Activation of Histamine H 3 -Receptors Inhibits Carrier-Mediated Norepinephrine Release During Protracted Myocardial Ischemia

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Abstract
We previously showed that prejunctional histamine H3-receptors downregulate norepinephrine exocytosis, which is markedly enhanced in early myocardial ischemia. In the present study, we investigated whether H3-receptors modulate nonexocytotic norepinephrine release during protracted myocardial ischemia. In this setting, decreased pHi in sympathetic nerve endings sequentially leads to a compensatory activation of the Na+-H+ antiporter (NHE), accumulation of intracellular Na+, reversal of the neuronal uptake of norepinephrine, and thus carrier-mediated release of norepinephrine. Accordingly, norepinephrine overflow from isolated guinea pig hearts undergoing 20-minute global ischemia and 45-minute reperfusion was attenuated ≈80% by desipramine (10 nmol/L) and 70% by 5-(N-ethyl-N-isopropyl)-amiloride (EIPA, 10 μmol/L), inhibitors of norepinephrine uptake and NHE, respectively. The H3-receptor agonist imetit (0.1 μmol/L) decreased carrier-mediated norepinephrine release by ≈50%. This effect was blocked by the H3-receptor antagonist thioperamide (0.3 μmol/L), indicating that H3-receptor activation inhibits carrier-mediated norepinephrine release. At lower concentrations, imetit (10 nmol/L) or EIPA (3 μmol/L) did not inhibit carrier-mediated norepinephrine release. However, a 25% inhibition occurred with imetit (10 nmol/L) and EIPA (3 μmol/L) combined. This synergism suggests an association between H3-receptors and NHE. Conceivably, activation of H3-receptors may lead to inhibition of NHE. In fact, α2-adrenoceptor activation, which is known to stimulate NHE, enhanced norepinephrine release, whereas α2-adrenoceptor blockade attenuated it. Furthermore, activation of adenosine A1-receptors markedly attenuated norepinephrine release, whereas their inhibition potentiated it. Because norepinephrine release directly correlated with the severity of reperfusion arrhythmia and imetit reduced the incidence of ventricular fibrillation by 50%, our findings with H3-receptor agonists may further the development of novel pharmacological means to reduce reperfusion arrhythmias in the clinical setting.