Endocardial Endothelium-Dependent Positive Inotropy by Ca²⁺ Pump Inhibitors: Possible Involvement of Store-Operated Ca²⁺ Entry

Publisher： Karger

E-ISSN： 1423-0313|80|4|200-206

ISSN： 0031-7012

Source： Pharmacology, Vol.80, Iss.4, 2007-07, pp. : 200-206

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Abstract

Positive inotropy by sarcoplasmic/endoplasmic reticulum Ca²⁺ pump inhibitors was found and its mechanisms were analyzed pharmacologically. Thapsigargin and cyclopiazonic acid produced positive inotropy in isolated mouse left atria. The responses were inhibited by pretreatment of the endocardial surface with Triton X-100 or by indomethacin, which suggests that the inotropic responses were mediated by prostaglandin(s) released from the endocardial endothelium as well as acetylcholine-induced positive inotropy. The thapsigargin- and acetylcholine-induced positive inotropy was significantly inhibited by Gd³⁺, La³⁺ and lavendustin A, a tyrosine kinase inhibitor, but not by Ni²⁺ and LOE908, a non-selective cation channel inhibitor. Gd³⁺ and lavendustin A had no effect on the exogenously applied PGF₂α-induced positive inotropy. In addition, acetylcholine did not induce any positive inotropy when applied after the application of thapsigargin. These results strongly suggest that thapsigargin- as well as acetylcholine-induced prostaglandin release from endocardial endothelium is mediated by store-operated Ca²⁺ entry through Gd³⁺-sensitive channels and activation of tyrosine kinase.