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J Appl Physiol 82: 1488-1492, 1997;
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Journal of Applied Physiology
Vol. 82, No. 5, pp. 1488-1492, May 1997
EXERCISE AND MUSCLE

Training improves endothelium-dependent vasodilation in resistance vessels of patients with heart failure

Stuart D. Katz, Jeannette Yuen, Rachel Bijou, and Thierry H. Lejemtel

Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Bronx 10461; and Division of Circulatory Physiology, Department of Medicine, Columbia University College of Physicians and Surgeons, Columbia Presbyterian Medical Center, New York, New York 10032

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Katz, Stuart D., Jeannette Yuen, Rachel Bijou, and Thierry H. LeJemtel. Training improves endothelium-dependent vasodilation in resistance vessels of patients with heart failure. J. Appl. Physiol. 82(5): 1488-1492, 1997.---The effects of physical training on endothelium-dependent vasodilation in skeletal muscle resistance vessels were investigated in patients with heart failure. Forearm blood flows (ml · min-1 · 100 ml-1) in response to brachial arterial administration of acetylcholine (5 × 10-5 and 5 × 10-4 M at 1 ml/min) and nitroglycerin (5 × 10-6 and 5 × 10-5 M at 1 ml/min) were determined by strain-gauge venous occlusion plethysmography before and after 8 wk of daily handgrip exercise in 12 patients with chronic heart failure. After 8 wk of daily handgrip exercise, the vasodilatory responses to acetylcholine significantly increased from pretraining values, i.e., 16.6 ± 2.0 vs. 8.6 ± 1.3 ml · min-1 · 100 ml-1 (P < 0.05) and 27.5 ± 1.5 vs. 14.6 ± 1.7 ml · min-1 · 100 ml-1 (P < 0.05), respect- ively, whereas the vasodilatory responses to nitroglycerin did not change. Handgrip exercise training appears to specifically enhance endothelium-dependent vasodilation in the forearm skeletal muscle circulation of patients with heart failure.

congestive; exercise; physical training; acetylcholine; endothelium-derived relaxing factor

INTRODUCTION

PHYSICAL TRAINING is associated with adaptations in skeletal muscle vascular structure and functional alterations in the regulation of vascular resistance that increase the maximal vascular transport capacity in the trained skeletal muscle circulation (23). Structural vascular adaptations associated with training include increased capillary density and increased maximal diameter of resistance arterioles in the trained skeletal muscle circulation (15). Alterations in regulation of vascular resistance associated with training include increased endothelium-dependent vasodilation in both conduit and resistance blood vessels, increased nitric oxide synthesis in microvessels, and increased levels of endothelial nitric oxide synthase mRNA (3, 22, 26). In normal human subjects, physical training has been shown to increase maximal limb vascular conductance and to enhance endothelium-dependent vasodilation in response to muscarinic stimulation in the trained limb vasculature (11, 24).

The vascular adaptations associated with physical training are particularly relevant for patients with congestive heart failure in whom peak exercise capacity is partially limited by an impaired vasodilatory response to exercise (8, 17). Increased peripheral vasomotor tone during exercise in patients with congestive heart failure appears to be related to both structural and functional changes in skeletal muscle resistance arterioles, as evidenced by decreased maximal limb vascular conductance in response to metabolic vasodilatory stimuli and decreased endothelium-dependent vasodilation in response to regional muscarinic stimulation (10, 13, 29).

Physical training has been previously shown to increase peak limb blood flow during exercise and to enhance flow-dependent vasodilation in conduit vessels in patients with congestive heart failure (7, 25). Whether physical training specifically enhances endothelium-dependent vasodilation in skeletal muscle resistance vessels in patients with heart failure is unknown. Accordingly, the present study was undertaken to determine the forearm blood flow responses to administration of acetylcholine and nitroglycerin in the brachial artery before and after 8 wk of daily handgrip exercise training in patients with severe congestive heart failure.

METHODS

Study population. Ten men and two women with idiopathic dilated cardiomyopathy (mean age 58 ± 3 yr, mean left ventricular ejection fraction 25 ± 5%) and symptoms of congestive heart failure compatible with functional class II-III according to the criteria of the New York Heart Association were studied. The mean peak oxygen uptake of the patients was 15.2 ± 2.1 ml · kg-1 · min-1. All patients were treated with the angiotensin-converting enzyme inhibitors furosemide and digoxin. Ten of the twelve patients were also receiving long-acting nitrates. No patient had a history of diabetes mellitus, hypertension, smoking, or hypercholesterolemia. The study was approved by the Ethical Review Board of the Albert Einstein College of Medicine and Montefiore Medical Center. All patients gave written informed consent before training.

