Naloxone and the ventilatory response to exercise in man

Endogenous opiate peptides are known to exert a depressant action on ventilation (VE), and their plasma levels have been shown to be elevated during a variety of exercise protocols. We investigated whether they might modulate the control of the hyperpnea of short-term constant-load (CLE) and incremental (IE) cycle-ergometer exercise. Four healthy subjects performed CLE tests at ca. 80% of the anaerobic threshold (theta an) for 5 min following a period of unloaded pedaling, and IE tests (10 or 20 W min-1) to the limit of tolerance. Normal saline (3 ml) or the opiate antagonist naloxone (1.2 mg in 3 ml) were administered intravenously prior to each test. Naloxone elicited no discernible effect on VE, alveolar gas tensions, or heart rate throughout the entire range of work rates; neither were theta an nor the maximum work rate affected. It is concluded that, for short-term exercise ranging in intensity from moderate to severe, the role played by endogenous opiate peptides in the control of the exercise hyperpnea appears to be negligible in man.     

Effect of dopamine on transient ventilatory response to exercise

The effect of exogenous dopamine on the development of exercise hyperpnea was studied. Using a bicycle ergometer, five subjects performed repetitive square-wave work-load testing from unloaded pedaling to 80% of each subject's estimated anaerobic threshold. The breath-by-breath ventilation (VE), CO2 production (VCO2), and O2 consumption (VO2) responses were analyzed by curve fitting a first-order exponential model. Comparisons were made between control experiments and experiments with a 3-micrograms X kg-1 X min-1 intravenous infusion of dopamine. Steady-state VE, VCO2 and VO2 were unchanged by the dopamine infusion, both during unloaded pedaling and at the heavier work load. The time constants for the increase in VE (tau VE) and VCO2 (tau CO2) were significantly (P less than 0.05) slowed (tau VE = 56.5 +/- 16.4 s for control, and tau VE = 76.4 +/- 26.6 s for dopamine; tau CO2 = 51.5 +/- 10.6 s for control, and tau CO2 = 64.8 +/- 17.4 s for dopamine) (mean +/- SD), but the time constant for VO2 (tau O2) was not significantly affected (tau O2 = 27.5 +/- 11.7 s for control, and tau O2 = 31.0 +/- 10.1 s for dopamine). We conclude that ablation of carotid body chemosensitivity with dopamine slows the transient ventilatory response to exercise while leaving the steady-state response unaffected.     

Mediation of reduced ventilatory response to exercise after endurance training

To investigate the mechanism by which ventilatory (VE) demand is modulated by endurance training, 10 normal subjects performed cycle ergometer exercise of 15 min duration at each of four constant work rates. These work rates represented 90% of the anaerobic threshold (AT) work rate and 25, 50, and 75% of the difference between maximum O2 consumption and AT work rates for that subject (as determined from previous incremental exercise tests). Subjects then underwent 8 wk of strenuous cycle ergometer exercise for 45 min/day. They then repeated the four constant work rate tests at work rates identical to those used before training. During tests before and after training, VE and gas exchange were measured breath by breath and rectal temperature (Tre) was measured continuously. A venous blood sample was drawn at the end of each test and assayed for lactate (La), epinephrine (EPI), and norepinephrine (NE). We found that the VE for below AT work was reduced minimally by training (averaging 3 l/min). For the above AT tests, however, training reduced VE markedly, by an average of 7, 23, and 37 l/min for progressively higher work rates. End-exercise La, NE, EPI, and Tre were all lower for identical work rates after training. Importantly, the magnitude of the reduction in VE was well correlated with the reduction in end-exercise La (r = 0.69) with an average decrease of 5.8 l/min of VE per milliequivalent per liter decrease in La. Correlations of VE with NE, EPI, and Tre were much less strong (r = 0.49, 0.43, and 0.15, respectively).     

