Thapsigargin, a Ca2+-ATPase inhibitor, relaxes guinea pig tracheal smooth muscle by producing epithelium-dependent relaxing factors

Naotsugu Takahashi, Hisamichi Aizawa, Satoru Fukuyama, Hiromasa Inoue, Sankei Nishima, Nobuyuki Hara

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

A non-phorbol ester-type tumor promoter, thapsigargin has been reported to deplete Ca2+ stores in endothelial cells by inhibiting Ca2+-ATPase, which in turn increases intracellular Ca2+ by mobilization of extracellular Ca2+, leading to activation of constitutive nitric oxide synthase (cNOS) and resultant generation of nitric oxide (NO). In the present study, to evaluate the role of Ca2+ in the release of epithelium-dependent relaxing factor (EpDRF), we determined the effect of thapsigargin (10-6 M) on the contraction evoked by exogenous Ca2+ or acetylcholine (10-5 M) in epithelium-denuded or epithelium-intact smooth muscle from guinea pig trachea. The following results were obtained: (1) In epithelium-denuded smooth muscle, the contraction evoked by exogenous Ca2+ in Ca2+-free solution or by acetylcholine (10-5 M) in Ca2+-containing solution did not change within 20 min after thapsigargin application, but the contraction evoked by exogenous Ca2+ increased markedly after 120 min, indicating that thapsigargin had no effect on smooth muscle itself within 20 min of application. The following experiments were performed within 20 min of thapsigargin application. (2) In epithelium-intact smooth muscle, thapsigargin significantly suppressed the contraction evoked by acetylcholine, suggesting that thapsigargin stimulate the epithelium to produce EpDRF. NG-nitro-L-arginine methylester (L-NAME) partly, but significantly, attenuated this inhibitory effect of thapsigargin. (3) In epithelium-denuded smooth muscle, atropine (10-6 M) and L-NAME (10-5 M) did not change the contraction evoked by exogenous Ca2+ after application of thapsigargin, suggesting that thapsigargin did not stimulate acetylcholine and NO release from nerve terminals. These results suggest that thapsigargin (10-6 M) may stimulate EpDRF, including NO and other factor(s) by Ca2+-dependent mechanisms.

Original languageEnglish
Pages (from-to)61-68
Number of pages8
JournalEuropean Journal of Pharmacology
Volume410
Issue number1
DOIs
Publication statusPublished - Dec 20 2000

All Science Journal Classification (ASJC) codes

  • Pharmacology

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