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The ability to increase cardiac output during dynamic exercise is paramount for the ability to maintain workload performance. Reflex control of the cardiovascular system during exercise is complex and multifaceted involving multiple feedforward and feedback systems. One major reflex thought to mediate the autonomic adjustments to exercise is termed the muscle metaboreflex and is activated via afferent neurons within active skeletal muscle which respond to the accumulation of interstitial metabolites during exercise when blood flow and O2 delivery are insufficient to meet metabolic demands. This is one of the most powerful cardiovascular reflexes capable of eliciting profound increases in sympathetic nerve activity, arterial blood pressure, central blood volume mobilization, heart rate and cardiac output. This review summarizes the mechanisms meditating muscle metaboreflex‐induced increases in cardiac output. Although much has been learned from studies using anaesthetized and/or decerebrate animals, we focus on studies in conscious animals and humans performing volitional exercise. We discuss the separate and interrelated roles of heart rate, ventricular contractility, ventricular preload and ventricular–vascular coupling as well as the interaction with other cardiovascular reflexes which modify muscle metaboreflex control of cardiac output. We discuss how these mechanisms may be altered in subjects with heart failure with reduced ejection fraction and offer suggestions for future studies. [ABSTRACT FROM AUTHOR]

Exercise intolerance is a hallmark symptom of heart failure and to a large extent stems from reductions in cardiac output that occur due to the inherent ventricular dysfunction coupled with enhanced muscle metaboreflex-induced functional coronary vasoconstriction, which limits increases in coronary blood flow. This creates a further mismatch between O2 delivery and O2 demand, which may activate the cardiac sympathetic afferent reflex (CSAR), causing amplification of the already increased sympathetic activity in a positive-feedback fashion. We used our chronically instrumented conscious canine model to evaluate if chronic ablation of afferents responsible for the CSAR would attenuate the gain of muscle metaboreflex before and after induction of heart failure. After afferent ablation, the gain of the muscle metaboreflex control of mean arterial pressure was significantly reduced before (-239.5 ± 16 to -95.2 ± 8 mmHg/L/min) and after the induction of heart failure (-185.6 ± 14 to -95.7 ± 12 mmHg/L/min). Similar results were observed for the strength (gain) of muscle metaboreflex control of heart rate, cardiac output, and ventricular contractility. Thus, we conclude that the CSAR contributes significantly to the strength of the muscle metaboreflex in normal animals with heart failure serving as an effective positive-feedback amplifier thereby further increasing sympathetic activity. [ABSTRACT FROM AUTHOR]

Slow heart rate recovery following exercise may be influenced by persistent sympathoexcitation. This study examined 1) the effect of muscle metaboreflex activation (MMA) on heart rate recovery following dynamic exercise; and 2) whether the effect of MMA on heart rate recovery is reversible by reducing sympathoexcitation [baroreflex activation via phenylephrine (PE)] in canines. Twenty-two young adults completed control and MMA protocols during cycle ergometry at 110% ventilatory threshold with 5 min recovery. Heart rate recovery kinetics [tau (s), amplitude, end-exercise, and end-recovery heart rate] and root mean square of successive differences (RMSSD) were measured. Five chronically instrumented canines completed control, MMA (50%-60% imposed reduction in hindlimb blood flow), and MMA with end-exercise PE infusion (MMA þ PE) protocols during moderate exercise (6.4 km·h-1) and 3 min recovery. Heart rate recovery kinetics and MAP were measured. MAP increased during MMA versus control in canines (P < 0.001). Heart rate recovery s was slower during MMA versus control in humans (17% slower; P = 0.011) and canines (150% slower; P = 0.002). Heart rate recovery s was faster during MMA þ PE versus MMA (40% faster; P = 0.034) and was similar to control in canines (P = 0.426). Amplitude, end-exercise, and end-recovery heart rate were similar between conditions in humans (all P = 0.122) and in canines (all P ≥ 0.084). MMA decreased RMSSD in early recovery (P = 0.004). MMAinduced sympathoexcitation slows heart rate recovery and this effect is markedly attenuated with PE. Therefore, elevated sympathoexcitation via MMA impairs heart rate recovery and inhibition of this stimulus normalizes, in part, heart rate recovery. [ABSTRACT FROM AUTHOR]