Effect of glycogen depletion on the ventilatory response to exercise

Five male subjects performed two graded exercise studies, one during control conditions and the other after reduction of muscle glycogen content by repeated maximum exercise and a high fat-protein diet. Reduction in preexercise muscle glycogen from 59.1 to 17.1 mumol X g-1 (n = 3) was associated with a 14% reduction in maximum power output but no change in maximum O2 intake; at any given power output O2 intake, heart rate, and ventilation (VE) were significantly higher, CO2 output (VCO2) was similar, and the respiratory exchange ratio was lower during glycogen depletion compared with control. The higher VE during glycogen depletion was associated with a higher VE/VCO2 ratio, lower end-tidal and mixed venous CO2 partial pressures, and higher blood pH than in the control studies. Changes in exercise VE accompanying glycogen depletion were not explained by changes in CO2 flux to the lungs suggesting that other factors served to modulate VE in these experimental conditions.     

Effect of aging on ventilatory response to exercise and CO2

Studies were performed to determine the effects of aging on the ventilatory responsiveness to two known respiratory stimulants, inhaled CO2 and exercise. Although explanation of the physiological mechanisms underlying development of exercise hyperpnea remains elusive, there is much circumstantial evidence that during exercise, however mediated, ventilation is coupled to CO2 production. Thus matched groups of young and elderly subjects were studied to determine the relationship between increasing ventilation and increasing CO2 production (VCO2) during steady-state exercise and the change in their minute ventilation in response to progressive hypercapnia during CO2 rebreathing. We found that the slope of the ventilatory response to hypercapnia was depressed in elderly subjects when compared with the younger control group (delta VE/delta PCO2 = 1.64 +/- 0.21 vs. 2.44 +/- 0.40 l X min-1 X mmHg-1, means +/- SE, respectively). In contrast, the slope of the relationship between ventilation and CO2 production during exercise in the elderly was greater than that of younger subjects (delta VE/delta VCO2 = 29.7 +/- 1.19 vs. 25.3 +/- 1.54, means +/- SE, respectively), as was minute ventilation at a single work load (50 W) (32.4 +/- 2.3 vs. 25.7 +/- 1.54 l/min, means +/- SE, respectively). This increased ventilation during exercise in the elderly was not produced by arterial O2 desaturation, and increased anaerobiasis did not play a role. Instead, the increased ventilation during exercise seems to compensate for increased inefficiency of gas exchange such that exercise remains essentially isocapnic. In conclusion, in the elderly the ventilatory response to hypercapnia is less than in young subjects, whereas the ventilatory response to exercise is greater.     

Short-term modulation of the exercise ventilatory response in young men.

Arterial isocapnia is a hallmark of moderate exercise in humans and is maintained even when resting arterial Pco(2) (Pa(CO(2))) is raised or lowered from its normal level, e.g., with chronic acid-base changes or acute increases in respiratory dead space. When resting ventilation and/or Pa(CO(2)) are altered, maintenance of isocapnia requires active adjustments of the exercise ventilatory response [slope of the ventilation (Ve)-CO(2) production (Vco(2)) relationship, DeltaVe/DeltaVco(2)]. On the basis of animal studies, it has been proposed that a central neural mechanism links the exercise ventilatory response to the resting ventilatory drive without need for changes in chemoreceptor feedback from rest to exercise, a mechanism referred to as short-term modulation (STM). We tested the hypothesis that STM is elicited by increased resting ventilatory drive associated with added external dead space (DS) in humans. Twelve young men were studied in control conditions and with added DS (200, 400, and 600 ml; randomized) at rest and during mild-to-moderate cycle exercise. DeltaVe/DeltaVco(2) increased progressively as DS volume increased (P < 0.0001). While resting end-tidal Pco(2) (Pet(CO(2))) increased with DS, the change in Pet(CO(2)) from rest to exercise was not increased, indicating that increased chemoreceptor feedback from rest to exercise cannot account for the greater exercise ventilatory response. We conclude that STM of the exercise ventilatory response is induced in young men when resting ventilatory drive is increased with external DS, confirming the existence of STM in humans.     

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).