Type III-IV muscle afferents are not required for 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 but not others. A key unanswered question is whether such an effect is transient or persists in the steady state. Here we show that in healthy subjects undergoing constant-load cycling exercise IF significantly slows the transient exercise ventilatory kinetics but has no discernible effect on the ventilatory response when exercise is sufficiently prolonged. Thus, the ventilatory response to group III-IV muscle afferents input in healthy subjects is not a simple reflex but acts like a high-pass filter with maximum sensitivity during early-phase exercise and is reset in the late phase. In patients with chronic heart failure (CHF) IF causes sustained CO2 retention not only during exercise but also in the resting state, where muscle afferents feedback is minimal. In patients with chronic obstructive pulmonary disease (COPD), IF also elicits sustained decreases in the exercise ventilatory response but with little or no resultant CO2 retention due to concomitant decreases in physiological VD/VT (dead space-to-ventilation ratio). These results support the proposition that optimal long-term regulation of exercise hyperpnea in health and in disease is determined centrally by the respiratory controller through the continuing adaptation of an internal model which dynamically tracks the metabolic CO2 load and the ventilatory inefficiency 1/1-VD/VT that must be overcome for the maintenance of arterial PCO2 homeostasis, rather than being reflexively driven by group III-IV muscle afferents feedback per se.