Blood flow restriction training (BFRT) employs partial vascular occlusion of exercising muscle and has been shown to increase muscle performance while using reduced workload and training time. Numerous studies have demonstrated that BFRT increases muscle hypertrophy, mitochondrial function, and beneficial vascular adaptations. However, changes in cardiovascular hemodynamics during the exercise protocol remain unknown, as most studies measured blood pressure before the onset and after the cessation of exercise. With reduced perfusion to the exercising muscle during BFRT, the resultant accumulation of metabolites within the ischemic muscle could potentially trigger a large reflex increase in blood pressure, termed the muscle metaboreflex. At low workloads, this pressor response occurs primarily via increases in cardiac output. However, when increases in cardiac output are limited (e.g., heart failure or during severe exercise), the reflex shifts to peripheral vasoconstriction as the primary mechanism to increase blood pressure, potentially increasing the risk of a cardiovascular event. Using our chronically instrumented conscious canine model, we utilized a 60% reduction in femoral blood pressure applied to the hindlimbs during steadystate treadmill exercise (3.2 km/h) to reproduce the ischemic environment observed during BFRT. We observed significant increases in heart rate ( þ 19 ± 3 beats/min), stroke volume ( þ 2.52 ± 1.2 mL), cardiac output ( þ 1.21 ± 0.2 L/min), mean arterial pressure ( þ 18.2 ± 2.4 mmHg), stroke work ( þ 1.93 ± 0.2 L/mmHg), and nonischemic vascular conductance ( þ 3.62 ± 1.7 mL/mmHg), indicating activation of the muscle metaboreflex. NEW & NOTEWORTHY Blood flow restriction training (BFRT) increases muscle mass, strength, and endurance. There has been minimal consideration of the reflex cardiovascular responses that could be elicited during BFRT sessions. We showed that during low-intensity exercise BFRT may trigger large reflex increases in blood pressure and sympathetic activity due to muscle metaboreflex activation. Thus, we urge caution when employing BFRT, especially in patients in whom exaggerated cardiovascular responses may occur that could cause sudden, adverse cardiovascular events. [ABSTRACT FROM AUTHOR]

Rapid regulation of arterial blood pressure on a beat-by-beat basis occurs primarily via arterial baroreflex control of cardiac output (CO) via rapid changes in heart rate (HR). Previous studies have shown that changes in HR do not always cause changes in CO, because stroke volume may vary. Whether these relationships are altered in hypertension is unknown. Using the spontaneous baroreflex sensitivity (SBRS) approach, we investigated whether baroreflex control of HR and CO were impaired after the induction of hypertension in conscious, chronically instrumented canines at rest, during mild exercise, and during exercise with metaboreflex activation (induced via reductions in hindlimb blood flow) both before and after induction of hypertension (induced via a modified Goldblatt approach--unilateral reduction in renal blood flow to >30% of control values until systolic pressure < 140 mmHg and a diastolic pressure < 90 mmHg for >30 days). After induction of hypertension, SBRS control of both HR and CO was reduced in all settings. In control, only about 50% of SBRS changes in HR caused changes in CO. This pattern was sustained in hypertension. Thus, in hypertension, the reduced SBRS in the control of HR caused reduced SBRS control of CO and this likely contributes to the increased incidence of orthostatic hypotension seen in hypertensive patients. [ABSTRACT FROM AUTHOR]

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

Our previous study showed that stimulation of adenosine [A.sub.1] receptors located in the nucleus of the solitary tract (NTS) exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and [beta]-adrenergic vasodilation versus vasoconstriction mediated by neural and unknown humoral factors. In the present study we investigated the relative contribution of three major potential humoral vasoconstrictors: vasopressin, angiotensin II, and norepinephrine in this response. In urethane-chloralose anesthetized rats we compared the integral changes in iliac vascular conductance evoked by microinjections into the NTS of the selective [A.sub.1] receptor agonist [N.sup.6]-cyclopentyladenosine (CPA; 330 pmol in 50 nl) in intact (Int) animals and following: [V.sub.1] vasopressin receptor blockade (VX), angiotensin II [AT.sub.1] receptor blockade (ATX), bilateral adrenalectomy + ganglionic blockade (ADX + GX; which eliminated the potential increases in circulating norepinephrine and epinephrine), ADX + GX + VX and ADX + GX + VX + ATX. In Int animals, stimulation of NTS [A.sub.1] adenosine receptors evoked typical variable responses with prevailing pressor and vasoconstrictor effects. VX reversed the responses to depressor ones. ATX did not significantly alter the responses. ADX + GX accentuated pressor and vasoconstrictor responses, whereas ADX + GX + VX and ADX + GX + VX + ATX virtually abolished the responses. Stimulation of NTS [A.sub.1] adenosine receptors increased circulating vasopressin over fourfold (26.4 [+ or -] 10.4 vs. 117.0 [+ or -] 19 pg/ml). These data strongly suggest that vasopressin is a major vasoconstrictor factor opposing [beta]-adrenergic vasodilation in iliac vascular responses triggered by stimulation of NTS [A.sub.1] adenosine receptors, whereas angiotensin II and norepinephrine do not contribute significantly to the vasoconstrictor responses. purinergic receptors; [V.sub.1] receptor blockade; angiotensin II type 1 receptor blockade; ganglionic blockade; adrenalectomy; lumbar sympathectomy; iliac vascular conductance doi: 10.1152/ajpheart.00432.2009.

