Impact of heart failure and exercise capacity on sympathetic response to handgrip exercise

Peak oxygen uptake (VO(2 peak)) in patients with heart failure (HF) is inversely related to muscle sympathetic nerve activity (MSNA) at rest. We hypothesized that the MSNA response to handgrip exercise is augmented in HF patients and is greatest in those with low VO(2 peak). We studied 14 HF patients and 10 age-matched normal subjects during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50% MVC) handgrip exercise that was followed by 2 min of posthandgrip ischemia (PHGI). MSNA was significantly increased during exercise in HF but not normal subjects. Both MSNA and HF levels remained significantly elevated during PHGI after 30% isometric and 50% isotonic handgrip in HF but not normal subjects. HF patients with lower VO(2 peak) (<56% predicted; n = 8) had significantly higher MSNA during rest and exercise than patients with VO(2 peak) > 56% predicted (n = 6) and normal subjects. The muscle metaboreflex contributes to the greater reflex increase in MSNA during ischemic or intense nonischemic exercise in HF. This occurs at a lower threshold than normal and is a function of VO(2 peak).     

Cardiovascular and sympathetic response to exercise after long-term beta-adrenergic blockade.

The response to dynamic exercise was investigated in 21 patients receiving long-term treatment with beta-adrenoceptor antagonists and 22 controls. An electrocardiogram (ECG) and blood pressure were recorded before and after treadmill exercise, and plasma dopamine-beta-hydroxylase (DBH) activity was measured as an index of changes in sympathetic activity. Heart rate and blood pressure were lower at rest and throughout exercise in treated patients, although the pressor effect of exercise was not reduced. The ECG P-R interval was lengthened, and in addition the Q-T interval was prolonged. After exercise, plasma DBH activity was significantly increased in controls but not in treated patients. We conclude that long-term administration of beta-adrenergic blockers increases myocardial repolarisation time and reduces sympathetic nervous activity. These actions may contribute to the antiarrhythmic and hypotensive effects of long-term beta-blockade.     

Chronic endothelin-1 blockade reduces sympathetic nerve activity in rabbits with heart failure

Endothelin-1 (ET-1) is elevated in chronic heart failure (CHF). In this study, we determined the effects of chronic ET-1 blockade on renal sympathetic nerve activity (RSNA) in conscious rabbits with pacing-induced CHF. Rabbits were chronically paced at 320--340 beats/min for 3--4 wk until clinical and hemodynamic signs of CHF were present. Resting RSNA and arterial baroreflex control of RSNA were determined. Responses were determined before and after the ET-1 antagonist L-754,142 (a combined ET(A) and ET(B) receptor antagonist, n = 5) was administered by osmotic minipump infusion (0.5 mg. kg(-1) x h(-1) for 48 h). In addition, five rabbits with CHF were treated with the specific ET(A) receptor antagonist BQ-123. Baseline RSNA (expressed as a percentage of the maximum nerve activity during sodium nitroprusside infusion) was significantly higher (58.3 +/- 4.9 vs. 27.0 +/- 1.0, P < 0.001), whereas baroreflex sensitivity was significantly lower in rabbits with CHF compared with control (3.09 +/- 0.19 vs. 6.04 +/- 0.73, P < 0.001). L-754,142 caused a time-dependent reduction in arterial pressure and RSNA in rabbits with CHF. In addition, BQ-123 caused a reduction in resting RSNA. For both compounds, RSNA returned to near control levels 24 h after removal of the minipump. These data suggest that ET-1 contributes to sympathoexcitation in the CHF state. Enhancement of arterial baroreflex sensitivity may further contribute to sympathoinhibition after ET-1 blockade in heart failure.     

