the flow meters (Transonic System). HR was computed by a cardiotachometer triggered by the CO signal. The arterial catheter was connected to a pressure transducer (Transpac IV; Abbott Laboratories). The LV implant was turned on and the quality of the signal verified. All crystals were coupled to the sonomicrometer. All data were recorded on a pen-chart recorder (Gould model RS 3800) as well as computerized analog-to-digital recording systems for subsequent off-line analyses. For a given experimental session, data were collected at rest and then at a randomly selected workload (mild exercise: 3.2 km/h, 0% grade elevation; moderate exercise: 6.4 km/h, 10% grade elevation). Steady-state data and data recorded during transient vena cavae occlusions (several sets of variably loaded P-V loops) were recorded at rest while the animal was standing on the motorized treadmill, during exercise with unrestricted blood flow to the hindlimbs, and after MMR activation. MMR was elicited by reductions in HLBF by partial inflation of the terminal aortic occluder as shown in previous studies (26–28, 30). Each dog completed several experiments at both workloads, and thus each animal served as it own control.

Data analysis. During the experiments, MAP, HR, LVP, CO, HLBF, and LV short- and long-axis dimensions were collected continuously. Later, off-line data analyses yielded LV dP/dt_max-min, SV, and LV end-diastolic and end-systolic pressure and volume loops (Advanced CODAS, Dataq Instruments).

The data obtained before caval occlusion were averaged during steady state for 30 s so that the recording period spanned multiple respiratory cycles. The data were averaged at each condition (at rest, during exercise with unrestricted blood flow to the hindlimbs, and after MMR activation) across all experiments for each animal. These mean values were then averaged across animals to obtain the mean values for the population studied. Thus each animal contributed only once to the overall averages. The ESPVR and its slope (E_max) were assessed by using the following method: LV volume (LVV) was calculated as a modified ellipsoid (4) using the equation LVV = (/6) x D_SA x D_SA x D_LA, where D_SA is the anterior-to-posterior (short axis) LV diameter and D_LA is the apex-to-base (long axis) LV diameter. Nozawa et al. (24) and other investigators (23) previously demonstrated that this method gives a consistent measure of LVV despite changes in LV loading conditions, configurations, and HR. The P-V relationship for each beat during cavae occlusion was plotted, and the end-systolic pressure and volume values were selected as the upper left corner point of each loop (as shown in Fig. 1). Any ectopic beat and the following beat were discarded. During the later stage in the occlusion, if HR rose by more than 10%, then the subsequent beats were excluded. For the validated beats, a linear regression analysis was performed on the selected points to determine E_max.

View larger version (27K): [in this window] [in a new window]   Fig. 1. Simultaneous left ventricular (LV) volume and pressure recordings during caval occlusion from a conscious dog standing at rest (top) and its resulting pressure-volume loops (bottom). The slope of the line passing through the end-systolic points of the loops quantifies the maximal ventricular elastance (Emax) and is indicative of the contractile state of the ventricle.

	RESULTS

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Figure 1 shows LV pressure and volume waves and the resulting set of P-V loops obtained at different preloads induced by inferior and superior vena cavae occlusion, performed at rest. In the same manner, P-V loops were obtained during mild or moderate exercise under free-flow conditions and, finally, during exercise after the MMR was activated via partial reduction of the terminal aortic flow.

Table 1 shows the average levels of HLBF in each workload. Figures 2 and 3 show the effects of mild and moderate exercise and MMR activation via imposed decreases in HLBF on MAP, SV, HR, CO, dP/dt_max, dP/dt_min, and E_max.

View larger version (23K): [in this window] [in a new window]   Fig. 2. Levels of mean arterial pressure (MAP), stroke volume (SV), heart rate (HR), and cardiac output (CO) at rest, during mild and moderate exercise under free-flow conditions (exercise), and with metaboreflex activation (exercise + MRA). #Significantly different from resting levels. *Significantly different from respective exercise control levels. From rest to exercise at both workloads, note the significant increases of SV and HR, resulting in an increase in CO but without any significant influence on MAP. With muscle metaboreflex (MMR) activation, the 4 cardiovascular parameters increased significantly at mild exercise. At moderate workload, SV was maintained constant, whereas the other parameters increased significantly. bpm, beats/min.

