Dynamic cardiac output regulation at rest, during exercise, and muscle metaboreflex activation: impact of congestive heart failure.

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.

Activation of NTS A(1) adenosine receptors inhibits regional sympathetic responses evoked by activation of cardiopulmonary chemoreflex.

Previously we have shown that adenosine operating via the A(1) receptor subtype may inhibit glutamatergic transmission in the baroreflex arc within the nucleus of the solitary tract (NTS) and differentially increase renal (RSNA), preganglionic adrenal (pre-ASNA), and lumbar (LSNA) sympathetic nerve activity (ASNA>RSNA≥LSNA). Since the cardiopulmonary chemoreflex and the arterial baroreflex are mediated via similar medullary pathways, and glutamate is a primary transmitter in both pathways, it is likely that adenosine operating via A(1) receptors in the NTS may differentially inhibit regional sympathetic responses evoked by activation of cardiopulmonary chemoreceptors. Therefore, in urethane-chloralose-anesthetized rats (n = 37) we compared regional sympathoinhibition evoked by the cardiopulmonary chemoreflex (activated with right atrial injections of serotonin 5HT(3) receptor agonist phenylbiguanide, PBG, 1-8 µg/kg) before and after selective stimulation of NTS A(1) adenosine receptors [microinjections of N(6)-cyclopentyl adenosine (CPA), 0.033-330 pmol/50 nl]. Activation of cardiopulmonary chemoreceptors evoked differential, dose-dependent sympathoinhibition (RSNA>ASNA>LSNA), and decreases in arterial pressure and heart rate. These differential sympathetic responses were uniformly attenuated in dose-dependent manner by microinjections of CPA into the NTS. Volume control (n = 11) and blockade of adenosine receptor subtypes in the NTS via 8-(p-sulfophenyl)theophylline (8-SPT, 1 nmol in 100 nl) (n = 9) did not affect the reflex responses. We conclude that activation of NTS A(1) adenosine receptors uniformly inhibits neural and cardiovascular cardiopulmonary chemoreflex responses. A(1) adenosine receptors have no tonic modulatory effect on this reflex under normal conditions. However, when adenosine is released into the NTS (i.e., during stress or severe hypotension/ischemia), it may serve as negative feedback regulator for depressor and sympathoinhibitory reflexes integrated in the NTS.

Progressive muscle metaboreflex activation gradually decreases spontaneous heart rate baroreflex sensitivity during dynamic exercise.

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 > or =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, CO, 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.

Modulation of cardiac output alters the mechanisms of the muscle metaboreflex pressor response.

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.

Activation of NTS A2a adenosine receptors differentially resets baroreflex control of renal vs. adrenal sympathetic nerve activity.

The role of nucleus of solitary tract (NTS) A(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(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(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(2a) receptor agonist (CGS-21680; 2.0, 20 pmol/50 nl), selective A(2a) receptor antagonist (ZM-241385; 40 pmol/100 nl), and nonselective A(1) + A(2a) receptor antagonist (8-SPT; 1 nmol/100 nl) in urethane/alpha-chloralose anesthetized rats. Activation of A(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(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.

Enhanced heat loss responses induced by short-term endurance training in exercising women.

We investigated the effects of short-term endurance training and detraining on sweating and cutaneous vasodilatation during exercise in young women, taking into account changes in maximal oxygen uptake (VO2max) and the phase of the menstrual cycle. Eleven untrained women participated in endurance training; cycle exercise at approximately 60% VO2max for 60 min day(-1), 4-5 days week(-1) (30 degrees C, 45% relative humidity) for three complete menstrual cycles. The standard exercise test consisted of exercise at 50% VO2max for 30 min (25 degrees C, 45% relative humidity), and was conducted before training (Pre), during training sessions (T1, T2 and T3) and after cessation of training (D1 and D2). Values of VO2max increased significantly from 32.7 +/- 1.2 to 37.8 +/- 1.2 ml min(-1) kg(-1) at the end of the training. Local sweat rate in the chest and thigh, but not in the back and forearm, were significantly greater during T1 and T2 only in women who started training from the midfollicular phase. Cutaneous blood flow did not change with training. The threshold oesophageal temperatures for heat loss responses were significantly decreased during T1 versus Pre (averaged values for each body site: sweating, 37.49 +/- 0.08 versus 37.22 +/- 0.12 degrees C; and cutaneous vasodilatation, 37.40 +/- 0.07 versus 37.17 +/- 0.10 degrees C) and maintained through T3; the sensitivities of heat loss responses were not altered. These changes returned to the Pre level by D1. Our data indicate that physical training improves heat loss responses by decreasing the threshold temperatures and that these effects occur within a month of training and disappear within a month after cessation of training. The degree of increase in sweating with training differs among body sites and might be affected by the phase of the menstrual cycle.

