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