RT Journal Article SR Electronic T1 Histamine H3-Receptors: A New Frontier in Myocardial Ischemia JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 825 OP 830 VO 292 IS 3 A1 Levi, Roberto A1 Smith, Neil C. E. YR 2000 UL http://jpet.aspetjournals.org/content/292/3/825.abstract AB 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 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. The American Society for Pharmacology and Experimental Therapeutics