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We investigated to what extent maximal ventricular elastance ([E.sub.max]) is dynamically controlled by the arterial baroreflex and force-frequency relation in conscious dogs and to what extent these mechanisms are attenuated after the induction of heart failure (HF). We mathematically analyzed spontaneous beat-to-beat hemodynamic variability. First, we estimated [E.sub.max] for each beat during a baseline period using the ventricular unstressed volume determined with the traditional multiple beat method during vena cava occlusion. We then jointly identified the transfer functions (system gain value and time delay per frequency) relating beat-to-beat fluctuations in arterial blood pressure (ABP) to [E.sub.max] (ABP [right arrow] [E.sub.max]) and beat-to-beat fluctuations in heart rate (HR) to [E.sub.max] (HR [right arrow] [E.sub.max]) to characterize the dynamic properties of the arterial baroreflex and force-frequency relation, respectively. During the control condition, the ABP [right arrow] [E.sub.max] transfer function revealed that ABP perturbations caused opposite direction [E.sub.max] changes with a gain value of -0.023 [+ or -] 0.012 [ml.sup.-1] whereas the HR [right arrow] [E.sub.max] transfer function indicated that HR alterations caused same direction [E.sub.max] changes with a gain value of 0.013 [+ or -] 0.005 mmHg x [ml.sup.-1] x [(beats/min).sup.-1]. Both transfer functions behaved as low-pass filters. However, the ABP [right arrow] [E.sub.max] transfer function was more sluggish than the HR [right arrow][E.sub.max] transfer function with overall time constants (indicator of full system response time to a sudden input change) of 11.2 [+ or -] 2.8 and 1.7 [+ or -] 0.5 s (P < 0.05), respectively. During the HF condition, the ABP [right arrow] [E.sub.max] and HR [right arrow] [E.sub.max] transfer functions were markedly depressed with gain values reduced to -0.0002 [+ or -] 0.007 [ml.sup.-1] and -0.001 [+ or -] 0.004 mmHg x [ml.sup.-1] x [(beats/min).sup.-1] (p < 0.1). [E.sub.max] is rapidly and significantly controlled at rest, but this modulation is virtually abolished in HF. autonomic nervous system; beat-to-beat variability; system identification; Treppe effect; ventricular contractility doi: 10.1152/ajpheart.00922.2009.

Sala-Mercado JA, Ichinose M, Coutsos M, Li Z, Fano D, Ichinose T, Dawe E J, O'Leary DS. Progressive muscle metaboreflex activation gradually decreases spontaneous heart rate baroreflex sensitivity during dynamic exercise. Am J Physiol Heart Circ Phrsiol 298: H594-H600, 2010. First published December 4, 2009: doi:10.1152/ajpheart.00908.2009.--Ischemia of active skeletal muscle elicits a pressor response termed the muscle metaboreflex. We tested the hypothesis that in normal dogs during dynamic exercise, graded muscle metaboreflex activation (MMA) would progressively attenuate spontaneous heart rate baroreflex sensitivity (SBRS). The animals were chronically instrumented to measure heart rate (HR), cardiac output (CO), mean and systolic arterial pressure (MAP and SAP), and left ventricular systolic pressures (LVSP) at rest and during mild or moderate treadmill exercise before and during progressive MMA [via graded reductions of hindlimb blood flow (HLBF)]. SBRS [slopes of the linear relationships (LRs) between HR and LVSP or SAP during spontaneous sequences of [greater than or equal to]3 consecutive beats when HR changed inversely vs. pressure] decreased during mild exercise from the resting values (-5.56 [+ or -] 0.86 vs. -2.67 [+ or -] 0.50 beats * [min.sup.-l] * [mmHg.sup.-1], P exercise reflexes; pressor response; arterial baroreflex sensitivity doi: 10.1152/ajpheart.00908.2009