The role of nucleus of solitary tract (NTS) [A.sub.2a] adenosine receptors in baroreflex mechanisms is controversial. Stimulation of these receptors releases glutamate within the NTS and elicits baroreflex-like decreases in mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas inhibition of these receptors attenuates HR baroreflex responses. In contrast, stimulation of NTS [A.sub.2a] adenosine receptors increases preganglionic adrenal sympathetic nerve activity (pre-ASNA), and the depressor and sympathoinhibitory responses are not markedly affected by sinoaortic denervation and blockade of NTS glutamatergic transmission. To elucidate the role of NTS [A.sub.2a] adenosine receptors in baroreflex function, we compared full baroreflex stimulus-response curves for HR, RSNA, and pre-ASNA (intravenous nitroprusside/phenylephrine) before and after bilateral NTS microinjections of selective adenosine [A.sub.2a] receptor agonist (CGS-21680; 2.0, 20 pmol/50 nl), selective [A.sub.2a] receptor antagonist (ZM-241385; 40 pmol/100 nl), and nonselective [A.sub.1] + [A.sub.2a] receptor antagonist (8-SPT; 1 nmol/100 nl) in urethane/[alpha]-chloralose anesthetized rats. Activation of [A.sub.2a] receptors decreased the range, upper plateau, and gain of baroreflex-response curves for RSNA, whereas these parameters all increased for pre-ASNA, consistent with direct effects of the agonist on regional sympathetic activity. However, no resetting of baroreflex-response curves along the MAP axis occurred despite the marked decreases in baseline MAP. The antagonists had no marked effects on baseline variables or baroreflex-response functions. We conclude that the activation of NTS [A.sub.2a] adenosine receptors differentially alters baroreflex control of HR, RSNA, and pre-ASNA mostly via non-baroreflex mechanism(s), and these receptors have virtually no tonic action on baroreflex control of these sympathetic outputs. [A.sub.2a] adenosine receptor agonist; [A.sub.2a] adenosine receptor antagonist; baroreflex function; renal nerve; adrenal nerve

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

Previously we showed that pressor and differential regional sympathoexcitatory responses (adrenal > renal [greater than or equal to] lumbar) evoked by stimulation of [A.sub.1] adenosine receptors located in the nucleus of the solitary tract (NTS) were attenuated/abolished by baroreceptor denervation or blockade of glutamatergic transmission in the NTS, suggesting [A.sub.1] receptor-elicited inhibition of glutamatergic transmission in baroreflex pathways. Therefore we tested the hypothesis that stimulation of NTS [A.sub.1] adenosine receptors differentially inhibits/resets baroreflex responses of preganglionic adrenal (pre-ASNA), renal (RSNA), and lumbar (LSNA) sympathetic nerve activity. In urethane-chloralose-anesthetized male Sprague-Dawley rats (n = 65) we compared baroreflex-response curves (iv nitroprusside and phenylephrine) evoked before and after bilateral microinjections into the NTS of [A.sub.1] adenosine receptor agonist ([N.sup.6]-cyclopentyladenosine, CPA; 0.033-330 pmol/50 nl). CPA evoked typical dose-dependent pressor and differential sympathoexcitatory responses and similarly shifted baroreflex curves for pre-ASNA, RSNA, and LSNA toward higher mean arterial pressure (MAP) in a dose-dependent manner; the maximal shifts were 52.6 [+ or -] 2.8, 48.0 [+ or -] 3.6, and 56.8 [+ or -] 6.7 mmHg for pre-ASNA, RSNA, and LSNA, respectively. These shifts were not a result of simple baroreceptor resetting because they were two to three times greater than respective increases in baseline MAP evoked by CPA. Baroreflex curves for pre-ASNA were additionally shifted upward: the maximal increases of upper and lower plateaus were 41.8 [+ or -] 16.4% and 45.3 [+ or -] 8.7%, respectively. Maximal gain (%/mmHg) measured before vs. after CPA increased for pre-ASNA (3.0 [+ or -] 0.6 vs. 4.9 [+ or -] 1.3), decreased for RSNA (4.1 [+ or -] 0.6 vs. 2.3 [+ or -] 0.3), and remained unaltered for LSNA (2.1 [+ or -] 0.2 vs. 2.0 [+ or -] 0.1). Vehicle control did not alter the baroreflex curves. We conclude that the activation of NTS [A.sub.1] adenosine receptors differentially inhibits/resets baroreflex control of regional sympathetic outputs. nucleus of the solitary tract; purinergic receptors; adrenal nerve; renal nerve; lumbar nerve; pressor reflex

