Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings.
Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.
Silver
Randi B
RB
Department of Physiology-Biophysics, Cornell University, Weill Medical College, 1300 York Avenue, New York, NY 10021, USA.
Poonwasi
Kumar S
KS
Seyedi
Nahid
N
Wilson
Sandy J
SJ
Lovenberg
Timothy W
TW
Levi
Roberto
R
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia; D009206:Myocardium / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology*; D011188:Potassium / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D020960:omega-Conotoxins / Q000378:metabolism / Q000494:pharmacology
D002121:Calcium Channel Blockers; D017442:Histamine Agonists; D007093:Imidazoles; D018100:Receptors, Histamine H3; D020960:omega-Conotoxins; C077430:imetit; D013890:Thiourea; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine