In
myocardial ischemia,
adrenergic nerves release excessive amounts of
norepinephrine (NE), causing dysfunction and arrhythmias. 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 activates 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 activation is pivotal in this process; NHE inhibitors attenuate carrier-mediated NE release. We previously reported that activation of
histamine H(3) receptors (H(3)R) on cardiac sympathetic nerves also reduces carrier-mediated NE release and alleviates arrhythmias. Thus, H(3)R activation may be negatively coupled to NHE. We tested this hypothesis in individual human SKNMC
neuroblastoma cells stably transfected with H(3)R
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 (NH(4)Cl). We found that the selective H(3)R-agonist
imetit markedly diminished NHE activity, and so did the
amiloride derivative
EIPA. The selective H(3)R antagonist
thioperamide abolished the
imetit-induced NHE attenuation. Thus, our results provide a link between H(3)R 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 adrenergic neurons as a means to prevent ischemic arrhythmias associated with carrier-mediated NE release.