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

Stimulation of nucleus of the solitary tract (NTS) [A.sub.2a]-adenosine receptors elicits cardiovascular responses quite similar to those observed with rapid, severe hemorrhage, including bradycardia, hypotension, and inhibition of renal but activation of preganglionic adrenal sympathetic nerve activity (RSNA and pre-ASNA, respectively). Because adenosine levels in the central nervous system increase during severe hemorrhage, we investigated to what extent these responses to hemorrhage may be due to activation of NTS adenosine receptors. In urethane- and [alpha]-chloralose-anesthetized male Sprague-Dawley rats, rapid hemorrhage was performed before and after bilateral nonselective or selective blockade of NTS adenosine-receptor subtypes [A.sub.1]- and A.sub.2a] -adenosine-receptor antagonist 8-(p-sulfophenyl)theophylline (1 nmol/100 nl) and [A.sub.2a]-receptor antagonist ZM-241385 (40 pmol/100 nl)]. The nonselective blockade reversed the response in RSNA (-21.0 [plus or minus] 9.6 [DELTA]% vs. +7.3 [plus or minus] 5.7 [DELTA]%) (where [DELTA]% is averaged percent change from baseline) and attenuated the average heart rate response (change of [plus or minus] 4.8 vs. -4.4 [plus or minus] 3.4 beats/min). The selective blockade attenuated the RSNA response (-30.4 [plus or minus] 5.2 [DELTA]% vs. -11.1 [plus or minus] 7.7 [DELTA]%) and tended to attenuate heart rate response (change of -27.5 [plus or minus] 5.3 vs. -15.8 [plus or minus] 8.2 beats/min). Microinjection of vehicle (100 nl) had no significant effect on the responses. The hemorrhage-induced increases in pre-ASNA remained unchanged with either adenosine-receptor antagonist. We conclude that adenosine operating in the NTS via [A.sub.2a] and possibly [A.sub.1] receptors may contribute to posthemorrhagic sympathoinhibition of RSNA but not to the sympathoactivation of pre-ASNA. The differential effects of NTS adenosine receptors on RSNA vs. pre-ASNA responses to hemorrhage supports the hypothesis that these receptors are differentially located/expressed on NTS neurons/synaptic terminals controlling different sympathetic outputs. nucleus of the solitary tract; tonic activity of pudnergic receptors; hypotensive hemorrhage; adrenal sympathetic nerve; renal sympathetic nerve