Am J Physiol Heart Circ Physiol 298: H245-H250, 2010. First published November 6, 2009; doi: 10.1152/ajpheart.00909.2009.--Muscle metaboreflex activation during submaximai dynamic exercise in normal subjects elicits a pressor response primarily due to increased cardiac output (CO). However, when the ability to increase CO is limited, such as in heart failure or during maximal exercise, the muscle metaboreflex-induced increases in arterial pressure occur via peripheral vasoconstriction. How the mechanisms of this pressor response are altered is unknown. We tested the hypothesis that this change in metaboreflex function is dependent on the level of CO. The muscle metaboreflex was activated in dogs during mild dynamic exercise (3.2 km/h) via a partial reduction of hindlimb blood flow. Muscle metaboreflex activation increased CO and arterial pressure, whereas vascular conductance of all areas other than the hindlimbs did not change. CO was then reduced to the same level observed during exercise before the muscle metaboreflex activation via partial occlusion of the inferior and superior vena cavae. Arterial pressure dropped rapidly with the reduction in CO but, subsequently, nearly completely recovered. With the removal of the muscle metaboreflex-induced rise in CO, substantial peripheral vasoconstriction occurred that maintained arterial pressure at the same levels as before CO reduction. Therefore, the muscle metaboreflex function is nearly instantaneously shifted from increased CO to increased vasoconstriction when the muscle metaboreflex-induced rise in CO is removed. We conclude that whether vasoconstriction occurs with muscle metaboreflex depends on whether CO rises. integrative cardiovascular regulation; exercise reflexes; peripheral vascular regulation

We have previously shown that spontaneous baroreflex-induced changes in heart rate (HR) do not always translate into changes in cardiac output (CO) at rest. We have also shown that heart failure (HF) decreases this linkage between changes in HR and CO. Whether dynamic exercise and muscle metaboreflex activation (via imposed reductions in hindlimb blood flow) further alter this translation in normal and HF conditions is unknown. We examined these questions using conscious, chronically instrumented dogs before and after pacing-induced HF during mild and moderate dynamic exercise with and without muscle metaboreflex activation. We measured left ventricular systolic pressure (LVSP), CO, and HR and analyzed the spontaneous HR-LVSP and CO-LVSP relationships. In normal animals, mild exercise significantly decreased HR-LVSP (-3.08 [+ or -] 0.5 vs. -5.14 [+ or -] 0.6 beats x [min.sup.-1] x [mmHg.sup.-1]; P < 0.05) and CO-LVSP (-134.74 [+ or -] 24.5 vs. -208.6 [+ or -] 22.2 ml x [min.sup.-1] x [mmHg.sup.-l]; p < 0.05). Moderate exercise further decreased both and, in addition, significantly reduced HR-CO translation (25.9 [+ or -] 2.8% vs. 52.3 [+ or -] 4.2%; P < 0.05). Muscle metaboreflex activation at both workloads decreased HR-LVSP, whereas it had no significant effect on CO-LVSP and the HR-CO translation. HF significantly decreased HR-LVSP, CO-LVSP, and the HR-CO translation in all situations. We conclude that spontaneous baroreflex HR responses do not always cause changes in CO during exercise. Moreover, muscle metaboreflex activation during mild and moderate dynamic exercise reduces this coupling. In addition, in HF the HR-CO translation also significantly decreases during both workloads and decreases even further with muscle metaboreflex activation. arterial baroreflex sensitivity; exercise reflexes; pressor response; impaired cardiac performance

Dynamic cardiac baroreflex responses are frequently investigated by analyzing the spontaneous reciprocal changes in arterial pressure and heart rate (HR). However, whether the spontaneous baroreflex-induced changes in HR translate into changes in cardiac output (CO) is unknown. In addition, this linkage between changes in HR and changes in CO may be different in subjects with heart failure (HF). We examined these questions using conscious dogs before and after pacing-induced HF. Spontaneous baroreflex sensitivity in the control of HR and CO was evaluated as the slopes of the linear relationships between HR or CO and left ventricular systolic pressure (LVSP) during spontaneous sequences of greater or equal to three consecutive beats when HR or CO changed inversely versus pressure. Furthermore, the translation of baroreflex HR responses into CO responses (HR-CO translation) was examined by computing the overlap between HR and CO sequences. In normal resting conditions, 44.0 [+ or -] 4.4% of HR sequences overlapped with CO sequences, suggesting that only around half of the baroreflex HR responses cause CO responses. In HF, HR-LVSP, CO-LVSP, and the HR-CO translation significantly decreased compared with the normal condition (-2.29 [+ or -] 0.5 vs. -5.78 [+ or -] 0.7 beats x [min.sup.-1] x [mmHg.sup-1] -70.95 [+ or -] 11.8 vs. -229.89 [+ or -] 29.6 ml x [min.sup.-1] x [mmHg.sup.-1]; and 19.66 [+ or -] 4.9 vs. 44.0 [+ or -] 4.4%, respectively). We conclude that spontaneous baroreflex HR responses do not always cause changes in CO. In addition, HF significantly decreases HR-LVSP, CO-LVSP, and HR-CO translation. arterial baroreflex sensitivity; parasympathetic activity; stroke volume

