P2X3 Receptors as a New Target for Heart Failure Treatment
Authors: Lataro Renata M. , Gava Fabio N. , Omoto Ana Carolina M. , Silva Carlos A. A. , Moraes Davi J. A. , Ford Anthony P. , Paton Julian A. F. R. , Salgado Helio C. 
Published: June 2021

In heart failure (HF) chemoreceptor hyperactivity contributes to autonomic dysfunction, reduced pump function, disturbed breathing, and increased mortality. We hypothesized that the excessive carotid body activity present in HF would be attenuated by antagonism of P2X3 receptors thereby alleviating HF symptoms. We evaluated the effect of chronic administration of a highly selective P2X3 receptor inhibitor, AF‐130, in rats with HF induced by coronary artery ligation. Rat groups included: sham coronary ligation (SHAM; n=6–8), HF (n=6–11) and HF treated with AF‐130 (HF+AF‐130, n=6–10). Data were collected after 6 weeks of treatment with AF‐130 (30 mg/Kg/day; s.c.) or vehicle. Heart rate was recorded by electrocardiography while cardiac autonomic modulation was assessed by heart rate variability (HRV), cardiac function was evaluated by echocardiography and respiration measured by whole‐body plethysmography and electromyography (diaphragm, abdominal). Plasma N‐Terminal Pro‐B‐Type natriuretic peptide (NT‐proBNP) was measured by ELISA. AF‐130 treatment improved cardiac sympatho‐vagal modulation in HF rats such that the HRV low‐frequency band was reduced (SHAM:11±2; HF: 23±4; HF+AF‐130: 10±2 nu; p<0.05), while the high‐frequency band increased on drug (SHAM: 89±2; HF: 77±4; HF+AF‐130: 90±2 nu; p<0.05). Thus, AF‐130 normalised the low/high frequency ratio (SHAM: 0.13±0.02; HF: 0.34±0.08; HF+AF‐130: 0.12±0.02; p<0.05). P2X3‐receptor antagonism reduced basal minute ventilation (SHAM: 351±25; HF: 630±61; HF+AF‐130: 469±41 mL/Kg/min; p<0.05), normalised respiratory frequency (SHAM:97±5; HF: 130±6; HF+AF‐130: 109±7 cycles/min; p<0.05) and restored breathing stability in HF rats by reducing both the coefficient of variation (SHAM:0.15±0.01; HF: 0.31±0.05; HF+AF‐130: 0.18±0.01; p<0.05) and incidence of apnea‐hypopnea (SHAM:14±2; HF: 26±4; HF+AF‐130: 12±2 events/h; p<0.05). In HF rats, AF‐130 improved left ventricle ejection fraction (SHAM:61±3; HF: 29±4; HF+AF‐130: 40±4 %; p<0.05), shortening fraction (SHAM:19±1; HF: 8±2; HF+AF‐130: 13±2 %; p<0.05), and stroke volume (SHAM: 529±30; HF: 301±41; HF+AF‐130: 416±37 μL; p<0.05), while reducing plasma NT‐proBNP (SHAM: 161±25; HF: 609±164; HF+AF‐130: 177±36 ng/mL; p<0.05). Regarding the chemoreflex, AF‐130 normalised the inspiratory (SHAM:121±3.4; HF: 157±3.7; HF+AF‐130: 123±3.9 cycles/min; p<0.05), and active expiratory activity responses (abdominal; SHAM:222±7.8; HF: 336±10.2; HF+AF‐130: 220±6.6 %; p<0.05) as well as the evoked carotid sinus nerve volley to cyanide stimulation recorded under anesthesia (SHAM: 234±8.4; HF: 363±15.7; HF+AF‐130: 248±12.5 spikes/s; p<0.05). Thus, we conclude that chronic blockade of P2X3 receptors in HF rats restores normal cardiac autonomic modulation and respiratory function, and improves cardiac pump function; part of this mechanism is mediated by tempering carotid body activity. We suggest that P2X3 receptors are considered as a new clinical target for HF treatment.

Support or Funding Information

CAPES, CNPq, FAPESP, Afferent Pharm and BHF funded research.

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.