Activation of adenosine [A.sub.2a] receptors in the nucleus of the solitary tract (NTS) decreases mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA), whereas increases in preganglionic adrenal sympathetic nerve activity (pre-ASNA) occur, a pattern similar to that observed during hypotensive hemorrhage. Central vasopressin [V.sub.1] receptors may contribute to posthemorrhagic hypotension and bradycardia. Both [V.sub.1] and [A.sub.2a] receptors are densely expressed in the NTS, and both of these receptors are involved in cardiovascular control; thus they may interact. The responses elicited by NTS [A.sub.2a] receptors are mediated mostly via nonglutamatergic mechanisms, possibly via release of vasopressin. Therefore, we investigated whether blockade of NTS [V.sub.1] receptors alters the autonomic response patterns evoked by stimulation of NTS [A.sub.2a], receptors (CGS-21680, 20 pmol/50 nl) in [alpha]-chloralose-urethane anesthetized male Sprague-Dawley rats. In addition, we compared the regional sympathetic responses to microinjections of vasopressin (0.1-100 ng/50 nl) into the NTS. Blockade of [V.sub.1] receptors reversed the normal decreases in MAP into increases (-95.6 [+ or -] 28.3 vs. 51.4 [+ or -] 15.7 [integral] [DELTA] %), virtually abolished the decreases in HR (-258.3 [+ or -] 54.0 vs. 18.9 [+ or -] 57.8 [integral [DELTA]beats/min) and RSNA (-239.3 [+ or -] 47.4 vs. 15.9 [+ or -] 36.1 [integral [DELTA] %), and did not affect the increases in pre-ASNA (279.7 [+ or -] 48.3 vs. 233.1 [+ or -] 54.1 [integral] [DELTA] %) evoked by [A.sub.2a] receptor stimulation. The responses partially returned toward normal values ~90 min after the blockade. Microinjections of vasopressin into the NTS evoked dose-dependent decreases in HR and RSNA and variable MAP and pre-ASNA responses with a tendency toward increases. We conclude that the decreases in MAP, HR, and RSNA in response to NTS [A.sub.2a] receptor stimulation may be mediated via release of vasopressin from neural terminals in the NTS. The differential effects of NTS [V.sub.1] and [A.sub.2a] receptors on RSNA versus pre-ASNA support the hypothesis that these receptor subtypes are differentially located/expressed on NTS neurons/neural terminals controlling different sympathetic outputs. nucleus tractus solitarii; purinoceptors; vasopressin [V.sub.1] receptor antagonist; adrenal sympathetic nerve; renal sympathetic nerve

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

We have previously shown that activation of P2X purinoceptors in the subpostremal nucleus tractus solitarius (NTS) produces a rapid bradycardia and hypotension. This bradycardia could occur via sympathetic withdrawal, parasympathetic activation, or a combination of both mechanisms. Thus we investigated the relative roles of parasympathetic activation and sympathetic withdrawal in mediating this bradycardia in chloralose-urethane anesthetized male Sprague-Dawley rats. Microinjections of the selective P2X purinoceptor agonist [alpha], [beta]-methylene ATP (25 pmol/50 nl and 100 pmol/50 nl) were made into the subpostremal NTS in control animals, after atenolol (2 mg/kg iv), a [beta]-selective antagonist, and after atropine methyl bromide (2 mg/kg iv), a muscarinic receptor antagonist. The bradycardia observed with activation of P2X receptors at the low dose of the agonist is mediated almost entirely by sympathetic withdrawal. After [[beta].sub.1]-adrenergic blockade, the bradycardia was reduced to just -5.1 [+ or -] 0.5 versus -28.8 [+ or -] 5.1 beats/min in intact animals. Muscarinic blockade did not produce any significant change in the bradycardic response at the low dose. At the high dose, both [[beta].sub.1]-adrenergic blockade and muscarinic blockade attenuated the bradycardia similarly, -37.4 [+ or -] 6.4 and -40.6 [+ or -] 3.7 beats/min, respectively, compared with -88.0 [+ or -] 11 beats/min in control animals. Double blockade of both [[beta].sub.1]-adrenergic and muscarinic receptors virtually abolished the response (-2.5 [+.sub. -] 0.8 beats/min). We conclude that the relative contributions of parasympathetic activation and sympathetic withdrawal are dependent on the extent of P2X receptor activation. heart rate; nucleus tractus solitarius; [alpha],[beta]-methylene adenosine 5'triphosphate