Effects of hyperglycemia on the cerebrovascular response to rhythmic handgrip exercise

Dynamic cerebral autoregulation (CA) is challenged by exercise and may become less effective when exercise is exhaustive. Exercise may increase arterial glucose concentration, and we evaluated whether the cerebrovascular response to exercise is affected by hyperglycemia. The effects of a hyperinsulinemic euglycemic clamp (EU) and hyperglycemic clamp (HY) on the cerebrovascular (CVRI) and systemic vascular resistance index (SVRI) responses were evaluated in seven healthy subjects at rest and during rhythmic handgrip exercise. Transfer function analysis of the dynamic relationship between beat-to-beat changes in mean arterial pressure and middle cerebral artery (MCA) mean blood flow velocity (V(mean)) was used to assess dynamic CA. At rest, SVRI decreased with HY and EU (P < 0.01). CVRI was maintained with EU but became reduced with HY [11% (SD 3); P < 0.01], and MCA V(mean) increased (P < 0.05), whereas brain catecholamine uptake and arterial Pco(2) did not change significantly. HY did not affect the normalized low-frequency gain between mean arterial pressure and MCA V(mean) or the phase shift, indicating maintained dynamic CA. With HY, the increase in CVRI associated with exercise was enhanced (19 +/- 7% vs. 9 +/- 7%; P < 0.05), concomitant with a larger increase in heart rate and cardiac output and a larger reduction in SVRI (22 +/- 4% vs. 14 +/- 2%; P < 0.05). Thus hyperglycemia lowered cerebral vascular tone independently of CA capacity at rest, whereas dynamic CA remained able to modulate cerebral blood flow around the exercise-induced increase in MCA V(mean). These findings suggest that elevated blood glucose does not explain that dynamic CA is affected during intense exercise.     

Effect of static handgrip on plasma adrenomedullin concentration in patients with heart failure and in healthy subjects.

Adrenomedullin (ADM) release is enhanced in pheochromocytoma, chronic heart failure (HF), hypertension and renal diseases. This study was designed to test the hypothesis that ADM secretion increases also in response to acute stimuli, such as static effort and to compare plasma ADM response to this stimulus in patients with chronic HF and healthy persons. Eight male HF patients (II/III class NYHA) and eight healthy subjects (C) performed two 3-min bouts of static handgrip at 30% of maximal voluntary contraction, alternately with each hand without any break between the bouts. At the end of both exercise bouts and in 5 min of the recovery period, plasma ADM and catecholamines were determined. In addition, heart rate, blood pressure, and stroke volume (SV) were measured. The baseline plasma ADM and noradrenaline levels were higher, whilst plasma adrenaline and SV were lower in HF patients than in C group. The 1st exercise bout caused an increase in plasma ADM from 3.32 +/- 0.57 to 4.98 +/- 0.59 pmol l(-1) (p<0.01) in C and from 6.88 +/- 0.58 to 7.80 +/- 0.43 pmol x l(-1) (p<0.02) in HF patients. The 2nd exercise bout did not produce further elevation in plasma ADM and during recovery the hormone concentration declined to pre-exercise or lower values. There were no differences between groups in exercise-induced increases in plasma ADM. Plasma ADM correlated with SV (r = -0.419) and with noradrenaline concentrations (r = 0.427). It is concluded that static exercise causes the short-lasting increase in plasma ADM concentration which is similar in healthy subjects and in patients with mild heart failure.     

Central neural control of sympathetic nerve activity in heart failure following exercise training

Typical characteristics of chronic congestive heart failure (HF) are increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation. These abnormalities lead to an increased risk of mortality, particularly in the late stage of chronic HF. Recent evidence suggests that central nervous system (CNS) mechanisms may be important in these abnormalities during HF. Exercise training (ExT) has emerged as a nonpharmacological therapeutic strategy substitute with significant benefit to patients with HF. Regular ExT improves functional capacity as well as quality of life and perhaps prognosis in chronic HF patients. The mechanism(s) by which ExT improves the clinical status of HF patients is not fully known. Recent studies have provided convincing evidence that ExT significantly alleviates the increased sympathetic drive, altered autonomic reflexes, and altered body fluid regulation in HF. This review describes and highlights the studies that examine various central pathways involved in autonomic outflow that are altered in HF and are improved following ExT. The increased sympathoexcitation is due to an imbalance between inhibitory and excitatory mechanisms within specific areas in the CNS such as the paraventricular nucleus (PVN) of the hypothalamus. Studies summarized here have revealed that ExT improves the altered inhibitory pathway utilizing nitric oxide and GABA mechanisms within the PVN in HF. ExT alleviates elevated sympathetic outflow in HF through normalization of excitatory glutamatergic and angiotensinergic mechanisms within the PVN. ExT also improves volume reflex function and thus fluid balance in HF. Preliminary observations also suggest that ExT induces structural neuroplasticity in the brain of rats with HF. We conclude that improvement of the enhanced CNS-mediated increase in sympathetic outflow, specifically to the kidneys related to fluid balance, contributes to the beneficial effects of ExT in HF.     

