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Vol. 283, Issue 2, 494-500, 1997
Department of Pharmacology, Cornell University Medical College, New
York, New York
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 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.
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