Coupling of histamine H-3 receptors to neuronal Na+/H+ exchange: A novel protective mechanism in myocardial ischemia

In myocardial ischemia, adrenergic nerves release excessive amounts of nore pinephrine (NE), causing dysfunction and arrhythmias. With anoxia and the c oncomitant ATP depletion, vesicular storage of NE is impaired, resulting in accumulation of free NE in the axoplasm of sympathetic nerves. Intraneuron al acidosis activates the Na+/H+ exchanger (NHE), leading to increased Naentry in the nerve terminals. These conditions favor availability of the NE transporter to the axoplasmic side of the membrane, causing massive carrie r-mediated efflux of free NE. Neuronal NHE activation is pivotal in this pr ocess; NHE inhibitors attenuate carrier-mediated NE release. We previously reported that activation of histamine H-3 receptors (H3R) on cardiac sympat hetic nerves also reduces carrier-mediated NE release and alleviates arrhyt hmias. Thus, H3R activation may be negatively coupled to NHE. We tested thi s hypothesis in individual human SKNMC neuroblastoma cells stably transfect ed with H3R cDNA, loaded with the intracellular pH (pH(i)) indicator BCECF. These cells possess amiloride-sensitive NHE. NHE activity was measured as the rate of Na+-dependent pH(i) recovery in response to an acute acid pulse (NH4Cl). We found that the selective H3R-agonist imetit markedly diminishe d NHE activity, and so did the amiloride derivative EIPA. The selective H3R antagonist thioperamide abolished the imetit-induced NHE attenuation. Thus , our results provide a link between H3R and NHE, which may limit the exces sive release of NE during protracted myocardial ischemia. Our previous and present findings uncover a novel mechanism of cardioprotection: NHE inhibit ion in cardiac adrenergic neurons as a means to prevent ischemic arrhythmia s associated with carrier-mediated NE release.