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(Circulation Research. 1996;78:475-481.)
© 1996 American Heart Association, Inc.

Articles

Activation of Histamine H₃-Receptors Inhibits Carrier-Mediated Norepinephrine Release During Protracted Myocardial Ischemia

Comparison With Adenosine A₁-Receptors and ₂-Adrenoceptors

Presented as preliminary data at the Experimental Biology '95 meeting in Atlanta, Ga, and published in abstract form (FASEB J. 1995;9:A9).

Michiaki Imamura, Harry M. Lander, Roberto Levi

From the Department of Pharmacology, Cornell University Medical College, New York, NY.

Correspondence to Roberto Levi, MD, Department of Pharmacology, Cornell University Medical College, 1300 York Ave, New York, NY 10021. E-mail rlevi@med.cornell.edu.

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 pH_i 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, ₂-adrenoceptor activation, which is known to stimulate NHE, enhanced norepinephrine release, whereas ₂-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.

Key Words: ischemia/reperfusion • norepinephrine release • histamine H₃-receptors • adenosine A₁-receptors • ₂-adrenoceptors • arrhythmias

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