Endocardial endothelium-dependent positive inotropy by Ca2+ pump inhibitors: possible involvement of store-operated Ca2+ entry.
Positive inotropy by sarcoplasmic/endoplasmic reticulum Ca(2+) 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 Gd(3+), La(3+) and lavendustin A, a tyrosine kinase inhibitor, but not by Ni(2+) and LOE908, a non-selective cation channel inhibitor. Gd(3+) and lavendustin A had no effect on the exogenously applied PGF(2)alpha-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 Ca(2+) entry through Gd(3+)-sensitive channels and activation of tyrosine kinase.
Nishimaru
Kazuhide
K
Department of Pharmacology, Toho University Faculty of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Fujiki
Shinpei
S
Tanaka
Yoshio
Y
Tanaka
Hikaru
H
Shigenobu
Koki
K
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors*; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology*; D005682:Gadolinium / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D013268:Stimulation, Chemical; D019284:Thapsigargin / Q000494:pharmacology*
D015220:Calcium Channels; D007211:Indoles; D019284:Thapsigargin; D005682:Gadolinium; D015237:Dinoprost; D000252:Calcium-Transporting ATPases; D000109:Acetylcholine; D002118:Calcium; C000543:cyclopiazonic acid