ACTIVATION OF HISTAMINE H-3 RECEPTORS INHIBITS CARRIER-MEDIATED NOREPINEPHRINE RELEASE IN A HUMAN-MODEL OF PROTRACTED MYOCARDIAL-ISCHEMIA

During protracted myocardial ischemia, ATP depletion promotes Na+ accu mulation in sympathetic terminals and prevents vesicular storage of no repinephrine (NE). This forces the reversal of the neuronal uptake, tr ansporter, 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 myoca rdial ischemia to investigate whether H(3)Rs may control carrier-media ted NE release. Surgical specimens of human atrium were incubated in a noxic conditions. NE release increased similar to 7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca++ inde pendent and inhibited by the uptake, inhibitor desipramine. Furthermor e, the Na+/H+ exchanger (NHE) inhibitors ethyl-isopropyl-amiloride and HOE 642, and the Na+ channel blocker tetrodotoxin inhibited NE releas e, whereas the Na+ channel activator aconitine potentiated it. The sel ective H3R agonist imetit decreased NE release, an effect that was blo cked by each of the H3R antagonists thioperamide and clobonpropit. Not ably, 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-depen dent Na+ channels. Most importantly, endogenous histamine was released from the anoxic human heart, and thioperamide and clobenpropit each a lone increased NE release, indicating that H3R become activated in myo cardial ischemia. Our findings indicate that H(3)Rs are likely to miti gate sympathetic overactivity in the ischemic human heart and suggest new therapeutic strategies to alleviate dysfunctions associated with m yocardial ischemia.