Activation of histamine H3 receptors inhibits carrier-mediated norepinephrine release in a human model of protracted myocardial ischemia.
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 approximately 7-fold within 70 min of anoxia. This release was carrier mediated because it was Ca++ independent and inhibited by the uptake1 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 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.
Hatta
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E
Department of Pharmacology, Cornell University Medical College, New York, New York 10021, USA.
Yasuda
K
K
Levi
R
R
D000368:Aged; D002352:Carrier Proteins / Q000502:physiology*; D003891:Desipramine / Q000494:pharmacology; D005260:Female; D006636:Histamine Release; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000503:physiopathology*; D009638:Norepinephrine / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000502:physiology*; D012964:Sodium / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology
D002352:Carrier Proteins; D018100:Receptors, Histamine H3; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium; D003891:Desipramine; D009638:Norepinephrine