P2X3 receptor antagonism improves hindlimb blood flow during exercise in a conscious ovine model of hypertensive heart failure with preserved ejection fraction.

Exercise intolerance in heart failure with preserved ejection fraction (HFpEF) is linked to impaired vascular regulation and exaggerated autonomic responses. Although sensory afferent signalling via P2X3 receptors (P2X3Rs) contributes to exaggerated cardiovascular reflex activity in hypertension, its role in mediating haemodynamic limitation during HFpEF is unknown. We tested whether selective P2X3R antagonism improved blood pressure and exercise haemodynamics in a conscious ovine model of hypertensive HFpEF. Female hypertensive HFpEF sheep and age-matched sham controls were instrumented for chronic measurement of arterial pressure, cardiac output and blood flow to the hindlimbs, kidney and coronary vasculature. Haemodynamic responses were assessed at rest and during graded treadmill exercise before and after systemic selective P2X3R blockade. Postexercise heart‑rate recovery was assessed as an index of physical fitness. L4 dorsal root ganglia (DRG) were analysed for gene expression related to neuronal excitability. P2X3R antagonism lowered resting mean arterial pressure (from 116 ± 10.2 to 110 ± 7.8 mmHg, P = 0.014), increased hindlimb blood flow at peak exercise (vehicle 4.4 ± 2.6 vs. P2X3R blockade 5.2 ± 2.9 L/min, P = 0.009) and improved postexercise heart rate recovery in HFpEF sheep, despite no difference in P2X3R mRNA expression compared with sham controls. These findings demonstrate that P2X3R signalling contributes to resting hypertension and impaired exercise haemodynamics in hypertensive HFpEF. The improvement in peak exercise haemodynamics in the absence of altered gene expression suggests receptor hypersensitivity or posttranslational gain of function in HFpEF. These findings identify P2X3R signalling as a potential mechanistic contributor to exercise limitation in HFpEF and support further investigation of this pathway as a possible therapeutic strategy. KEY POINTS: Exercise intolerance is an important symptom in heart failure with preserved ejection fraction (HFpEF) and is linked to impaired autonomic responses. Although purinergic receptors (P2X3 subtype) have been linked to autonomic reflex control, the role of these receptors in mediating the haemodynamic limitation during HFpEF is unknown. We used a preclinical large-animal model of hypertensive HFpEF to show that P2X3R signalling contributes to resting hypertension. Blockade of these receptors improved hindlimb blood flow during peak exercise and improved heart rate recovery. Our findings identify P2X3R signalling as a potential mechanistic contributor to exercise limitation in HFpEF.