Figure 1.

Schematic overview of systemic P2X4R stimulation. An overall cardioprotective effect is observed with P2X4R stimulation. Permeation of Na⁺ and Ca²⁺ ions through P2X4R interferes with the forward mode of the Na⁺-Ca²⁺ exchanger (NCX) and Ca²⁺-dependent activation of endothelial nitric oxide synthase (eNOS) (right panels). In the heart, stimulation of P2X4R improves cardiac muscle contraction and optimizes myocardial energy supply vs. demand by reducing chronotropy. The diuretic effect of P2X4R activation together with its vasodilation properties in both systemic and pulmonary arteries optimizes preload and afterload and, thereby, cardiac output in HF. Chronic activation of the P2X4R reverses maladaptive cardiac remodeling and improves the outcome of HF. Future P2X4R agonist therapies must deal with the wide P2X4R distribution throughout the human body resulting in putative unwanted side-effects (marked in orange). Figure composition used elements from Servier Medical Art (https://smart.servier.com).