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Decreased intracellular calcium mediates the histamine [H.sub.3]-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings. (Pharmacology)
- Source :
- Proceedings of the National Academy of Sciences of the United States. Jan 8, 2002, Vol. 99 Issue 1, p501, 6 p.
- Publication Year :
- 2002
-
Abstract
- Activation of presynatic histamine [H.sub.3] receptors ([H.sub.3]R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of [[alpha].sub.2]-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, [H.sub.3]R-mediated antiexocytotic effects could result from a decreased [Ca.sup.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.sub.3]R cDNA (SH-SY5Y-[H.sub.3]). We found that reducing [Ca.sup.2+] influx in response to membrane depolarization by inhibiting N-type [Ca.sup.2+] channels with [omega]-conotoxin ([omega]-CTX) greatly attenuated the exocytosis of [[sup.3]H]norepinephrine from both SH-SY5Y and SH-SY5Y-[H.sub.3] cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to [omega]-CTX, activation of [H.sub.3]R with the selective [H.sub.3]R-agonist imetit also reduced both the rise in intracellular [Ca.sup.2+] concentration ([Ca.sub.i]) and norepinephrine exocytosis in response to membrane depolarization. The selective [H.sub.3]R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking [H.sub.3]R, imetit affected neither the rise in [Ca.sub.i] nor [[sup.3]H]norepinephrine exocytosis, demonstrating that the presence of [H.sub.3]R is a prerequisite for a decrease in [Ca.sub.i] in response to imetit and that [H.sub.3]R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in [Ca.sub.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.sub.3]R agonists may offer a novel therapeutic approach to this condition.
Details
- ISSN :
- 00278424
- Volume :
- 99
- Issue :
- 1
- Database :
- Gale General OneFile
- Journal :
- Proceedings of the National Academy of Sciences of the United States
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.82652057