Our previous studies concluded that stimulation of the nucleus of the solitary tract (NTS) [A.sub.2a] receptors evokes preferential hindlimb vasodilation mainly via inducing increases in preganglionic sympathetic nerve activity (preASNA) directed to the adrenal medulla. This increase in pre-ASNA causes the release of epinephrine and subsequent activation of [beta]-adrenergic receptors that are preferentially located in the skeletal muscle vasculature. Selective activation of NTS [A.sub.1] adenosine receptors evokes variable, mostly pressor effects and increases pre-ASNA, as well as lumbar sympathetic activity, which is directed to the hindlimb. These counteracting factors may have opposite effects on the hindlimb vasculature resulting in mixed vascular responses. Therefore, in chloralose-urethane-anesthetized rats, we evaluated the contribution of vasodilator versus vasoconstrictor effects of stimulation of NTS [A.sub.1] receptors on the hindlimb vasculature. We compared the changes in iliac vascular conductance evoked by microinjctions into the NTS of the selective [A.sub.1] receptor agonist [N.sup.6]-cyclopentyladenosine (330 pmol in 50 nl volume) in intact animals with the responses evoked after [beta]-adrenergic blockade, bilateral adrenalectomy, bilateral lumbar sympathectomy, and combined adrenalectomy + lumbar sympathectomy. In intact animals, stimulation of NTS [A.sub.1] receptors evoked variable effects: increases and decreases in mean arterial pressure and iliac conductance with prevailing pressor and vasoconstrictor effects. Peripheral [beta]-adrenergic receptor blockade and bilateral adrenalectomy eliminated the depressor component of the responses, markedly potentiated iliac vasoconstriction, and tended to increase the pressor responses. Lumbar sympathectomy tended to decrease the pressor and vasoconstrictor responses. After bilateral adrenalectomy plus lumbar sympathectomy, a marked vasoconstriction in lilac vascular bed still persisted, suggesting that the vasoconstrictor component of the response to stimulation of NTS Am receptors is mediated mostly via circulating factors (e.g., vasopressin, angiotensin II, or circulating catecholamines released from other sympathetic terminals). These data strongly suggest that stimulation of NTS [A.sub.1] receptors exerts counteracting effects on the iliac vascular bed: activation of the adrenal medulla and [beta]-adrenergic vasodilation versus vasoconstriction mediated by neural and humoral factors. nucleus of the solitary tract; purinergic receptors; [beta]-adrenergic blockade; adrenalectomy; lumbar sympathectomy; iliac vascular conductance

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

Our previous studies showed that preganglionic adrenal (pre-ASNA), renal (RSNA), lumbar, and post-ganglionic adrenal sympathetic nerve activities (post-ASNA) are inhibited after stimulation of arterial baroreceptors, nucleus of the solitary tract (NTS), and glutamatergic and [P.sub.2x] receptors and are activated after stimulation of adenosine [A.sub.1] receptors. However, stimulation of adenosine [A.sub.2a] receptors inhibited RSNA and post-ASNA, whereas it activated pre-ASNA. Because the effects evoked by NTS [A.sub.2a] receptors may be mediated via activation of nitric oxide (NO) mechanisms in NTS neurons, we tested the hypothesis that NO synthase (NOS) inhibitors would attenuate regional sympathetic responses to NTS [A.sub.2a] receptor stimulation, whereas NO donors would evoke contrasting responses from pre-ASNA versus RSNA and post-ASNA. Therefore, in chloralose/urethane-anesthetized rats, we compared hemodynamic and regional sympathetic responses to microinjections of selective [A.sub.2a] receptor agonist (CGS-21680, 20 pmol/50 nl) after pretreatment with NOS inhibitors [N.sup.[omega]]-nitro-L-arginine methyl ester (10 nmol/100 nl) and 1-[2-(trifluoromethyl)phenyl]imidazole (100 pmol/100 nl) versus pretreatment with vehicle (100 nl). In addition, responses to microinjections into the NTS of different NO donors [40 and 400 pmol/50 nl sodium nitroprusside (SNP); 0.5 and 5 nmol/50 nl 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene (DETA NONOate, also known as NOC-18), and 2 nmol/50 nl 3-(2-hydroxy-2-nitroso-1-propylhydrazino)-1-propanamine (PAPA NONOate, also known as NOC-15)], the NO precursor L-arginine (10-50 nmol/50 nl), and sodium glutamate (500 pmol/50 nl) were evaluated. SNP, DETA NONOate, and PAPA NONOate activated pre-ASNA and inhibited RSNA and post-ASNA, whereas L-arginine and glutamate microinjected into the same site of the NTS inhibited all these sympathetic outputs. Decreases in heart rate and depressor or biphasic responses accompanied the neural responses. Pretreatment with NOS inhibitors reversed the normal depressor and sympathoinhibitory responses to stimulation of NTS [A.sub.2a] receptors into pressor and sympathoactivatory responses and attenuated the heart rate decreases: however, it did not change the increases in pre-ASNA. We conclude that NTS NO mechanisms differentially affect regional sympathetic outputs and differentially contribute to the pattern of regional sympathetic responses evoked by stimulation of NTS [A.sub.2a] receptors. nitric oxide donors and inhibitors; adrenal sympathetic nerve; renal sympathetic nerve