View larger version (23K): [in this window] [in a new window]   Fig. 3. Levels of contractility (LV dP/dtmax and Emax) and relaxation (LV dP/dtmin) indexes at rest and during mild and moderate exercise without (exercise) or with MMR activation (exercise + MRA). #Significantly different from resting levels. *Significantly different from respective exercise control levels. From rest to mild exercise, there were no changes in either Emax or dP/dtmin values; meanwhile, LV dP/dtmax increased significantly. All 3 indexes increased substantially with MMR activation. From rest to moderate exercise, pronounced increases in all parameters occurred, increasing even further with MMR activation.

As shown in Fig. 3, from rest to mild exercise, neither E_max nor LV dP/dt_min changed; only LV dP/dt_max showed a small (<5%) yet statistically significant increase. When MMR was activated, the three indexes increased substantially. In contrast, from resting position to moderate exercise, LV dP/dt_max, LV dP/dt_min, and E_max increased significantly, and after MMR activation, all parameters significantly increased even further.

	DISCUSSION

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To our knowledge, this is the first study to investigate the effects of muscle metaboreflex activation on ventricular performance in the pressure-volume plane. It has been well established that the muscle metaboreflex is a very potent cardiovascular reflex capable of inducing a large rise in SNA, which results in significant increases of MAP, HR, CO, central blood volume mobilization, plasma levels of vasoactive hormones, and vasoconstriction in the peripheral vasculatures (1, 2, 8, 25–28, 30, 33, 35, 36, 44). Previous studies performed by others and our group (25) concluded that the increase in HR was an important component of the reflex. After -receptor blockade (25), most of the HR response was abolished and the pressor response was smaller. However, in a subsequent study (26) when HR was held constant, a similar increase in CO occurred due to MMR activation, but this time resulting from an increase in SV. In addition, this increase in SV, with HR maintained constant, was abolished by -receptor blockade (30, 35). Furthermore, White et al. (43) showed that when HR is increased within a range similar to that observed with MMR activation but only via external pacing rather than increased SNA, little increase in CO occurred because of large decreases in SV. Importantly, when the MMR is activated, CO increases significantly not only via a rise in HR but also because SV remains constant or increases slightly. The latter results from an increase in ventricular performance regardless of decreases in ventricular filling time due to the reflex tachycardia. Nobrega et al. (22) demonstrated in humans with atrioventricular block (otherwise normal hearts) that when HR was fixed at resting values during static forearm contractions, SV increased by means of an increase in ventricular contractility plus the Frank-Starling mechanism. We do not know how much of the pressor response in that study was due to MMR activation, because static muscle contraction activates both mechano- and metabosensitive skeletal muscle afferents. In a recent publication, Crisafulli et al. (6) demonstrated in humans that the MMR elicited an increase in SV. Together, these investigations indirectly suggest that increases in ventricular contractility are probably more important in eliciting a significant increase in CO, rather than HR by itself. In agreement with previous investigations, in the present study we found that MMR activation during the mild workload generated a substantial tachycardia and a small but significant increase in SV. As a result, a considerable rise in CO occurred. During moderate exercise, the reflex also elicited a substantial increase in HR, but SV did not increase further; however, by maintaining the elevated SV, a significant increase in CO occurred with the tachycardia.

For decades it has been a challenge for cardiovascular physiologists and cardiologists to accurately evaluate ventricular contractility. For relative ease of assessment, methods, such as cardiothoracic ratio, circumferential shortening velocity, SV, ejection fraction, or peak rate of LV isovolumetric contraction (dP/dt_max), have been widely used despite their major limitations: they are known to be sensitive not only to changes in contractile state but also to loading conditions (7, 17, 34). This motivated us to study the effect of MMR on ventricular contractility not only with the +dP/dt_max approach but also in the pressure-volume plane. Several investigators have demonstrated that the ESPVR, as well as its slope (maximal ventricular elastance), E_max, is relatively insensitive under physiological conditions to changes in preload and afterload yet sensitive to changes to the contractile state of the ventricle (5, 10, 11, 15, 16, 40). In the present study, we observed that from rest to mild exercise, dP/dt_max rose significantly, yet this rise was <5%. In addition, under the same conditions, although E_max tended to increase, the rise was not significant. From rest to moderate workload, there were statistically significant increases in both +dP/dt_max and E_max. These results are in accordance with previous investigations where it was shown that with mild exercise, there is little or no increase in cardiac SNA in dogs (3, 25, 29). Furthermore, when -blockers were administered to the dogs performing mild exercise, no change in the pattern of HR increase was obtained (29). In contrast to the responses during mild exercise, moderate exercise elicited a significant increase in sympathetic nerve activity as reflected by increases in +dP/dt_max in agreement with previous studies (3, 25, 29). Collectively, these studies indicate that in dogs, substantial increases in sympathetic activity to the heart occur at moderate to heavy workloads, which increases ventricular performance. When the MMR was activated at both workloads, ventricular contractility increased significantly, as shown by substantial increases in ±dP/dt and E_max. These increases in E_max strongly support others' and our previous investigations, where increases in ventricular performance have been observed with the activation of the MMR (1, 6, 26).

As previously stated, during exercise under free-flow conditions and when the reflex is activated, SV increases or is maintained constant. As shown by Sheriff et al. (35), this can be achieved via peripheral vascular adjustments that effectively defend cardiac filling pressure despite the increases in HR, CO, and MAP that would otherwise decrease it. In addition, the mean LV filling rate also must increase, because the tachycardia decreases the diastolic filling time (4, 18). Animal and human investigations have shown that the LV is able to increase its mean filling rate and raise or maintain SV constant during exercise by shortening the duration of diastasis and increasing the peak filling rate early in diastole. Little et al. (17) studied conscious dogs during steady-state submaximal exercise with the pressure-volume technique and found a downward shift of the early diastolic portion of the loops. This results in an increased early diastolic pressure gradient across the mitral valve that increases the rate of the early diastolic LV filling. The reduction in early diastolic LV pressure was shown to be due to the combined effects of HR and the adrenergic stimulation occurring during exercise (4, 18). In the present study, we hypothesized that during exercise, MMR activation and its resultant increased sympathetic activity would contribute to enhance the rate of LV relaxation that would produce a fall in early LV diastolic pressure and favor LV filling rate. We explored LV diastolic function by calculating dP/dt_min. As expected, there was no significant change in the minimal rate of LV relaxation (dP/dt_min) from the resting position to mild exercise, but we did observe a significant decrease in dP/dt_min from rest to moderate exercise. In addition, a substantial fall in dP/dt_min values occurred upon metaboreflex activation at both workloads. These results (decrease in dP/dt_min values) are in agreement with the study of Little at al. (4, 18) and indicate that MMR activation improves both systolic and diastolic function.

One limitation we found during the study was that, on average, the SV calculated from the crystals consistently underestimated by 54% the SV obtained by integration of the flow signal from an ultrasonic time-transit probe placed on the ascending aorta. However, the correspondence between both techniques was extremely close. A linear regression performed on the SV values measured with the use of both techniques, for all occlusions at rest, exercise, and during metaboreflex activation, yielded a slope of 0.463 ± 0.0864 with an r value of 0.923 ± 0.02. An explanation for this SV discrepancy could be that the number of crystals and the placement can have an impact on the measurement. Considering the large amount of instrumentation placed in the heart, we decided to use two pairs of crystals to reduce the insult to the left ventricle. Furthermore, the SV values we obtained with the crystals technique are highly consistent with those reported in the literature by other investigators (17, 23). It should also be noted that we studied the responses originating from the hindlimbs, and Hayashi et al. (9) previously showed in anesthetized cats that the responses to electrically induced static muscle contraction differ between the forelimbs and hindlimbs. In settings in which blood flow to all active muscles during exercise is diminished (e.g., heart failure), responses may depend on the relative level of ischemia as well as which muscles are ischemic.

We conclude that at mild and moderate dynamic exercise, muscle metaboreflex improves LV performance via increases in contractility and enhancing ventricular relaxation. This increased LV performance contributes importantly to the reflex increase in CO.

	GRANTS

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This study was supported by National Heart, Lung, and Blood Institute Grant HL-55473 and a joint award from the Departments of Defense and Veterans Affairs.

	ACKNOWLEDGMENTS

 
We thank Sue Harris and Phillip McDonald 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 East 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.

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