Addressing the enigma of treating heart failure with preserved ejection fraction with P2X3 receptor antagonism

Heart failure with preserved ejection fraction (HFpEF) is a major health burden and a primary cause of death globally, yet there remains no curative treatment. Previous studies have indicated an important role for P2X3 receptors (P2X3R) in mediating high levels of sympathetic drive in hypertension (1). Given the high sympathetic drive in HFpEF(2), we investigated whether P2X3R antagonism would improve this condition. We tested the hypotheses that in HFpEF, P2X3R activation causes high levels of blood pressure and excessive vasoconstriction in the hindlimb vasculature during exercise. Following unilateral renal artery clipping, an ovine model of HFpEF was established in female sheep displaying hypertension and diastolic dysfunction. A sham-operated group acted as a control. Mean arterial pressure (MAP), heart rate (HR), and hindlimb blood flow (HLBF) were recorded before and during treadmill exercise, and the effect of either a P2X3R antagonist (L227, 10mg/kg) or vehicle was assessed. The clipping of one renal artery increased MAP (91±5 vs. 131±6, p≤0.05). The administration of the P2X3R antagonist reduced both MAP (-6±7 mmHg, p≤0.05) and HR (-6±6 bpm, p<0.05) in HFpEF sheep but no effect in sham-operated animals. HLBF during exercise was attenuated in the HFpEF model compared to sham-operated sheep (an increase of 2±1 vs. 4±2 L/min, respectively, p<0.05). Importantly, P2X3R blockade improved the change in HLBF during exercise from 1±0.1 to 2±0.4 L/min in HFpEF sheep, but there was no change in the sham-operated animals. There was no change in the MAP or HR response to the exercise with the P2X3R blockade. P2X3R plays a role in the aetiology of hypertension and in the attenuation of HLBF responses during exercise in HFpEF. P2X3R antagonism may provide a novel target to alleviate symptoms of HFpEF and improve exercise tolerance through increased HLBF. 1. Pijacka W, Moraes DJ, Ratcliffe LE, Nightingale AK, Hart EC, da Silva MP, Machado BH, McBryde FD, Abdala AP, Ford AP and Paton JFR. Purinergic receptors in the carotid body as a new drug target for controlling hypertension. Nature medicine 22: 1151-1159, 2016. 2. Seravalle G, Quarti-Trevano F, Dell’Oro R, Gronda E, Spaziani D, Facchetti R, Cuspidi C, Mancia G, and Grassi G. Sympathetic and baroreflex alterations in congestive heart failure with preserved, midrange and reduced ejection fraction. Journal of Hypertension 37: 443-448, 2019. Health Research Council of New Zealand and Sidney Taylor Trust. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.