We also provide some hints about problems to be solved regarding unwanted side effects that may emerge upon activation of P2X4R to stimulate the cardiovascular system, such as arrhythmias and worsening of diastolic dysfunction in the heart; water–electrolyte imbalance and remodeling in renal injury; inflammation, mucous secretion, and hyperreactivity in airway diseases; and nociceptive-related changes. This evidence concerns the gene P2RX4 and cardiac arrhythmia.