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

Selective activation of adenosine [A.sub.1] and [A.sub.2a] receptors in the subpostremal nucleus tractus solitarius (NTS) increases and decreases mean arterial pressure (MAP), respectively, and decreases heart rate (HR). We have previously shown that the decreases in MAP evoked by NTS [A.sub.2a] receptor stimulation were accompanied with differential sympathetic responses in renal (RSNA), lumbar (LSNA), and preganglionic adrenal sympathetic nerve activity (pre-ASNA). Therefore, now we investigated whether stimulation of NTS [A.sub.1] receptors via unilateral microinjection of [N.sup.6]-cyclopentyladenosine (CPA) elicits differential activation of the same sympathetic outputs in [alpha]-chloralose-urethane-anesthetized male Sprague-Dawley rats. CPA (0.33-330.0 pmol in 50 nl) evoked dose-dependent increases in MAP, variable decreases in HR, and differential increases in all recorded sympathetic outputs: [up arrow] pre-ASNA [much greater than] [up arrow] RSNA [greater than or equal to] [up arrow] LSNA. Sinoaortic denervation + vagotomy abolished the MAP and LSNA responses, reversed the normal increases in RSNA into decreases, and significantly attenuated increases in pre-ASNA. NTS ionotropic glutamatergic receptor blockade with kynurenate sodium (4.4 nmol/100 nl) reversed the responses in MAP, LSNA, and RSNA and attenuated the responses in pre-ASNA. We conclude that afferent inputs and intact glutamatergic transmission in the NTS are necessary to mediate the pressor and differential sympathoactivatory responses to stimulation of NTS [A.sub.1] receptors. nucleus of the solitary tract; purinergic receptors; adrenal sympathetic nerve; renal sympathetic nerve; lumbar sympathetic nerve

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF) and vascular conductance (CVC) in conscious, chronically instrumented dogs during treadmill exercise ranging from mild to severe workloads. Metaboreflex responses were also observed during mild exercise with constant heart rate (HR) of 225 beats/min and [[beta].sub.1]-adrenergic receptor blockade to attenuate the substantial reflex increases in cardiac work. The muscle metaboreflex was activated via graded partial occlusion of hindlimb blood flow. During mild exercise, with muscle metaboreflex activation, hindlimb ischemia elicited significant reflex increases in mean arterial pressure (MAP), HR, and cardiac output (CO) (+39.0 [+ or -] 5.2 mmHg, +29.9 [+ or -] 7.7 beats/min, and +2.0 [+ or -] 0.4 l/min, respectively; all changes, P < 0.05). CBF increased from 51.9 [+ or -] 4.3 to 88.5 [+ or -] 6.6 ml/min, (P < 0.05), whereas no significant change in CVC occurred (0.56 [+ or -] 0.06 vs. 0.59 [+ or -] 0.05 ml * [min.sup.-1] * mm[Hg.sup.-1]; P > 0.05). Similar responses were observed during moderate exercise. In contrast, with metaboreflex activation during severe exercise, no further increases in CO or HR occurred, the increases in MAP and CBF were attenuated, and a significant reduction in CVC was observed (1.00 [+ or -] 0.12 vs. 0.90 [+ or -] 0.13 ml * [min.sup.-1] * mm[Hg.sup.-1]; P < 0.05). Similarly, when the metaboreflex was activated during mild exercise with the rise in cardiac work lessened (via constant HR and [[beta].sub.1]-blockade), no increase in CO occurred, the MAP and CBF responses were attenuated (+15.6 [+ or -] 4.5 mmHg, +8.3 [+ or -] 2 ml/min), and CVC significantly decreased from 0.63 [+ or -] 0.11 to 0.53 [+ or -] 0.10 ml * [min.sup.-1] * mm[Hg.sup.-1]. We conclude that the muscle metaboreflex induced increases in sympathetic nerve activity to the heart functionally vasoconstricts the coronary vasculature. exercise; ischemia; skeletal muscle; vascular conductance