Forearm blood flow measurement. Forearm blood flow (ml · min-1 · 100 ml-1 of forearm volume) was determined with venous occlusion strain-gauge plethysmography, as previously described in detail (5). Briefly, with the arm resting comfortably 10 cm above the right atrium, a mercury-in-Silastic strain gauge was placed around the widest portion of the upper one-third of the forearm. The strain gauge was electrically coupled to a plethysmograph (Parks Electronics, Aloha, OR) calibrated to measure percent change in volume. The plethysmographic tracings of forearm blood flow were digitally recorded on a personal computer at 40 Hz for later analysis (MacLab Software). For each measurement, forearm venous blood flow was occluded just proximal to the elbow with the rapid inflation of a blood pressure cuff to 40 mmHg (model E 20, Hokanson Instruments). A wrist cuff was inflated to suprasystolic pressures 1 min before and during each measurement to exclude the hand circulation from the blood flow determination. The venous occluding cuff was inflated for 5 s at 15-s intervals; five plethysmographic measurements were averaged for determination of forearm blood flows at rest and during administration of acetylcholine and nitroglycerin. Peak reactive hyperemic blood flow was measured as the first blood flow measurement within 5 s after release of an arterial occluding cuff inflated to 200 mmHg for 5 min.

Drug administration. All drugs were prepared on the day of the study in 5% dextrose in water solution and administered directly into the brachial artery. Acetylcholine at concentrations of 5 × 10-5 and 5 × 10-4 M was administered in the brachial artery to assess endothelium-dependent, nitric oxide-mediated vasodilation, and nitroglycerin at concentrations of 5 × 10-6 and 5 × 10-5 M was administered in the brachial artery to assess endothelium-independent, nitric oxide-mediated vasodilation. Each concentration of acetylcholine and nitroglycerin was administered as continuous 2-min infusions at a rate of 1 ml/min. Sequential infusions were separated by 3-5 min to allow forearm blood flow to return to resting values. The doses of acetylcholine and nitroglycerin were selected to induce submaximal vasodilation in the forearm vasculature, as previously reported (12).

Forearm training protocol. Forearm training was adapted from the protocol previously described by Sinoway et al. (24). The maximum amount of forearm work was determined as the highest work rate patients could sustain for 3 min on a handgrip dynanometer. The training work rate was adjusted to 70% of maximal work rate. Patients performed repetitive handgrip exercise with the nondominant hand 30 min daily at a rate of 20 contractions/min. Training sessions were monitored three times weekly under direct observation to ensure adequate compliance with the training regimen. The duration of handgrip training was 8 wk.

Study design. Subjects were studied on 2 days, before and after 8 wk of handgrip training. Cardiovascular medications were withheld for 24 h before each study day. On each study day, forearm circumference (measured at 25% of the distance from the olecranon process to the wrist) and maximum voluntary contraction were determined in the dominant (untrained) and nondominant (trained) forearms on a handgrip dynanometer. Maximal voluntary contraction of the nondominant forearm was determined with a dynanometer as the average of three maximal efforts sustained for 3 s. Resting and peak reactive hyperemic blood flows were then determined sequentially in both forearms. After return of forearm blood flow to basal values, a 20-gauge Angiocath was placed into the brachial artery of the nondominant forearm under local anesthesia for regional administration of acetylcholine and nitroglycerin. Thirty minutes after insertion of the Angiocath, the regional vasodilatory responses to intra-arterial administration of graded doses of acetylcholine and nitroglycerin were determined. Blood pressure was measured in the contralateral arm by the automated cuff method at 1-min intervals during all forearm blood flow measurements. Measurements of forearm circumference, maximum voluntary contraction, and forearm blood flows at rest in response to 5 min of arterial occlusion and in response to administration of acetylcholine and nitroglycerin were repeated before and after 8 wk of handgrip training.

Reproducibility of the vascular response to acetylcholine. The responses of the forearm vasculature to intra-arterial administration of acetylcholine (5 × 10-5 M at 1 ml/min) had been assessed in an additional six patients with congestive heart failure at an 8-wk interval. The vasodilatory responses to administration of acetylcholine were similar at the two time points (Table 1).

