Introduction 

The carotid body has a key role in the control of breathing in humans¹. There is now strong evidence that the carotid chemoreflex, is overactive in a range of conditions such as heart failure² and COPD³. Dopamine has been used to inhibit the carotid chemoreflex but its use is limited by its intravenous access⁴, short half-life and non-selective nature. Our group has shown that P2X3 receptors in the carotid body can be targeted to reduce carotid chemoreflex overactivity in animal models of hypertension⁵ and heart failure⁶. Whether P2X3 receptor antagonism in humans impacts carotid chemoreflex control of ventilation is unknown. 

Objective 

Our objective was to assess whether oral P2X3 antagonism with gefapixant influences the carotid body chemoreflex and breathing during exercise, in healthy adults. 

Hypothesis 

We hypothesised that oral P2X3 antagonism would reduce carotid chemoreflex sensitivity and temper ventilation during exercise in healthy adults.  

Methods 

This was a pilot feasibility crossover study. Healthy adults with no major co-morbidities were recruited. Participants received an acute oral dose of gefapixant (45 mg) and placebo (randomised in order and double-blinded). Participants underwent testing for the hypoxic ventilatory response (HVR; via intermittent hypoxia induced by added nitrogen), a measure of carotid chemoreflex sensitivity, as well as cardiopulmonary exercise testing (CPET), to assess ventilatory responses to exercise (ramped incremental exercise test on cycle ergometer; Lovemedical Ergostik CPET system). HVR was evaluated as the slope of the linear regression relating the minute ventilation (V_E) to the nadir of oxygen saturation for each nitrogen exposure. Data were compared with a Wilcoxen matched pairs test. Data are median with range.  

Results 

Four participants (3 males, age; 47 [IQR 39-52] years and BMI; 23 [IQR 21-25] kg/m²) volunteered to participate (REC number 25/HRA/0973). Gefapixant reduced the HVR compared with placebo (-0.24 [-0.30 to -0.14] L/min/% vs -0.31 [-0.34 to -0.21] L/min/%; p=0.0209, effect size Cohen’s dRM=3.5). The V_E/volume of CO₂ expired (V_E/VCO₂) nadir during CPET was also decreased by gefapixant (23.7±1.9) vs. placebo (24.8±1.5), p=0.0531, effect size Cohen’s dRM= -2.19. Importantly, no side effects or adverse events were reported. Gefapixant did not impact maximum heart rate, peak oxygen consumption (VO2) or exercise duration, compared with placebo (171bpm vs 173bpm, p=0.8088; 41.5ml/min/kg vs 43.3ml/min/kg, p=0.2530; 837s vs 868ms, p=0.3646, respectively).  

Conclusion 

This is the first study in humans to demonstrate that oral P2X3 antagonism with gefapixant reduces carotid chemoreflex sensitivity to hypoxia. We also found that gefapixant may improve ventilatory efficiency (V_E/VCO₂ nadir) during exercise. Future studies are required to assess the potential physiological effects in patients with exaggerated carotid chemoreflex functions such as heart failure.