Effect of caffeine supplementation on the extracellular heat shock protein 72 response to exercise.

The stimulus for the release of 72-kDa heat shock protein (HSP72) during exercise in humans is currently unclear. Recent evidence in an animal model is suggestive of an involvement of catecholamines. The present study, therefore, investigated the effect of caffeine supplementation, a known stimulator of sympathetic activity, on the extracellular (e)HSP72 response to prolonged exercise. Ten healthy male endurance-trained cyclists were recruited (age: 21 +/- 1 yr, maximum O(2) uptake 61.1 +/- 1.7 ml x kg(-1) x min(-1), mean +/- SE). Each subject was randomly assigned to ingest either 6 mg/kg body mass of caffeine (Caff) or placebo (Pla) 60 min before one of two 90-min bouts of cycling at 74 +/- 1% maximum O(2) uptake. Trials were performed at least 7 days apart in a counterbalanced design. Venous blood samples were collected by venepuncture at pretreatment, preexercise, postexercise, and 1 h postexercise. Serum caffeine and plasma catecholamines were determined using a spectrophotometric assay and high-performance liquid chromatography, respectively. Plasma HSP72 and cortisol were determined by ELISA. Serum caffeine concentrations were significantly increased throughout Caff, while no increases were detected in Pla. Caffeine supplementation and exercise was associated with a greater eHSP72 response than exercise alone (postexercise Caff 8.6 +/- 1.3 ng/ml; Pla 5.9 +/- 0.9 ng/ml). This greater eHSP72 response was associated with a greater epinephrine response to exercise in Caff. There was a significant increase in norepinephrine and cortisol, with no intertrial differences. The present data suggest that, in humans, catecholamines may be an important mediator of the exercise-induced increase in eHSP72 concentration.     

Static handgrip exercise modifies arterial baroreflex control of vascular sympathetic outflow in humans

To examine effects of static exercise on the arterial baroreflex control of vascular sympathetic nerve activity, 22 healthy male volunteers performed 2 min of static handgrip exercise at 30% of maximal voluntary force, followed by postexercise circulatory arrest (PE-CA). Microneurographic recording of muscle sympathetic nerve activity (MSNA) was made with simultaneous recording of arterial pressure (Portapres). The relationship between MSNA and diastolic arterial pressure was calculated for each condition and was defined as the arterial baroreflex function. There was a close relationship between MSNA and diastolic arterial pressure in each subject at rest and during static exercise and PE-CA. The slope of the relationship significantly increased by >300% during static exercise (P < 0.001), and the x-axis intercept (diastolic arterial pressure level) increased by 13 mmHg during exercise (P < 0.001). These alterations in the baroreflex relationship were completely maintained during PE-CA. It is concluded that static handgrip exercise is associated with a resetting of the operating range and an increase in the reflex gain of the arterial barorelex control of MSNA.     

Endothelin receptor blockade has an oxygen-saving effect in Dahl salt-sensitive rats with heart failure

The effects of endothelin (ET) receptor blockade on energy utilization in heart failure (HF) are unknown. We administered ET type A (ETA), ET type B (ETB), and ETA/ETB antagonists to isolated hearts from Dahl salt-sensitive (DS) rats with HF and controls. Contractile efficiency was assessed as slope-1 of myocardial O consumption (VO2)-pressure-volume area relation. In HF, ETA and ETA/ETB but not ETB blockade decreased the contractility index (Emax)(-15 +/- 3% and -17 +/- 2%, P < 0.05), excitation-contraction (E-C) coupling VO2 (-39 +/- 4% and -37 +/- 5%, P < 0.01), and efficiency (-15 +/- 4% and -17 +/- 2%, P < 0.05). Despite decreased efficiency, ETA and ETA/ETB blockade decreased total VO2 (-24 +/- 3% and -22 +/- 2%, P < 0.05). Na+/H+ exchanger inhibition decreased Emax and E-C coupling VO2 similar to ETA and ETA/ETB blockade, but did not alter efficiency. In HF, endogenous ET-1 maintains contractility at expense of increased VO2 through ETA receptor activation, likely mediated by Na+/H+ exchange.     