We previously developed a mathematical analysis technique for estimating the static gain values of the arterial total peripheral resistance (TPR) baroreflex ([G.sub.A]) and the cardiopulmonary TPR baroreflex ([G.sub.C]) from small, spontaneous beat-to-beat fluctuations in arterial blood pressure, cardiac output, and stroke volume. Here, we extended the mathematical analysis so as to also estimate the entire arterial TPR baroreflex impulse response [[h.sub.A](t)] as well as the lumped arterial compliance (AC). The extended technique may therefore provide a linear dynamic characterization of TPR baroreflex systems during normal physiological conditions from potentially noninvasive measurements. We theoretically evaluated the technique with respect to realistic spontaneous hemodynamic variability generated by a cardiovascular simulator with known system properties. Our results showed that the technique reliably estimated [h.sub.A](t) [error = 30.2 [+ or -] 2.6% for the square root of energy ([E.sub.A]), 19.7 [+ or -] 1.6% for absolute peak amplitude ([P.sub.A]), 37.3 [+ or -] 2.5% for [G.sub.A], and 33.1 [+ or -] 4.9% for the overall time constant] and AC (error = 17.6 [+ or -] 4.2%) under various simulator parameter values and reliably tracked changes in [G.sub.C]. We also experimentally evaluated the technique with respect to spontaneous hemodynamic variability measured from seven conscious dogs before and after chronic arterial baroreceptor denervation. Our results showed that the technique correctly predicted the abolishment of [h.sub.A](t) [[E.sub.A] = 1.0 [+ or -] 0.2 to 0.3 [+ or -] 0.1, [P.sub.A] = 0.3 [+ or -] 0.1 to 0.1 [+ or -] 0.0 [s.sup.-1], and [G.sub.A] = -2.1 [+ or -] 0.6 to 0.3 [+ or -] 0.2 (P < 0.05)] and the enhancement of [G.sub.C] [-0.7 [+ or -] 0.44 to - 1.8 [+ or -] 0.2 (P < 0.05)] following the chronic intervention. Moreover, the technique yielded estimates whose values were consistent with those reported with more invasive and/or experimentally difficult methods. autonomic nervous system; hemodynamics; modeling; system identification; transfer function

In heart failure (HF), there is a reduced baroreflex sensitivity at rest, and during dynamic exercise there is enhanced muscle metaboreflex activation (MRA). However, how the arterial baroreflex modulates HR during exercise is unknown. We tested the hypothesis that spontaneous baroreflex sensitivity (SBRS) is attenuated during exercise in HF and that MRA further depresses SBRS. In seven conscious dogs we measured heart rate (HR), cardiac output, and left ventricular systolic pressure at rest and during mild and moderate dynamic exercise, before and during MRA (via imposed reductions of hindlimb blood flow), and before and after induction of HF (by rapid ventricular pacing). SBRS was assessed by the sequences method. In control, SBRS was reduced from rest with a progressive resetting of the baroreflex stimulus-response relationship in proportion to exercise intensity and magnitude of MRA. In HF, SBRS was significantly depressed in all settings; however, the changes with exercise and MRA occurred with a pattern similar to the control state. As in control, the baroreftex stimulus-response relationship showed an intensity- and muscle metaboreflex (MMR)-dependent rightward and upward shift. The results of this study indicate that HF induces an impairment in baroreflex control of HR at rest and during exercise, although the effects of exercise and MRA on SBRS occur with a similar pattern as in control, indicating the persistence of some vagal activity. nervous system; autonomic; blood pressure; skeletal muscle afferents

Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Dynamic exercise attenuates spontaneous baroreflex sensitivity (SBRS) in the control of heart rate (HR) during rapid, spontaneous changes in blood pressure (BP). Our objective was to determine whether muscle metaboreflex activation (MRA) further diminishes SBRS. Conscious dogs were chronically instrumented for measurement of HR, cardiac output, mean arterial pressure, and left ventricular systolic pressure (LVSP) at rest and during mild (3.2 km/h) or moderate (6.4 km/h at 10% grade) dynamic exercise before and after MRA (via partial reduction of hindlimb blood flow). SBRS was evaluated as the slopes of the linear relations (LRs) between HR and LVSP during spontaneous sequences of at least three consecutive beats when HR changed inversely vs. pressure (expressed as beats x [min.sup.-1] x mm[Hg.sup.-1]). During mild exercise, these LRs shifted upward, with a significant decrease in SBRS (-3.0 [+ or -] 0.4 vs. -5.2 [+ or -] 0.4, P < 0.05 vs. rest). MRA shifted LRs upward and rightward and decreased SBRS (-2.1 [+ or -] 0.1, P < 0.05 vs. mild exercise). Moderate exercise shifted LRs upward and rightward and significantly decreased SBRS (-1.2 [+ or -] 0.1, P < 0.05 vs. rest). MRA elicited further upward and rightward shifts of the LRs and reductions in SBRS (-0.9 [+ or -] 0.1, P < 0.05 vs. moderate exercise). We conclude that dynamic exercise resets the arterial baroreflex to higher BP and HR as exercise intensity increases. In addition, increases in exercise intensity, as well as MRA, attenuate SBRS. exercise reflexes; pressor response; heart rate variability; arterial baroreflex sensitivity doi:10.1152/ajpheart.00043.2007

Underperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreftex (MMR). In normal dogs during mild exercise, MMR activation causes large increases in cardiac output (CO) and mean arterial pressure (MAP); however, in heart failure (HF) although MAP increases, the rise in CO is virtually abolished, which may be due to an impaired ability to increase left ventricular contractility (LVC). The objective of the present study was to determine whether the increases in LVC seen with MMR activation during dynamic exercise in normal animals are abolished in HF. Conscious dogs were chronically instrumented to measure CO, MAP, and left ventricular (LV) pressure and volume. LVC was calculated from pressure-volume loop analysis [LV maximal elastance ([E.sub.max]) and preload-recruitable stroke work (PRSW)] at rest and during mild and moderate exercise under free-flow conditions and with MMR activation (via partial occlusion of hindlimb blood flow) before and after rapid ventricular pacing-induced HF. In control experiments, MMR activation at both workloads [mild exercise (3.2 km/h) and moderate exercise (6.4 km/h at 10% grade)] significantly increased CO, [E.sub.max], and PRSW. In contrast, after HF was induced, CO, [E.sub.max], and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, [E.sub.max] and PRSW did not change. In addition, MMR activation caused no significant change in CO, [E.sub.max], or PRSW at either workload. We conclude that MMR causes large increases in LVC in normal animals but that this ability is abolished in HF. pressor response; elastance; preload recruitable stroke work doi:10.1152/ajpheart.01240.2006

Feedback control of total peripheral resistance (TPR) by the arterial and cardiopulmonary baroreflex systems is an important mechanism for short-term blood pressure regulation. Existing methods for measuring this TPR baroreflex mechanism typically aim to quantify only the gain value of one baroreflex system as it operates in open-loop conditions. As a result, the normal, integrated functioning of the arterial and cardiopulmonary baroreflex control of TPR remains to be fully elucidated. To this end, the laboratory of Mukkamala et al. (Mukkamala R, Toska K, and Cohen RJ. Am J Physiol Heart Circ Physiol 284: H947-H959, 2003) previously proposed a potentially noninvasive technique for estimating the closed-loop (dimensionless) gain values of the arterial TPR baroreflex ([G.sub.A]) and the cardiopulmonary TPR baroreflex ([G.sub.C]) by mathematical analysis of the subtle, beat-to-beat fluctuations in arterial blood pressure, cardiac output, and stroke volume. Here, we review the technique with additional details and describe its experimental evaluation with respect to spontaneous hemodynamic variability measured from seven conscious dogs, before and after chronic arterial baroreceptor denervation. The technique was able to correctly predict the group-average changes in [G.sub.A] and [G.sub.C] that have previously been shown to occur following chronic arterial baroreceptor denervation. That is, reflex control by the arterial TPR baroreflex was virtually abolished ([G.sub.A] = -2.1 [+ or -] 0.6 to 0.3 [+ or -] 0.2; P < 0.05), while reflex control by the cardiopulmonary TPR baroreflex more than doubled ([G.sub.C] = -0.7 [+ or -] 0.4 to -1.8 [+ or -] 0.2; P < 0.05). With further successful experimental testing, the technique may ultimately be employed to advance the basic understanding of TPR baroreflex functioning in both humans and animals in health and disease. autonomic nervous system; blood pressure; cardiovascular modeling; hemodynamics; system identification

