P2X3 receptor-mediated the enhanced interaction between sensitized carotid body chemoreceptor and sympathetic overactivity promotes hypertension: a possible new target

This editorial refers to ‘Vitamin B6 (pyridoxal 5′ phosphate) antagonizes carotid body P2X3 receptors in hypertension’, by I.S.A. Felippe et al., https://doi.org/10.1093/cvr/cvaf195. Hypertension is a global health issue affecting over 1 billion people and is a major contributor to cardiovascular disease and premature death.1,2 It accounts for ∼10% of global healthcare expenditure, representing a global financial burden.1 Although traditional antihypertensive therapies are effective in many cases, they often exhibit inconsistent efficacy, poor compliance, and adverse effects.1,2 The changes of O2, CO2, and pH in arterial blood stimulate the carotid body (CB) chemoreceptor, leading to reflex ventilation, cardiovascular, and humoral responses that maintain homeostasis in the body.1 The superior cervical ganglion (SCG) overactivity during hypertension increased CB sensitivity and CB reflex hyperactivity.1 The increased activity of CB chemoreceptor in hypertension promotes sympathetic overactivity in essential hypertension and neurogenic hypertension.1 The SCG serves as a primary source of sympathetic innervation of CB.1 Anand A's works (J Physiol. 1996) indicated that the stellate ganglion (SG) is involved in the excitation of aortic chemoreceptors and CB following hypoxic stimulation. Furthermore, experiments conducted by Peruzzi D et al. (Am J Physiol. 1991) on spontaneously hypertensive rats have shown that SG neurons exhibit increased total dendritic length and more active synapses, alongside a thickening of the carotid artery wall. This structural remodelling provides a larger target area for ganglion innervation and potentially increases cellular excitability in the carotid region. The SCG and SG innervate the heart and participate in the physiology and pathophysiology of the cardiovascular system.1,3 CB-mediated remodelling of neuronal structure and function in SCG and SG may result in pathological sympathetic overactivation after myocardial infarction.4 The enhanced CB chemo-sensitivity-related cardiac reflex is associated with heart diseases such as hypertension and chronic heart failure.4 The potential interaction between CB and SCG or SG can enhance the CB’s chemo-sensitive cardiac reflex triggered by the cardiac ischaemic injury.4 The enhanced interaction between the sensitized CB chemoreceptor and the increased sympathetic activity play an important role in the pathogenesis of hypertension.1 CB sensitively adjusts oxygen and glucose through feedback from blood-derived hormones that regulate metabolism.1 CB dysfunction is considered the pathological basis of sympathetic-mediated diseases, especially neurogenic hypertension and type 2 diabetes.1 The increased P2X3 receptor is involved in chemical hyperreflexia and abnormal CB discharge in hypertensive patients.1,5 Connolly GP's research (Br J Pharmacol. 1995) showed that pyridoxal-5'-phosphate (PLP; a cheaper vitamin B6 derivative) may act on the P2X3 receptor to inhibit α, β-Me ATP-induced depolarization of rat SCG. Felippe et al.'s5 study found that intravenous injection of PLP by blocking P2X3 receptor can reduce CB hyperreflexia, sympathetic activity, and blood pressure in spontaneously hypertensive rats. Clinical trials in hypertensive patients have indicated that oral administration of pyridoxine hydrochloride (precursor of PLP) at therapeutic doses can alleviate hypoxia ventilation response in hypertensive patients with high peripheral chemoreflex sensitivity (Figure 1).5 Antihypertension by blocking P2X3. Pathological stimuli (e.g. hypoxia, metabolic dysregulation) trigger P2X3 receptor up-regulation in both the CB and the SCG or SG. These two key nodes interact via a positive feedback loop: CB sensitization elicits enhanced afferent signalling to the nucleus tractus solitarius (NTS), which in turn drives sympathetic overactivity. The SCG overactivity increased CB sensitivity and CB reflex hyperactivity. The structural and functional remodelling between CB