Effect of adenosine receptor blockade on pial arteriolar dilation during sciatic nerve stimulation

In the present study, we report the effects of adenosine receptor antagonists on pial vasodilatation during contralateral sciatic nerve stimulation (SNS). The pial circulation was observed through a closed cranial window in alpha-chloralose-anesthetized rats. In artificial cerebrospinal fluid (CSF), SNS resulted in a 30.5 +/- 13.2% increase in pial arteriolar diameter in the hindlimb somatosensory cortex. Systemic administration of the selective adenosine A2A receptor antagonist, 4-(2-[7-amino-2-[2-furyl][3,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino] ethyl)phenol (ZM-241385), significantly (P < 0.05, n = 6) attenuated the SNS-induced vasodilatation. Systemic administration of 8-(p-sulfophenyl)theophylline (8SPT), a nonselective antagonist that is blood-brain barrier (BBB) impermeable, had no effect on vasodilatation to SNS. In contrast, systemic theophylline, which readily penetrates the BBB, nearly abolished the SNS-induced vasodilatation (P < 0.01; n = 7). Topical superfusion of 8SPT significantly (P < 0.01; n = 6) attenuated vasodilatation during SNS. Topical superfusion of 8- cyclopentyl-1,3-dipropylxanthine (DPCPX), a selective adenosine A1 receptor antagonist, significantly potentiated SNS-induced vasodilatation (P < 0.01; n > or = 5). Hypercarbic vasodilatation and somatosensory-evoked potentials were not affected by any of the compounds tested. Our findings suggest that luminal endothelial adenosine receptors are not involved in the arteriolar response to SNS, as demonstrated by a lack of effect with systemic 8SPT. Furthermore, the adenosine A2A receptor subtype appears to be involved in the dilator response to SNS. Finally, the neuromodulatory action of adenosine, via the A1 receptor subtype, significantly influences SNS-induced vasodilatation. Thus the present study provides further evidence for a role of adenosine in the regulation of CBF during somatosensory stimulation.     

Influences of adenosine receptor antagonism on vasodilator responses to adenosine and exercise in adenosine responders and nonresponders.

We previously demonstrated a bimodal distribution of vasodilator responsiveness to adenosine (Ado) infusion in human subjects, despite similar responses to exercise between subgroups [subjects responsive to Ado infusion (Ado responders) and subjects with blunted vasodilator responses to Ado infusion (Ado nonresponders]). (Martin EA, Nicholson WT, Eisenach JH, Charkoudian N, and Joyner MJ. J Appl Physiol 101: 492-499, 2006). A component of this difference was attributed to a larger nitric oxide component of Ado-mediated vasodilation in responders. However, there may also be differences in Ado receptors between these subgroups. We hypothesized that Ado receptor antagonism would reduce vasodilator responsiveness to Ado and exercise only in Ado responders. To test this hypothesis, we compared forearm vasodilation induced by intra-arterial infusion of three doses of Ado to vasodilation during three workloads of forearm handgrip exercise before and after Ado receptor antagonism with aminophylline (Aph) in 19 subjects. In Ado responders, the change in forearm vascular conductance above baseline for the low, medium, and high doses of Ado, respectively, was 93 +/- 16, 140 +/- 14, 194 +/- 18 before Aph and 27 +/- 12, 71 +/- 19, and 134 +/- 34 ml.min(-1).100 mmHg(-1) after Aph (P < 0.05 for low and medium dose before vs. after Aph). For nonresponders, these values were 30 +/- 5, 39 +/- 6, and 78 +/- 9 ml.min(-1).100 mmHg(-1) before Aph (P < 0.05 vs. responders), with no difference after Aph (P > 0.05). We found that Ado receptor blockade significantly inhibited exercise hyperemia only at high workloads in both responders and nonresponders (P < 0.05 before vs. after Aph). We conclude that there may be reduced Ado receptor responsiveness or sensitivity in nonresponders. Furthermore, Ado may play a limited role exercise hyperemia in both subgroups.     

