Activation of histamine H-3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia

作者：Hatta E; Yasuda K; Levi R

来源：Journal of Pharmacology and Experimental Therapeutics, 1997, 283(2): 494-500.

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 uptake, transporter, and NE is massively released (carrier-mediated release). We had shown that histamine H-3 receptors (H(3)Rs) modulate ischemic NE release in animals. We have now used a human model of protracted myocardial ischemia to investigate whether H(3)Rs may control carrier-mediated NE release. Surgical specimens of human atrium were incubated in anoxic conditions. NE release increased similar to 7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca++ independent and inhibited by the uptake, inhibitor 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 clobonpropit. 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 H(3)Rs are likely to mitigate sympathetic overactivity in the ischemic human heart and suggest new therapeutic strategies to alleviate dysfunctions associated with myocardial ischemia.

• 出版日期1997-11