and SCG or SG enhances sympathetic overactivity. This circuit culminates in sustained elevation of sympathetic outflow, leading to cardiac sympathetic dysfunction. Crucially, antagonizing P2X3 receptor (pyridoxal-5'-phosphate/MK7264/puerarin) reduces sympathetic overactivity, thereby P2X3 as a promising novel therapeutic target for hypertension. Hypertension is closely related to type 2 diabetes mellitus (T2DM) and coronary artery diseases involving myocardial ischaemia (MI) in strengthening the cardiac sympathetic reflex. Traditional antihypertensive drugs primarily act on end organs such as the heart, kidneys, and blood vessels. Felippe et al.'s study focuses on the CB—a tiny organ located in the bifurcation of the common carotid artery that senses blood chemical composition. Targeting the CB for blood pressure regulation is a relatively novel strategy. The main novel viewpoint of this work is that PLP acts as an antagonist of the P2X3 receptor in the CB, which is associated with chemoreflex-mediated sympathetic overactivity in hypertension.5 This study also translates the findings of animal models into humans, indicating a novel treatment approach for hypertensive patients. Hypertension is a serious risk factor for sudden cardiac death and cardiovascular disease (Tereshchenko LG et al., J Electrocardiol. 2017). The coexistence of hypertension and type 2 diabetes is complicated with coronary artery disease involving myocardial ischaemia (Grossman A and Grossman E, Cardiovasc Diabetol. 2017). The studies found that myocardial ischaemia and type 2 diabetes up-regulated P2X3 receptor in the SCG or SG.6–9 Myocardial ischaemia and type 2 diabetes increased sympathoexcitatory reflex mediated by up-regulated P2X3 in SCG or SG, manifested as enhanced blood pressure, heart rate, and sympathetic never discharge and abnormal heart rate variability.6–9 Inhibiting the up-regulated P2X3 receptor in the SCG and SG can reduce the increased sympathoexcitatory reflex and improve cardiac dysfunction.6,7,9 There are many effective options for hypertension drugs, but a combination of two or more drugs is required to achieve clinical goals (Gottwald-Hostalek U et al., Clin Pharmacol Drug Dev. 2017). Some natural medicines reduce the blood pressure of spontaneously hypertensive rats and have a strong antihypertensive effect on type 2 diabetes patients (Zhou DD et al., Oxid Med Cell Longev. 2021). Puerarin reduces blood pressure by improving the structural remodelling and functional abnormalities of the carotid artery wall in spontaneously hypertensive rats (Fang X et al., BMC Complement Med Ther. 2021). Studies in clinical patients have shown that puerarin has been used to treat acute heart failure and diabetic neuropathy. Some natural medicines have an antagonistic effect on P2X3 receptor.9 Natural medicine puerarin inhibits the P2X3 receptor by binding to V64A of human P2X3 protein.6 By antagonizing the P2X3 receptor, natural medicines may inhibit the sympathetic overactivity mediated by sensitive CB chemoreceptor, offering a potential therapeutic strategy for hypertension. The application of PLP and natural medicines in the treatment of hypertension may help to reduce the cost burden associated with hypertension management. The pathological causes of hypertension in humans are complex. Conte G et al. (Cells. 2021) reported that P2X receptors in the blood are used as diagnostic biomarkers for diseases. Monitoring blood level of the P2X3 protein may help identify the underlying reasons for poor therapeutic effects of P2X3 antagonist drugs. Applying the latest advances in artificial intelligence (AI) to optimize drug selection, predict efficacy, and adverse reactions shows great potential in improving the effectiveness of antihypertension drugs.10 In summary, antagonizing P2X3 receptor represents a promising therapeutic strategy that directly targets the potential pathophysiological mechanisms driving hypertension. This study was funded by grants from the National Natural Science Foundation of China (82460166, 82160163, 81870574) and Key Project of Jiangxi Provincial Natural Science Foundation (20252BAC250149).