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.sub.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.sub.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.sub.max] to 159.6 [+ or -] 8.83 and 155.8 [+ or -] 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 that heart failure (HF) or sinoaortic denervation (SAD) alters the strength and mechanisms of the muscle metaboreflex during dynamic exercise. However, it is still unknown to what extent SAD may modify the muscle metaboreflex in HF. Therefore, we quantified the contribution of cardiac output (CO) and peripheral vasoconstriction to metaboreflex-mediated increases in mean arterial blood pressure (MAP) in conscious, chronically instrumented dogs before and after induction of HF in both barointact and SAD conditions during mild and moderate exercise. The muscle metaboreflex was activated via partial reductions in hindlimb blood flow. After SAD, the metaboreflex pressor responses were significantly higher with respect to the barointact condition despite lower CO responses. The pressor response was significantly lower in HF after SAD but still higher than that of HF in the barointact condition. During control experiments in the barointact condition, total vascular conductance summed from all beds except the hindlimbs did not change with muscle metaboreflex activation, whereas in the SAD condition both before and after induction of HF significant vasoconstriction occurred. We conclude that SAD substantially increased the contribution of peripheral vasoconstriction to metaboreflex-induced increases in MAP, whereas in HF SAD did not markedly alter the patterns of the reflex responses, likely reflecting that in HF the ability of the arterial baroreflex to buffer metaboreflex responses is impaired. sinoaortic denervation; exercise; cardiac output; arterial baroreflex; exercise pressor response

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 (COL 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/rain) 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. exercise; arterial pressure; cardiac output; ventricular contractility

Heart failure alters the strength and mechanisms of arterial baroreflex pressor responses during dynamic exercise. Am J Physiol Heart Circ Physiol 287: H1682-H1688, 2004. First published June 17, 2004; 10.1152/ajpheart.00358.2004.--Arterial baroreflex function is well preserved during dynamic exercise in normal subjects. In subjects with heart failure (HF), arterial baroreflex ability to regulate blood pressure is impaired at rest. However, whether exercise modifies the strength and mechanisms of baroreflex responses in HF is unknown. Therefore, we investigated the relative roles of cardiac output and peripheral vasoconstriction in eliciting the pressor response to bilateral carotid occlusion (BCO) in conscious, chronically instrumented dogs at rest and during treadmill exercise ranging from mild to heavy workloads. Experiments were performed in the same animals before and after rapid ventricular pacing-induced HF. At rest, the pressor response to BCO was significantly attenuated in HF (33.3 [+ or -] 1.2 vs. 18.7 [+ or -] 2.7 mmHg), and this difference persisted during exercise in part due to lower cardiac output responses in HF. However, both before and after the induction of HF, the contribution of vasoconstriction in active skeletal muscle toward the pressor response became progressively greater as workload increased. We conclude that, although there is an impaired ability of the baroreflex to regulate arterial pressure at rest and during exercise in HF, vasoconstriction in active skeletal muscle becomes progressively more important in mediating the baroreflex pressor response as workload increases with a pattern similar to that observed in normal subjects. carotid sinus hypotension; dog; regional vascular conductance; cardiac output; central venous pressure; pressor response

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Increases in myocardial oxygen consumption during exercise mainly occur via increases in coronary blood flow (CBF) as cardiac oxygen extraction is high even at rest. However, sympathetic coronary constrictor tone can limit increases in CBF. Increased sympathetic nerve activity (SNA) during exercise likely occurs via the action of and interaction among activation of skeletal muscle afferents, central command, and resetting of the arterial baroreflex. As SNA is heightened even at rest in subjects with hypertension (HTN), we tested whether HTN causes exaggerated coronary vasoconstriction in canines during mild treadmill exercise with muscle metaboreflex activation (MMA; elicited by reducing hindlimb blood flow by ~60%) thereby limiting increases in CBF and ventricular performance. Experiments were repeated after α1-adrenergic blockade (prazosin; 75 κg/kg) and in the same animals following induction of HTN (modified Goldblatt 2K1C model). HTN increased mean arterial pressure from 97.1 ± 2.6 to 132.1 ± 5.6 mmHg at rest and MMA-induced increases in CBF, left ventricular dP/dtmax, and cardiac output were markedly reduced to only 32 ± 13, 26 ± 11, and 28 ± 12% of the changes observed in control. In HTN, α1-adrenergic blockade restored the coronary vasodilation and increased in ventricular function to the levels observed when normotensive. We conclude that exaggerated MMA-induced increases in SNA functionally vasoconstrict the coronary vasculature impairing increases in CBF, which limits oxygen delivery and ventricular performance in HTN. [ABSTRACT FROM AUTHOR]