Ca++ mobilization mediated by endothelin ETA receptor in endothelium of rabbit aortic valve.
The mechanism of Ca++ mobilization induced by endothelins (ETs) and the receptor subtype responsible for this effect were examined in the endothelium of rabbit aortic valve. In the endothelium loaded with fura-2, ET-1 (1-100 nM) induced large transient increase followed by small sustained increase in cytosolic Ca++ level ([Ca++]i) in a concentration-dependent manner. ET-3 induced only a small increase in [Ca++]i at higher concentrations (100-300 nM) than ET-1, whereas a selective ETB agonist, 100 nM IRL 1620 (succinyl-[Glu9, Ala11,15]ET-1 8-21), was ineffective. A selective ETA antagonist, 3 microM BQ-123, (cyclo [-Asp-Pro-Val-Leu-Trp-]) but not a selective ETB antagonist, 10 microM RES-701-1 [cyclic (Gly1-Asp9) (Gly-Asn-Trp-His-Gly-Thr-Ala-Pro-Asp- Trp-Phe-Phe-Asn-Tyr-Tyr-Trp)], inhibited the effects of ET-1 and ET-3. The sustained increase in [Ca++]i induced by ET-1 was abolished by 30 microM La , although 100 nM nicardipine was ineffective. In the absence of external Ca++ (with 0.5 mM EGTA), ET-1 induced only a transient increase in [Ca++]i, which was inhibited by an inhibitor of Ca+(+)-ATPase in endoplasmic reticulum, 1 microM thapsigargin. However, an inhibitor and an activator of Ca+(+)-induced Ca+(+)-release channel, 10 microM ryanodine and 10 mM caffeine, did not change [Ca++]i. These results suggest that, in the endothelium of rabbit aortic valve, only the ETA receptor mediates the effects of ETs to increase [Ca++]i, which is attributable to the release of Ca++ from thapsigargin-sensitive and ryanodine-insensitive Ca++ stores and also to the Ca++ influx through La (-)sensitive and dihydropyridine-insensitive Ca++ channels.
Amano
K
K
Department of Veterinary Pharmacology, Faculty of Agriculture, University of Tokyo, Japan.
Hori
M
M
Ozaki
H
H
Matsuda
Y
Y
Karaki
H
H
D000595:Amino Acid Sequence; D000818:Animals; D001021:Aortic Valve / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D016232:Endothelins / Q000494:pharmacology; D004727:Endothelium / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008969:Molecular Sequence Data; D011817:Rabbits; D017466:Receptors, Endothelin / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology
D016232:Endothelins; D017466:Receptors, Endothelin; D012433:Ryanodine; D002110:Caffeine; D002118:Calcium