Abstract

In protracted myocardial ischemia, sympathetic nerve endings undergo ATP depletion, hypoxia and pH_i 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 α₂-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.