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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 α 1 -adrenergic blockade (prazosin; 75 µg/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/dt max , and cardiac output were markedly reduced to only 32 ± 13, 26 ± 11, and 28 ± 12% of the changes observed in control. In HTN, α 1 -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., New & Noteworthy: We found that metaboreflex-induced increases in coronary blood flow and ventricular contractility are attenuated in hypertension. α 1 -Adrenergic blockade restored these parameters toward normal levels. These findings indicate that the primary mechanism mediating impaired metaboreflex-induced increases in ventricular function in hypertension is accentuated coronary vasoconstriction., (Copyright © 2017 the American Physiological Society.)

Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in normal individuals increases mean arterial pressure (MAP) via increases in cardiac output (CO) with little peripheral vasoconstriction. The rise in CO occurs primarily via increases in heart rate (HR) with maintained or slightly increased stroke volume. When the reflex is sustained during recovery (postexercise muscle ischemia, PEMI), HR declines yet MAP remains elevated. The role of CO in mediating the pressor response during PEMI is controversial. In seven chronically instrumented canines, steady-state values with MMA during mild exercise (3.2 km/h) were observed by reducing hindlimb blood flow by ~60% for 3-5 min. MMA during exercise was followed by 60 s of PEMI. Control experiments consisted of normal exercise and recovery. MMA during exercise increased MAP, HR, and CO by 55.3 ± 4.9 mmHg, 42.5 ± 6.9 beats/min, and 2.5 ± 0.4 l/min, respectively. During sustained MMA via PEMI, MAP remained elevated and CO remained well above the normal recovery levels. Neither MMA during dynamic exercise nor during PEMI significantly affected peripheral vascular conductance. We conclude that the sustained increase in MAP during PEMI is driven by a sustained increase in CO not peripheral vasoconstriction.

We tested whether mild and moderate dynamic exercise and muscle metaboreflex activation (MMA) affect dynamic baroreflex control of heart rate (HR) and cardiac output (CO), and the influence of stroke volume (SV) fluctuations on CO regulation in normal (N) and pacing-induced heart failure (HF) dogs by employing transfer function analyses of the relationships between spontaneous changes in left ventricular systolic pressure (LVSP) and HR, LVSP and CO, HR and CO, and SV and CO at low and high frequencies (Lo-F, 0.04-0.15 Hz; Hi-F, 0.15-0.6 Hz). In N dogs, both workloads significantly decreased the gains for LVSP-HR and LVSP-CO in Hi-F, whereas only moderate exercise also reduced the LVSP-CO gain in Lo-F. MMA during mild exercise further decreased the gains for LVSP-HR in both frequencies and for LVSP-CO in Lo-F. MMA during moderate exercise further reduced LVSP-HR gain in Lo-F. Coherence for HR-CO in Hi-F was decreased by exercise and MMA, whereas that in Lo-F was sustained at a high level (>0.8) in all settings. HF significantly decreased dynamic HR and CO regulation in all situations. In HF, the coherence for HR-CO in Lo-F decreased significantly in all settings; the coherence for SV-CO in Lo-F was significantly higher. We conclude that dynamic exercise and MMA reduces dynamic baroreflex control of HR and CO, and these are substantially impaired in HF. In N conditions, HR modulation plays a major role in CO regulation. In HF, influence of HR modulation wanes, and fluctuations of SV dominate in CO variations.

Muscle metaboreflex activation during submaximal 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.

Arterial blood pressure (ABP) short term variability is due to beat-by-beat fluctuations in cardiac output (CO) and total peripheral resistance (TPR), which have distinct effects at low and high frequencies. In particular, it was shown that CO is able to buffer TPR slow oscillations in the LF band, but it has not been addressed if CO can contribute to oscillations of ABP in this band. In this paper, we propose a model for the identification of ABP variability sources, in order to show evidence that CO fluctuations are not a source of ABP LF oscillations, but they only buffer ABP variability of vasomotor origin.

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 +/- 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 +/- 0.5 vs. -5.78 +/- 0.7 beats.min(-1).mmHg(-1); -70.95 +/- 11.8 vs. -229.89 +/- 29.6 ml.min(-1).mmHg(-1); and 19.66 +/- 4.9 vs. 44.0 +/- 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.

