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Vol. 292, Issue 3, 825-830, March 2000
Department of Pharmacology, Cornell University, Weill Medical
College, New York, New York
In protracted myocardial ischemia, sympathetic nerve endings undergo
ATP depletion, hypoxia and pHi reduction. Consequently, norepinephrine (NE) accumulates in the axoplasm, because it is no
longer stored in synaptic vesicles, and intraneuronal Na+
concentration increases, as the Na+/H+
exchanger (NHE) is activated. This forces the reversal of the Na+- and Cl
-dependent NE transporter,
triggering a massive carrier-mediated release of NE and thus,
arrhythmias. Indeed, NE overflow in myocardial ischemia directly
correlates with the severity of arrhythmias. Histamine
H3-receptors (H3R) have been identified as
inhibitory heteroreceptors in adrenergic nerve endings of the heart. In
addition to inhibiting NE exocytosis from sympathetic nerve endings,
selective H3R agonists attenuate carrier-mediated release
of NE in both animal and human models of protracted myocardial
ischemia. Whereas H3R-mediated attenuation of exocytotic NE
release involves an inhibition of N-type Ca2+-channels,
H3R-mediated reduction of carrier-mediated NE release is
associated with diminished NHE activity. In addition to inhibiting NE
release, H3R stimulation significantly attenuates the
incidence and duration of ventricular fibrillation. Although other
presynaptic receptors also modulate NE release from sympathetic nerve
endings, H3R stimulation reduces both exocytotic and
carrier-mediated NE release, whereas 
2-adrenoceptor
agonists attenuate NE exocytosis but enhance carrier-mediated NE
release. Furthermore, unlike adenosine A1-receptors, whose
activation reduces both exocytotic and carrier-mediated NE release,
H3R stimulation is devoid of negative chronotropic and
dromotropic effects (i.e., sinoatrial and atrioventricular nodal
functions are unaffected). Because excess NE release can trigger severe
arrhythmias and sudden cardiac death, negative modulation of NE release
by H3R agonists may offer a novel therapeutic approach to
myocardial ischemia.
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