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

Area of Science:

• Neuroscience
• Cardiovascular Research
• Pharmacology

Background:

• Refractory hypertension is often linked to increased sympathetic nervous system activity originating in the brain.
• Current central therapeutic targets for hypertension remain limited.
• The histamine H4 receptor (H4R), a recently identified histamine receptor, has an unexplored role in central cardiovascular regulation.

Purpose of the Study:

• To investigate the role of the histamine H4 receptor (H4R) in central cardiovascular regulation.
• To explore H4R as a potential therapeutic target for hypertension.

Main Methods:

• Analysis of human brain single-nucleus RNA-sequencing data and rat brain RNAscope assays to determine H4R expression.
• Optogenetic stimulation of histaminergic afferents in the rostral ventromedial medulla (RVMM) in rats.
• Intranasal administration of an H4R agonist in spontaneously hypertensive and stress-induced hypertensive rat models.

Main Results:

• H4R is consistently expressed in the RVMM, a critical center for sympathetic cardiovascular control.
• Optoactivation of RVMM histaminergic afferents induced blood pressure reduction and decreased heart rate via H4R.
• H4R activation excites GABAergic presympathetic neurons, mediated by transient receptor potential vanilloid 1 (TRPV1).
• Intranasal H4R agonist administration led to sustained blood pressure reduction in hypertensive rat models.

Conclusions:

• The histamine H4 receptor in the RVMM plays an antihypertensive role.
• RVMM H4R represents a promising central therapeutic target for managing hypertension.