P2X3 receptor antagonism attenuates the progression of heart failure

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.

Carotid body dysregulation contributes to Long COVID symptoms

“…Interventions that temper carotid body excitability could be explored as a treatment option for long COVID. Previously our group had shown that P2X3 receptors in the carotid body can be targeted to reduce carotid chemoreflex hyperreflexia in an animal model of hypertension 17 and heart failure 69 , and could be a viable target in humans with long COVID. Gefapixant, an oral P2X3 receptor antagonist, has recently demonstrated efficacy and an acceptable safety profile in chronic cough in phase 3 clinical trials 70 .…”

Commonalities and differences in carotid body dysfunction in hypertension and heart failure

“…Whether these metabolic mechanisms exist in HF is unknown. However, in HF, recent evidence suggests that P2X3 receptor blockade attenuates carotid body afferent activity, reduces the augmented chemoreflex-evoked sympathetic responses, abolishes the apnoeas, reduces inflammation and improves cardiac pump function (Lataro et al, 2023). Future studies will need to assess whether drugs that modulate GLP1R or Trpm7 in the carotid body are therapeutic in animal models of HF.…”

“…Thus, pharmacological targeting of the carotid body continues to be of high interest. The clinical implication of using a purinergic P2X3 antagonist for treating carotid body-related autonomic dysfunction in cardiovascular diseases continues to be promising, as demonstrated in preclinical studies (Lataro et al, 2023;Pijacka et al, 2016b). Additionally, the use of genetic tools like single-cell RNAseq to find new molecular targets, as demonstrated by Pauza et al (2022), could revolutionise the field of carotid body drug discovery and development.…”

Correcting an overactive exercise pressor reflex: A new role for purinergic signalling?

“…The putative role of purinergic signalling pathways in cardiovascular disease has received considerable interest in recent times. In particular, P2X 3 receptors contained within the carotid body have been identified as potential therapeutic targets for hypertension (e.g., Pijacka et al., 2016) and heart failure (e.g., Lataro et al., 2023). While the current study focuses on the more localized purinergic upregulation in PAD, an abnormal exercise pressor reflex and subsequent sympathetic overactivation is a common feature of many cardiovascular conditions, including hypertension, diabetes and heart failure (Grotle et al., 2020).…”