Abstract

During protracted myocardial ischemia, ATP depletion promotes Na⁺ accumulation in sympathetic terminals and prevents vesicular storage of norepinephrine (NE). This forces the reversal of the neuronal uptake₁ transporter, and NE is massively released (carrier-mediated release). We had shown that histamine H₃ receptors (H₃Rs) modulate ischemic NE release in animals. We have now used a human model of protracted myocardial ischemia to investigate whether H₃Rs may control carrier-mediated NE release. Surgical specimens of human atrium were incubated in anoxic conditions. NE release increased ∼7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca⁺⁺ independent and inhibited by the uptake₁inhibitor desipramine. Furthermore, the Na⁺/H⁺exchanger (NHE) inhibitors ethyl-isopropyl-amiloride and HOE 642, and the Na⁺ channel blocker tetrodotoxin inhibited NE release, whereas the Na⁺ channel activator aconitine potentiated it. The selective H₃R agonist imetit decreased NE release, an effect that was blocked by each of the H₃R antagonists thioperamide and clobenpropit. Notably, imetit acted synergistically with ethyl-isopropyl-amiloride, HOE 642 and tetrodotoxin to reduce anoxic NE release. Thus, activation of H₃R appears to result in an inhibition of both NHE- and voltage-dependent Na⁺ channels. Most importantly, endogenous histamine was released from the anoxic human heart, and thioperamide and clobenpropit each alone increased NE release, indicating that H₃R become activated in myocardial ischemia. Our findings indicate that H₃Rs are likely to mitigate sympathetic overactivity in the ischemic human heart and suggest new therapeutic strategies to alleviate dysfunctions associated with myocardial ischemia.