Histamine H-3-receptors: A new frontier in myocardial ischemia

In protracted myocardial ischemia, sympathetic nerve endings undergo ATP de pletion, hypoxia and pH(i) reduction. Consequently, norepinephrine (NE) acc umulates in the axoplasm, because it is no longer stored in synaptic vesicl es, 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 thu s, arrhythmias. Indeed, NE overflow in myocardial ischemia directly correla tes with the severity of arrhythmias. Histamine H-3-receptors (H3R) have be en identified as inhibitory heteroreceptors in adrenergic nerve endings of the heart. In addition to inhibiting NE exocytosis from sympathetic nerve e ndings, 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 i s associated with diminished NHE activity. In addition to inhibiting NE rel ease, H3R stimulation significantly attenuates the incidence and duration o f ventricular fibrillation. Although other presynaptic receptors also modul ate NE release from sympathetic nerve endings, H3R stimulation reduces both exocytotic and carrier-mediated NE release, whereas a 2-adrenoceptor agoni sts attenuate NE exocytosis but enhance carrier-mediated NE release. Furthe rmore, unlike adenosine A(1)-receptors, whose activation reduces both exocy totic and carrier-mediated NE release, H3R stimulation is devoid of negativ e chronotropic and dromotropic effects (i.e., sinoatrial and atrioventricul ar nodal functions are unaffected). Because excess NE release can trigger s evere arrhythmias and sudden cardiac death, negative modulation of NE relea se by H3R agonists may offer a novel therapeutic approach to myocardial isc hemia.