ISSN:
1432-1912
Schlagwort(e):
Key words Endothelium-dependent relaxation
;
A23187
;
Nitric oxide
;
SK&F96365
;
Ni2+
;
Capacitative Ca2+ influx
;
Store-operated Ca2+ channels
;
Guinea-pig aorta
Quelle:
Springer Online Journal Archives 1860-2000
Thema:
Medizin
Notizen:
Abstract A23187 (6S-[6α,8β,9β,11α]-5-(methylamino)-2-[[3,9,11-trimethyl-8-[1-methyl-2-oxo-2-(1H-pyrrol-2-yl)ethyl]-1,7-dioxaspiro[5.5]undec-2-yl]methyl]-4-benzoxazolecarboxylic acid, calcimycin), an antibiotic Ca2+ ionophore, produces an endothelium-dependent vascular relaxation. In the present study, pharmacological features were functionally characterized of endothelium-dependent relaxant response of guinea-pig aorta to A23187, especially focusing on the possible Ca2+ source and Ca2+ mobilization mechanisms in endothelial cells responsible for the vasorelaxant response to the Ca2+ ionophore. A23187-induced endothelium-dependent relaxation was suppressed profoundly by N G-nitro-L-arginine (L-NNA; 3×10–4 M) or calmidazolium (3×10–5 M), suggesting that nitric oxide (NO) produced by the enhanced activation of Ca2+/calmodulin-dependent endothelial NO synthase (eNOS) is largely responsible for the relaxant response of this artery to A23187. In the Ca2+-free solution without EGTA, NO-mediated endothelium-dependent relaxation induced by A23187 was almost abolished, which suggests that Ca2+ entry from extracellular space into endothelial cells plays the key role in the A23187-induced functional vasorelaxation. On the other hand, SK&F96365 (1-[β-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole; 5×10–5 M) and Ni2+ (3×10–4 M), both of which inhibit capacitative Ca2+ influx through store-operated Ca2+ channels (SOCCs), attenuated significantly NO-mediated endothelium-dependent relaxation by A23187. Furthermore, A23187-induced endothelium-dependent relaxation was suppressed more strongly than endothelium-independent relaxation induced by SIN-1 (3-morpholino-sydnonimine), an NO donor, when aortic preparation was preconstricted with high KCl instead of agonistic stimulation (prostaglandin F2 α). These findings suggest that NO-mediated endothelium-dependent relaxant response of guinea-pig aorta to A23187 is preceded by the increase in endothelial cytosolic free Ca2+ concentration ([Ca2+]cyt) due to the enhanced Ca2+ influx from extracellular space. In the enhanced Ca2+ entry leading to the stimulation of eNOS and NO-mediated functional relaxant response of guinea-pig aorta to A23187, activation of SOCCs but not the Ca2+ entry through plasma membrane Ca2+-specific routes made by A23187 seems to play the predominant role. It is most likely that A23187 acts primarily at the Ca2+ store sites in endothelial cells, which subsequently depletes stored Ca2+ to activate SOCCs via unidentified mechanisms.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1007/s002109900033
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