P2X3 receptor antagonism attenuates the progression of heart failure
Renata Maria Lataro, Davi J. A. Moraes, Fábio Nelson Gava, Ana Carolina Mieko Omoto, Carlos A. A. Silva, Fernanda Brognara, Lais Alflen, Vânia Brazão, Rafaela Pravato Colato, José Clóvis do Prado Júnior, Anthony Ford, Hélio César Salgado, Julian F. R. Paton
Abstract
Despite advances in the treatment of heart failure, prognosis is poor, mortality high and there remains no cure. Heart failure is associated with reduced cardiac pump function, autonomic dysregulation, systemic inflammation and sleep-disordered breathing; these morbidities are exacerbated by peripheral chemoreceptor dysfunction. We reveal that in heart failure the carotid body generates spontaneous, episodic burst discharges coincident with the onset of disordered breathing in male rats. Purinergic (P2X3) receptors were upregulated two-fold in peripheral chemosensory afferents in heart failure, and when antagonized abolished these episodic discharges, normalized both peripheral chemoreceptor sensitivity and the breathing pattern, reinstated autonomic balance, improved cardiac function, and reduced both inflammation and biomarkers of cardiac failure. Aberrant ATP transmission in the carotid body triggers episodic discharges that via P2X3 receptors play a crucial role in the progression of heart failure and as such offer a distinct therapeutic angle to reverse multiple components of its pathogenesis.