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 +/- 0.5 vs. -5.14 +/- 0.6 beats.min(-1).mmHg(-1); P < 0.05) and CO-LVSP (-134.74 +/- 24.5 vs. -208.6 +/- 22.2 ml.min(-1).mmHg(-1); P < 0.05). Moderate exercise further decreased both and, in addition, significantly reduced HR-CO translation (25.9 +/- 2.8% vs. 52.3 +/- 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.

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 (Emax), 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 Emax. 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 Emax 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.

Previous studies showed that the arterial baroreflex opposes the pressor response mediated by muscle metaboreflex activation during mild dynamic exercise. However, no studies have investigated the mechanisms contributing to metaboreflex-mediated pressor responses during dynamic exercise after arterial baroreceptor denervation. Therefore, we investigated the contribution of cardiac output (CO) and peripheral vasoconstriction in mediating the pressor response to graded reductions in hindlimb perfusion in conscious, chronically instrumented dogs before and after sinoaortic denervation (SAD) during mild and moderate exercise. In control experiments, the metaboreflex pressor responses were mediated via increases in CO. After SAD, the metaboreflex pressor responses were significantly greater and significantly smaller increases in CO occurred. During control experiments, nonischemic vascular conductance (NIVC) did not change with muscle metaboreflex activation, whereas after SAD NIVC significantly decreased with metaboreflex activation; thus SAD shifted the mechanisms of the muscle metaboreflex from mainly increases in CO to combined cardiac and peripheral vasoconstrictor responses. We conclude that the major mechanism by which the arterial baroreflex buffers the muscle metaboreflex is inhibition of metaboreflex-mediated peripheral vasoconstriction.

During dynamic exercise, muscle metaboreflex activation (MMA; induced via partial hindlimb ischemia) markedly increases mean arterial pressure (MAP), and MAP is sustained when the ischemia is maintained following the cessation of exercise (postexercise muscle ischemia, PEMI). We previously reported that the sustained pressor response during PEMI in normal individuals is driven by a sustained increase in cardiac output (CO) with no peripheral vasoconstriction. However, we have recently shown that the rise in CO with MMA is significantly blunted in hypertension (HTN). The mechanisms sustaining the pressor response during PEMI in HTN are unknown. In six chronically instrumented canines, hemodynamic responses were observed during rest, mild exercise (3.2 km/h), MMA, and PEMI in the same animals before and after the induction of HTN [Goldblatt two kidney, one clip (2K1C)]. In controls, MAP, CO and HR increased with MMA (+52 ± 6 mmHg, +2.1 ± 0.3 l/min, and +37 ± 7 beats per minute). After induction of HTN, MAP at rest increased from 97 ± 3 to 130 ± 4 mmHg, and the metaboreflex responses were markedly attenuated (+32 ± 5 mmHg, +0.6 ± 0.2 l/min, and +11 ± 3 bpm). During PEMI in HTN, HR and CO were not sustained, and MAP fell to normal recovery levels. We conclude that the attenuated metaboreflex-induced HR, CO, and MAP responses are not sustained during PEMI in HTN. [ABSTRACT FROM AUTHOR]

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 ⩾3 consecutive beats when HR changed inversely vs. pressure] decreased during mild exercise from the resting values (-5.56 ± 0.86 vs. -2.67 ± 0.50 beats·min-1·mmHg-1, P <0.05), and in addition, these LRs were shifted upward. Progressive MMA gradually and linearly increased MAP, CO, and HR; linearly decreased SBRS; and shifted LRs upward and rightward to higher HR and pressures denoting baroreflex resetting. Moderate exercise caused a substantial reduction in SBRS (-1.57 ± 0.38 beats·min-1·mmHg-1,P <0.05) and both an upward and rightward resetting. Gradual MMA at this higher workload also caused significant progressive increases in MAP, CU, and HR and progressive decreases in SBRS, and the LRs were shifted to higher MAP and HR. Our results demonstrate that gradual MMA during mild and moderate dynamic exercise progressively decreases SBRS. In addition, baroreflex control of HR is progressively reset to higher blood pressure and HR in proportion to the extent of MMA. [ABSTRACT FROM AUTHOR]

Underperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex (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 (Emax) 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, Emax, and PRSW. In contrast, after HF was induced, CO, Emax and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, Emax and PRSW did not change. In addition, MMR activation caused no significant change in CO, Emax 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. [ABSTRACT FROM AUTHOR]

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 (GA) and the cardiopulmonary TPR baroreflex (GC) 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 GA and GC that have previously been shown to occur following chronic arterial baroreceptor denervation. That is, reflex control by the arterial TPR baroreftex was virtually abolished (GA = -2.1 ± 0.6 to 0.3 ± 0.2; P < 0.05), while reflex control by the cardiopulmonary TPR baroreflex more than doubled (GC = -0.7 ± 0.4 to -1.8 ± 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Previous studies showed that the arterial baroreflex opposes the pressor response mediated by muscle metaboreflex activation during mild dynamic exercise. However, no studies have investigated the mechanisms contributing to metaborefiex-mediated pressor responses during dynamic exercise after arterial baroreceptor denervation. Therefore, we investigated the contribution of cardiac output (CO) and peripheral vasoconstriction in mediating the pressor response to graded reductions in hindlimb perfusion in conscious, chronically instrumented dogs before and after sinoaortic denervation (SAD) during mild and moderate exercise. In control experiments, the metaboreflex pressor responses were mediated via increases in Co. After SAD, the metaboreflex pressor responses were significantly greater and significantly smaller increases in CO occurred. During control experiments, nonischemic vascular conductance (NIVC) did not change with muscle metaboreflex activation, whereas after SAD NIVC significantly decreased with metaboreflex activation; thus SAD shifted the mechanisms of the muscle metaboreflex from mainly increases in CO to combined cardiac and peripheral vasoconstrictor responses. We conclude that the major mechanism by which the arterial baroreflex buffers the muscle metaboreflex is inhibition of metaboreflex-mediated peripheral vasoconstriction. [ABSTRACT FROM AUTHOR]

We investigated to what extent heart failure alters the ability of the muscle metaboreflex to improve ventricular function. Dogs were chronically instrumented to monitor mean arterial pressure (MAP), cardiac output (CO), heart rate (HR), stroke volume (SV), and central venous pressure (CVP) at rest and during mild treadmill exercise (3.2 km/h) before and during reductions in hindlimb blood flow imposed to activate the muscle metaboreflex. These control experiments were repeated at constant heart rate (ventricular pacing 225 beats/min) and at constant heart rate coupled with a β-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 β-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 β-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. [ABSTRACT FROM AUTHOR]

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 ± 1.2 vs. 18.7 ± 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. [ABSTRACT FROM AUTHOR]

Underperfusion of active skeletal muscle elicits a reflex pressor response -- termed the muscle metaboreflex (MMR). In normal dogs during moderate dynamic exercise (MOD), MMR activation causes large increases in left ventricular contractility (LVC), cardiac output (CO) and mean arterial pressure (MAP) whereas in heart failure (HF), although MAP increases, the rise in CO is virtually abolished which may be due to an impaired ability to increase LVC. A widely accepted index of contractility is preload recruitable stroke work (PRSW) calculated from the stroke work-end diastolic volume relationship. The objective of the present study was to determine whether MMR increases in PRSW observed in normal dogs during MOD are abolished in HF. Conscious dogs were chronically instrumented to measure left ventricular pressure and volume at rest, during MOD with and without partial hind-limb ischemia to elicit MMR responses. In normal conditions, MMR activation increased PRSW from 107.1 ± 6 to 142.9 ± 10 mmHg (P < 0.05) and CO increased from 8.4 ± 0.5 to 9.8 ± 0.6 l/min. After induction of HF, CO and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, MMR activation caused no significant change in either CO or PRSW. We conclude that the ability of the MMR to induce increases in LVC is abolished in HF and that the reflex increases in MAP occur solely via peripheral vasoconstriction. [ABSTRACT FROM AUTHOR]