Table 1. Reproducibility of vasodilatory responses to administration of acetylcholine in the brachial artery of patients with congestive heart failure at 8-wk interval

Forearm Blood Flow, ml · min-1 · 100 ml-1
Rest Acetylcholine (5 × 10-5 M; 1 ml/min)
Baseline 2.8 ± 0.2  8.2 ± 0.5 
8 wk 2.6 ± 0.2  8.4 ± 0.6
Values are means ± SE for 6 patients.

Data analysis. All values are presented as means ± SE. Forearm blood flows at rest, after 5 min of arterial occlusion, and during administration of acetylcholine and nitroglycerin before and after training were compared with a two-factor repeated-measures analysis of variance model. Forearm circumference and maximum voluntary contraction before and after training were compared with Student's t-test for paired observations. Correlations of forearm blood flows in response to 5 min of arterial occlusion and administration of acetylcholine were determined with simple linear regression. Differences were considered to be statistically different if the two-tailed P value was <0.05.

RESULTS

After 8 wk of daily handgrip exercise, peak reactive hyperemic blood flow increased significantly in the trained forearm from the pretraining baseline but did not change in the untrained forearm (Fig. 1). Resting blood flows in the trained and untrained forearms were unchanged during the 8-wk study period (4.3 ± 0.3 vs. 3.5 ± 0.3 ml · min-1 · 100 ml-1 in the trained forearm and 4.5 ± 0.4 vs. 3.7 ± 0.4 ml · min-1 · 100 ml-1 in the untrained forearm; P = not significant for both comparisons of pretraining vs. posttraining values, respectively).

Fig. 1. Peak reactive hyperemic blood flow after 5 min of arterial occlusion in nondominant trained forearm and dominant untrained forearm in 12 patients with congestive heart failure before (open bars) and after (solid bars) 8 wk of handgrip exercise training. Values are means ± SE. * P < 0.05 vs. pretraining value.
[View Larger Version of this Image (14K GIF file)]

The vasodilatory responses to administration of acetylcholine (5 × 10-5 and 5 × 10-4 M at 1 ml/min) significantly increased from pretraining values after 8 wk of daily handgrip exercise, i.e., 16.6 ± 2.0 vs. 8.6 ± 1.3 ml · min-1 · 100 ml-1 and 27.5 ± 1.5 vs. 14.6 ± 1.7 ml · min-1 · 100 ml-1, respectively (P < 0.05; Fig. 2). In contrast, the vasodilatory responses to brachial arterial administration of nitroglycerin (5 × 10-6 and 5 × 10-5 M at 1 ml/min) did not change after 8 wk of daily handgrip exercise, i.e., 7.0 ± 0.6 vs. 7.0 ± 0.8 ml · min-1 · 100 ml-1 and 10.2 ± 1.0 vs. 10.7 ± 1.0 ml · min-1 · 100 ml-1, respectively.

Fig. 2. Forearm blood flows at rest and during administration of graded doses of acetylcholine (ACh) in 12 patients with congestive heart failure before (open bars) and after (solid bars) 8 wk of handgrip exercise. Values are means ± SE. * P < 0.05 vs. pretraining value.
[View Larger Version of this Image (14K GIF file)]

Training-induced increases in the forearm peak reactive hyperemic blood flow did not correlate with increases in the vasodilatory responses to acetylcholine (r = 0.12). Eight weeks of daily handgrip exercise significantly increased maximum voluntary contraction from 26.6 ± 3.2 to 31.6 ± 3.3 kg (P < 0.05). Forearm circumference also increased slightly from baseline in response to training (26.2 ± 1.1 vs. 26.8 ± 1.2 cm; P < 0.05). Mean arterial blood pressure did not change from baseline after physical training.

DISCUSSION

The present data clearly demonstrate that 8 wk of handgrip training is associated with a significant increase in the forearm blood flow response to regional administration of acetylcholine but not nitroglycerin. Thus physical training appears to specifically enhance endothelium-dependent vasodilation in the skeletal muscle circulation of patients with congestive heart failure.

In animals without heart failure, studies of the effects of physical training on vascular endothelial function have yielded conflicting findings. In isolated aortic rings of rats and rabbits, some investigators have observed enhanced endothelium-dependent vasodilation in response to 8-12 wk of training (1, 3), whereas others have not (6). In isolated conduit vessels from the canine and porcine coronary circulation, endothelium-dependent vasodilation is not altered by 8-12 wk of training (16, 21). In isolated resistance arterioles from the rat skeletal muscle circulation and the coronary circulation of pigs, 8-12 wk of physical training enhance endothelium-dependent vasodilation (20, 26). In the intact coronary circulation of chronically instrumented conscious dogs, 10 days of physical training were associated with enhanced endothelium-dependent vasodilation in conduit coronary arteries, increased nitric oxide production in isolated coronary microvessels, and increased nitric oxide synthase gene expression in aortic endothelial cells (22, 28).

