Coupling of histamine H3 receptors to neuronal Na~+/H~+ exchange: A novel protective mechanism in myocardial ischemia

摘要

In myocardial ischemia, adrenergic nerves release excessive amounts of norepinephrine (NE). causing dysfunction and arrhyth- mias. With anoxia and the concomitant ATP depletion. vesicular storage of NE is impaired, resulting in accumulation of free NE in the axoplasm of sympathetic nerves. Intraneuronal acidosis acti- vates the Na~+/H~+ exchanger (NHE), leading to increased Na~+ entry in the nerve terminals. These conditions favor availability of the NE transporter to the axoplasmic side of the membrane, causing massive carrier-mediated efflux of free NE. Neuronal NHE activa- tion is pivotal in this process: NHE inhibitors attenuate carrier- mediated NE release. We previously reported that activation of histamine H3 receptors (H_3R) on cardiac sympathetic nerves also reduces carrier-mediated NE release and alleviates arrhythmias. Thus, HsR activation may be negatively coupled to NHE. We tested this hypothesis in individual human SKNMC neuroblastoma cells stably transfected with H_3R 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 add pulse (NH4Cl). We found that the selective H_3R-agonist imetit markedly diminished NHE activity, and so did the amiloride derivative EIPA. The selective H_3R antag- onist thioperamide abolished the imetit-induced NHE attenuation. Thus, our results provide a link between H_3R and NHE. which may limit the excessive release of NE during protracted myocardial ischemia. Our previous and present findings uncover a novel mechanism of cardioprotection: NHE inhibition in cardiac adrener- gic neurons as a means to prevent ischemic arrhythmias associated with carrier-mediated NE release.