Targeting Histamine H4 Receptor in the Rostral Ventromedial Medulla to Relieve Hypertension

Abstract Refractory hypertension often involves centrally driven sympathetic augmentation. Yet effective central targets for the treatment of hypertension are still scarce. Here, the role of the histamine H4 receptor (H4R) is explored, the newest member of the histamine receptor family, in central cardiovascular regulation. Analysis of single‐nucleus RNA‐sequencing datasets of human brains and RNAscope assays of rat brains reveal a conservative expression of H4R in the rostral ventromedial medulla (RVMM), a key sympathetic cardiovascular center. Optoactivation of RVMM histaminergic afferents evokes depressor and bradycardic responses via H4R, whose activation excites GABAergic presympathetic neurons by transient receptor potential vanilloid 1 (TRPV1). Intranasal delivery of H4R agonist produces sustained blood pressure‐lowering effects in free‐moving spontaneously hypertensive rats and stress‐induced hypertensive rats. The findings reveal an antihypertensive role of RVMM histamine H4R and a potential central therapeutic target for hypertension.