In severe myocardial ischemia, norepinephrine (NE) is abundantly carried out of sympathetic nerve terminals by the NE transporter, neuronal NA⁺/H⁺ exchanger (NHE), and is a key arrhythmogenic determinant. Hashikawa-Hobara et al. investigated whether enhanced ischemic cardiac dysfunction, which is manifest when histamine H3 receptors (H₃R) are blocked or deleted, results from an unimpeded angiotensin II receptor (AT₁R)-NHE activation. These studies have uncovered a novel cardioprotective action resulting from activation of neuronal H₃R in mammalian heart. Binding of an endogenous ligand to H₃R, most likely histamine, released by action of reactive oxygen species produced during ischemia/reperfusion, reduces the formation of diacylglycerol, diminishing protein kinase C activity. This in turn decreases NHE activity, causing intracellular acidification, and stimulates the production of nitric oxide (NO), which suppresses AT₁R expression. H₃R-induced decrease in NHE activity and increased NO synthesis may be responsible for decreased AT₁R protein abundance. These findings suggest that down-regulation of AT₁R signaling and attenuation of NE release by activation of neuronal H₃R are plausible mechanisms of cardioprotection, not only in myocardial ischemia but also in other cardiac dysfunctions in which ANG II plays a major role, such as heart failure.

See article at J Pharmacol Exp Ther 2012, 340:185–191

• Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics