Targeting Histamine H4 Receptor in the Rostral Ventromedial Medulla to Relieve Hypertension
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.
Authors
- Hongzhao Li (ORCID: https://orcid.org/0000-0002-1587-8866)
- Wen‐Qiong Xue
- Jing‐Ning Zhu (ORCID: https://orcid.org/0000-0002-3695-9200)
- Huijie Ma (ORCID: https://orcid.org/0000-0002-6069-349X)
- Bo Song (ORCID: https://orcid.org/0000-0001-9172-1249)
- Hongyu Ma (ORCID: https://orcid.org/0000-0003-1310-1786)
- Junyi Chen (ORCID: https://orcid.org/0000-0002-9992-7273)
- Qipeng Zhang (ORCID: https://orcid.org/0000-0002-3697-0194)
- Ying Shi (ORCID: https://orcid.org/0000-0003-4307-6972)
- Wei Li (ORCID: https://orcid.org/0000-0001-5069-5945)
- Dong Chen (ORCID: https://orcid.org/0000-0003-1198-6058)
- Xiaoyang Zhang (ORCID: https://orcid.org/0009-0005-5114-2732)
- Jian‐Jun Wang (ORCID: https://orcid.org/0000-0002-1717-9567)
- Yating Li (ORCID: https://orcid.org/0000-0003-0454-9271)
- Sai Ma (ORCID: https://orcid.org/0000-0002-7638-9900)
- Lei Yu (ORCID: https://orcid.org/0000-0002-0237-8758)
- Qian‐Xiao Li
- Shu‐Tao Xie
- Yang‐Xun Zhang
Institutions
- Hebei Medical University (CN)
- Jiangsu Second Normal University (CN)
- Chembio (United States) (US)
- Nanjing Drum Tower Hospital (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-09-29
- DOI
- https://doi.org/10.1002/advs.202508176
- Citations
- 1
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 0.80