Type III‐IV Muscle Afferents are NOT Required for a Normal Steady‐State Exercise Hyperpnea in Healthy Subjects and Patients with COPD or Heart Failure

Blockade of group III‐IV muscle afferents by intrathecal injection of the µ‐opioid agonist fentanyl (IF) in humans has been variously reported to depress exercise hyperpnea in some studies (1, 2) but not others (3, 4). A key unanswered question is whether such an effect is transient or persists in the steady state of exercise. Here, we apply Dejours' three‐phase exercise ventilatory kinetics framework to show that the discrepancy in the reported results are ascribable to IF's differing effects on the nonsteady‐ and steady‐state ventilatory responses to exercise. Specifically, in healthy subjects undergoing mild to moderate cycling exercise IF significantly slows the exercise ventilatory kinetics as measured after 3 min of exercise, but otherwise has no discernible effect on the subsequent steady‐state ventilatory response which is attained after 5 min of constant‐load exercise. In healthy subjects performing heavy cycling exercise, IF also depresses the early‐phase exercise ventilatory response but this hypoventilatory effect gradually declines as exercise is prolonged, vanishing after ~7 min of constant‐load exercise (4). Finally, IF has been reported to depress the exercise ventilatory response in patients with heart failure (3) or COPD (5). We present evidence indicating that this ventilatory depression effect of IF is nonspecific to exercise as it is elicited even in the resting state in heart failure (3) and is secondary to an attendant decrease in physiological dead space in COPD (5). (Supported by HL093225)