Changes in muscle sympathetic nerve activity and calf blood flow during static handgrip exercise

To test the function of sympathetic vasco-constrictor nerves on blood flow in resting limbs during static muscle contraction, muscle sympathetic nerve activity (MSNA) to the leg muscle was recorded from the tibial nerve microneurographically before, during and after 2 min of static handgrip (SHG). Simultaneously, calf blood flow (CBF) was measured by strain gauge plethysmography. An increase in MSNA, a decrease in CBF and an increase in calf vascular resistance (CVR) in the same resting limb occurred concomitantly during SHG. However, the increase in CVR was blunted in the second minute of handgrip when MSNA was still increasing. The results indicated that the decrease of CBF during SHG reflects the increase in MSNA, while the dissociation between MSNA and CVR at the later period of SHG may be related to metabolic change produced by the vasoconstriction.     

Responses of muscle sympathetic nerve activity to static handgrip exercise after 14 days of exposure to simulated microgravity

Decrease in muscle perfusion affects on cardiovascular response to exercise. Muscle hypoperfusion enhances the increase in blood pressure responses to exercise. Muscle perfusion depends not only on central blood pressure but also how fit the active muscle is above or below the heart level; muscle perfusion decreases as arm is elevated. Static exercise increases muscle sympathetic nerve activity (MSNA) innervating vessels in non-active muscles. The exercise-induced increase in MSNA is mainly mediated by stimulating chemosensitive muscle afferents in active muscles. However, the effect of arm elevation on MSNA during forearm exercise is not examined. On the other hand, space flight and simulated microgravity exposure causes reduction in muscle blood flow, suggesting chronic muscle hypoperfused condition during simulated microgravity. Therefore, there is a possibility that arm elevation after microgravity exposure alters MSNA responsiveness during exercise. However, arm elevation effect after exposure to simulated microgravity is not examined.     

Discriminative stimulus properties of L-phenylisopropyl adenosine: blockade by caffeine and generalization to 2-chloroadenosine

Recent neurochemical data on the effects of activation and blockade of adenosine A1 receptors has suggested a direct role of adenosine in neurotransmission. The present research used a drug discrimination procedure to test the hypotheses that A1 adenosine receptor activation could serve as a discriminative stimulus and that caffeine, a drug believed to be an A1 receptor antagonist, could block the adenosine discrimination. Food-deprived rats were trained to press one of two levers on an FR 10 schedule of food-pellet delivery. Responses on one lever were reinforced following i.p. injection of N6 - (L-phenylisopropyl) adenosine (L-PIA); responses on the other lever were reinforced following i.p. injection of saline. L-PIA training dose was increased from 0.064 to 0.08 mg/kg L-PIA in the course of the study. Subjects required an average of 91 sessions to acquire this discrimination. Stimulus control by L-PIA was dose-dependent, with the ED-50 being approximately 0.03 mg/kg. 2-Chloroadenosine (2CA) generalized to L-PIA with a tenth the potency. Caffeine blocked L-PIA-induced lever selection. These results indicate that 1) rats can be trained to discriminate L-PIA from saline in a two-lever food-reinforced task and 2) the discriminative stimuli produced by L-PIA are based on its agonistic action at the adenosine A1 receptor.     

Renal sympathetic nerve regulation to heating is altered in rats with heart failure

Heart failure (HF) alters the regulation of basal sympathetic nerve discharge (SND); however, the effect of HF on SND responses to acute stress is not well established. In the present study, renal SND responses to hyperthermia were determined in chloralose-anesthetized HF rats and in sham controls. Whole body heating (colonic temperature increased from 38 to 41 degrees C) was used as an acute stressor because increased internal body temperature provides a potent stimulus to the sympathetic nervous system. Left ventricular end-diastolic pressure and the right ventricular wt-to-body wt ratio were increased (P < 0.05) in HF compared with sham rats. The following observations were made: 1) renal sympathoexcitatory responses to heating were significantly reduced in HF compared with sham rats, 2) renal blood flow remained unchanged from control levels during heating in HF rats but was significantly reduced in sham rats, and 3) renal SND responses to heating were significantly higher in HF rats with bilateral lesions of the hypothalamic paraventricular nucleus (PVN) compared with sham PVN-lesioned HF rats. These results demonstrate a marked attenuation in the responsiveness of renal SND to heating in HF rats and suggest that HF alters the organization of neural pathways mediating SND responses to heating.     

