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Mechanisms of the thapsigargin‐induced Ca 2+ entry in in situ endothelial cells of the porcine aortic valve and the endothelium‐dependent relaxation in the porcine coronary artery
Author(s) -
KuroiwaMatsumoto Mari,
Hirano Katsuya,
Ahmed Abu,
Kawasaki Junya,
Nishimura Junji,
Kanaide Hideo
Publication year - 2000
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0703548
Subject(s) - thapsigargin , thromboxane a2 , endocrinology , medicine , endothelium , chemistry , nitrendipine , nitric oxide , endothelium derived hyperpolarizing factor , calcium , platelet , charybdotoxin
The mechanisms of the thapsigargin (TG)‐induced capacitative Ca 2+ entry in in situ endothelial cells and its role in the regulation of arterial tone were investigated using front‐surface fluorimetry and fura‐2‐loaded strips of porcine aortic valve and coronary artery. In the presence of extracellular Ca 2+ , TG induced an initial rapid and a subsequent sustained elevation of cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in valvular strips. In the absence of extracellular Ca 2+ , TG induced only a transient increase in [Ca 2+ ] i . The TG‐induced sustained elevation of [Ca 2+ ] i in endothelial cells was inhibited completely by 1 m M Ni 2+ and partly by 10 μ M econazole and 30 μ M ML‐9, but not by 900 ng ml −1 pertussis toxin or 100 μ M wortmannin. Therefore, cytochrome P450 and protein phosphorylation are suggested to be involved in the TG‐induced Ca 2+ influx in in situ endothelial cells. TG induced an endothelium‐dependent large relaxation consisting of an initial and a late sustained relaxation in coronary arterial strip precontracted with U46619 (a thromboxane A2 analogue). Indomethacin alone had no effect, while indomethacin plus N ω ‐nitro‐ L ‐arginine ( L ‐NOARG) markedly inhibited the sustained phase and slightly inhibited the initial phase of the TG‐induced relaxation. TG induced a smaller but sustained relaxation during the 40 m M K + ‐induced precontraction than that seen during the U46619‐induced precontraction. This relaxation was completely abolished by the pretreatment with indomethacin plus L ‐NOARG. In conclusion, both nitric oxide (NO) and endothelium‐derived hyperpolarizing factor were suggested to mediate the TG‐induced relaxation, while NO plays a major role in the sustained relaxation. The TG‐induced sustained [Ca 2+ ] i elevation in endothelial cells was thus suggested to be mainly linked to the sustained production of NO.British Journal of Pharmacology (2000) 131 , 115–123; doi: 10.1038/sj.bjp.0703548