The effects of physical training on vascular endothelial function have been controversial in normal human subjects. Katz et al. (11) have previously shown that 8 wk of lower extremity aerobic training (bicycle or treadmill exercise) were associated with a specific increase in acetylcholine-mediated vasodilation in the trained lower extremity but not the untrained upper extremity in normal subjects. In contrast, Green et al. (4) reported that 4 wk of daily handgrip exercise did not alter the vascular response to acetylcholine in the forearm circulation. These disparate findings may be related to the duration of training because 4 wk may not be sufficient to observe alterations in vascular endothelium function in resistance vessels (16).

The vascular effects of physical training have been studied in the rat model of heart failure after ligation of the left anterior descending coronary artery (18). Treadmill training for 6 wk did not alter endothelial-dependent vasodilation in isolated aortic rings when compared with that observed in sedentary controls. In patients with congestive heart failure, Hornig et al. (7) demonstrated that 4 wk of handgrip exercise enhanced endothelium-dependent vasodilation in the radial artery but did not alter peak reactive hyperemic blood flow. The findings of Hornig et al. are consistent with the previously reported vascular effects of short-term training, which enhances endothelium-dependent vasodilation in conduit but not resistance vessels (16, 28). In the present study, the expected vascular effects of long-term training were confirmed by a significant increase in peak reactive hyperemic blood flow in the trained forearm. Because blood flow is primarily dependent on behavior of arteriolar resistance vessels, the present data extend the findings of Hornig and colleagues by demonstrating that 8 wk of handgrip training enhance endothelium-dependent vasodilation in resistance vessels of the trained forearm skeletal muscle vasculature. Although 8 wk of handgrip training were associated with significant increases in both metabolic vasodilation in response to 5 min of arterial occlusion and endothelium-dependent vasodilation in response to acetylcholine, the increased vasodilatory responses did not correlate. Thus the determinants of peak reactive hyperemia and endothelium-dependent vasodilation appear to be clearly distinct, as evidenced by the lack of effect of inhibition of nitric oxide synthesis on peak reactive hyperemia in normal human subjects (27).

The mechanisms that are responsible for the training-induced enhancement of vascular endothelial function cannot be ascertained from the present data. Nevertheless, the mechanisms are likely to be local rather than systemic in nature because 1) enhanced endothelium-dependent vasodilation induced by training is specific to the trained vasculature and 2) handgrip training is not associated with systemic training effects in patients with congestive heart failure (11, 19). Physical training may enhance endothelium-dependent vasodilation by periodically increasing blood flow in the trained skeletal muscle circulation. Muller and colleagues (20) demonstrated that chronic increases in regional blood flow are associated with enhanced endothelium-dependent, nitric oxide-mediated vasodilation. Endothelium-derived vasoactive substances may also regulate structural vascular adaptations in response to training (9, 14).

In accord with previous findings, the forearm blood flow responses to administration of nitroglycerin were less than the forearm blood flow responses to administration of acetylcholine in the present study (10, 12). Nitroglycerin was not administered at doses >10-5 M because doses >10-5 M occasionally produce a fall in systemic blood pressure. The inequality of the blood flow responses to acetylcholine and nitroglycerin is likely due to differences in vasodilatory potency and plasma half-life of these two agents.

In conclusion, the present study demonstrates that 8 wk of handgrip training specifically enhance endothelium-dependent vasodilation in the trained skeletal muscle circulation of patients with congestive heart failure. These findings suggest that enhancement of endothelial function may contribute to the clinical benefits of physical training that have previously been demonstrated in patients with heart failure (2, 25).

ACKNOWLEDGEMENTS

S. Katz is supported in part by an Investigatorship award from the American Heart Association, New York Affiliate, and by National Heart, Lung, and Blood Institute Grant R29-HL-51433.

FOOTNOTES

   This work was previously presented in abstract form at the American College of Cardiology Scientific Sessions in Anaheim, CA, in March 1993.

Address for reprint requests: T. H. LeJemtel, Albert Einstein College of Medicine, Div. of Cardiology, Forch G42, 1300 Morris Park Ave., Bronx, NY 10461.

Received 28 October 1996; accepted in final form 3 January 1997.

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0161-7567/97 $5.00 Copyright © 1997 the American Physiological Society


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