Interaction of exercise and adenosine receptor agonist and antagonist on rat heart antioxidant defense system

This study investigated the interactive effects of acute exercise and adenosine receptor agonist and antagonist on antioxidant enzyme activities, glutathione and lipid peroxidation in the heart of the rat. Male Fisher-344 rats were divided into six groups and treated as follows: (1) saline control; (2) acute exercise (100% VO_2max); (3) R-Phenyl isopropyl adenosine (R-PIA) (3.46 mol/kg, i.p.); (4) theophylline (1.70 mol/kg, i.p.) plus acute exercise; (5) theophylline plus R-PIA; and (6) theophylline. Animals were sacrificed 1 h after treatments; hearts were isolated and analyzed. The results show that acute exercise as well as adenosine receptor agonist R-PIA significantly enhanced cardiac superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activity by 36–135% and 16–51%, respectively. Adenosine receptor agonist R-PIA significantly decreased cardiac GSSG concentration and enhanced GSH/GSSG ratio by 22 and 30%, respectively. Whereas theophylline treatment blocked the activation of antioxidant enzyme activities enhanced by acute exercise and R-PIA. Theophylline treatment significantly increased lipid peroxidation by 43% in the heart of exercised rats. The study concluded that the adenosine receptors are involved in the upregulation of cardiac antioxidant defense system and attenuation of lipid peroxidation due to acute exercise in rats. (Mol Cell Biochem 270: 209–214, 2005)     

Effect of vitamin C and L-NMMA on the inotropic response to dobutamine in patients with heart failure

The positive effect of vitamin C on left ventricular (LV) inotropic responses to dobutamine, observed in patients with preserved LV function, is lost in heart failure (HF). We tested the hypothesis that in HF, endogenous nitric oxide (NO) opposes the positive effect of vitamin C on adrenergically stimulated contractility by examining the effects of vitamin C on dobutamine responses during NO synthase inhibition. In 11 HF patients, a micromanometer-tipped catheter was inserted into the LV and an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to intravenous dobutamine (Dob-1). After recontrol, intracoronary N(G)-monomethyl-L-arginine (l-NMMA) was infused before reinfusion of dobutamine (L-NMMA + Dob-2). Finally, intracoronary vitamin C was infused in addition to intracoronary L-NMMA and dobutamine (L-NMMA + Dob-2 + vitamin C). Intracoronary L-NMMA alone had no effect on LV +dP/dt. After a stable inotropic response to intracoronary L-NMMA and dobutamine was established, the addition of intracoronary vitamin C resulted in a modest but significant increase in LV +dP/dt. The change in LV +dP/dt in response to dobutamine alone was 25 +/- 5%, with intracoronary L-NMMA, 27 +/- 6%, and with intracoronary L-NMMA plus vitamin C, 37 +/- 5% (P < 0.05 vs. Dob-1 and L-NMMA + Dob-2). These findings demonstrate that an interaction between endogenous NO and redox environment exists and exerts some influence on stimulated contractility in HF.     

Effect of aerobic and resistance exercise training on vascular function in heart failure

Exercise training of a muscle group improves local vascular function in subjects with chronic heart failure (CHF). We studied forearm resistance vessel function in 12 patients with CHF in response to an 8-wk exercise program, which specifically excluded forearm exercise, using a crossover design. Forearm blood flow (FBF) was measured using strain-gauge plethysmography. Responses to three dose levels of intra-arterial acetylcholine were significantly augmented after exercise training when analyzed in terms of absolute flows (7.0 +/- 1.8 to 10.9 +/- 2.1 ml x 100 ml(-1) x min(-1) for the highest dose, P < 0.05 by ANOVA), forearm vascular resistance (21.5 +/- 5.0 to 15.3 +/- 3.9 ml x 100 ml forearm(-1) x min(-1), P < 0.01), or FBF ratios (P < 0.01, ANOVA). FBF ratio responses to sodium nitroprusside were also significantly increased after training (P < 0.05, ANOVA). Reactive hyperemic flow significantly increased in both upper limbs after training (27.9 +/- 2.7 to 33.5 +/- 3.1 ml x 100 ml(-1) x min(-1), infused limb; P < 0.05 by paired t-test). Exercise training improves endothelium-dependent and -independent vascular function and peak vasodilator capacity in patients with CHF. These effects on the vasculature are generalized, as they were evident in a vascular bed not directly involved in the exercise stimulus.