Changes in blood flow in conduit artery and veins of the upper arm during leg exercise in humans.

This study investigated changes in blood flow in the conduit artery, superficial vein, and deep vein of the upper arm during increase in internal temperature due to leg cycling. Additionally, we sought to demonstrate the contributions of blood velocity and vessel diameter on blood flow responses. Fourteen subjects performed supine cycling exercise at 60-69% maximal oxygen uptake for 30 min at an ambient temperature of 28 degrees C and relative humidity of 50%. Blood velocity and diameter in the brachial artery, basilic vein (superficial vein), and brachial vein (deep vein) were measured using ultrasound Doppler, and blood flow was calculated. Blood flow in the artery and superficial vein increased linearly with rising oesophageal temperature (DeltaT (oes)) after DeltaT (oes) was about 0.3 degrees C (within threshold), as well as cutaneous vascular conductance on the forearm. Changes in blood velocity in these vessels were similar to those in blood flow. Conversely, the brachial artery and superficial vein diameter did not affect the blood flow response. Blood flow variables in the deep vein did not change remarkably with rising DeltaT (oes). These results suggest that blood flow response, by an increase in velocity, in the conduit artery with rising DeltaT (oes) during exercise is similar to that in the superficial vein, but not deep vein. Also, it is indicated that these increases in blood flow relate to the increase in skin blood flow on the forearm with the rise in body temperature during exercise.

Spontaneous baroreflex control of cardiac output during dynamic exercise, muscle metaboreflex activation, and heart failure.

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.

Spontaneous baroreflex control of heart rate versus cardiac output: altered coupling in heart failure.

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.

Stimulation of NTS A1 adenosine receptors differentially resets baroreflex control of regional sympathetic outputs.

Previously we showed that pressor and differential regional sympathoexcitatory responses (adrenal > renal >/= lumbar) evoked by stimulation of A(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(1) receptor-elicited inhibition of glutamatergic transmission in baroreflex pathways. Therefore we tested the hypothesis that stimulation of NTS A(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(1) adenosine receptor agonist (N(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 +/- 2.8, 48.0 +/- 3.6, and 56.8 +/- 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 +/- 16.4% and 45.3 +/- 8.7%, respectively. Maximal gain (%/mmHg) measured before vs. after CPA increased for pre-ASNA (3.0 +/- 0.6 vs. 4.9 +/- 1.3), decreased for RSNA (4.1 +/- 0.6 vs. 2.3 +/- 0.3), and remained unaltered for LSNA (2.1 +/- 0.2 vs. 2.0 +/- 0.1). Vehicle control did not alter the baroreflex curves. We conclude that the activation of NTS A(1) adenosine receptors differentially inhibits/resets baroreflex control of regional sympathetic outputs.

Spontaneous baroreflex control of heart rate during exercise and muscle metaboreflex activation in heart failure.

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 baroreflex 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.

Muscle metaboreflex attenuates spontaneous heart rate baroreflex sensitivity during dynamic exercise.

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(-1) x mmHg(-1)). During mild exercise, these LRs shifted upward, with a significant decrease in SBRS (-3.0 +/- 0.4 vs. -5.2 +/- 0.4, P<0.05 vs. rest). MRA shifted LRs upward and rightward and decreased SBRS (-2.1 +/- 0.1, P<0.05 vs. mild exercise). Moderate exercise shifted LRs upward and rightward and significantly decreased SBRS (-1.2 +/- 0.1, P<0.05 vs. rest). MRA elicited further upward and rightward shifts of the LRs and reductions in SBRS (-0.9 +/- 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.