Inhibition by a receptor-mediated Ca2+ entry blocker, SK&F 96365, of Ca2+ and secretory responses in rat pancreatic acini.
The effect of a receptor-mediated Ca2+ entry blocker, 1-(beta-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365), on a secretagogue-induced secretory response and Ca2+ dynamics was examined in isolated acini of rat pancreas. SK & F 96365 inhibited the secretory response induced by 100 pM cholecystokinin octapeptide (CCK-8) or 3 microM ethanaminium, 2-[(aminocarbonyl)oxy]-N,N,N-trimethyl,-chloride (carbachol) in isolated incubated acini up to 73.2 +/- 6.1% or 70.3 +/- 3.8% with IC50 of 47.7 microM or 42.0 microM, respectively. The inhibitory effect of SK&F 96365 on the time courses of CCK-8-induced amylase release and [Ca2+]c (cytoplasmic Ca2+ concentration) elevation was further examined in isolated perifused acini or isolated acini loaded with Fura-2. In the 100 pM CCK-8-stimulated preparation, 30 microM SK&F 96365 partly, and 100 microM SK&F 96365 completely, inhibited the sustained plateau phase, but did not inhibit the initial phase of the Ca2+ and secretory responses. In the 5 pM CCK-8-stimulated preparation; (a) 30 microM SK&F 96365 reduced the frequency of the [Ca2+]c oscillations, but caused little, if any, changes in the secretory response; (b) 100 microM SK&F 96365 transformed the oscillatory [Ca2+]c dynamics to a transient increase followed by a gradual decay and caused a significant inhibition of the sustained secretory response. These results indicate that the sustained responses to secretagogues are dependent on a receptor-mediated Ca2+ entry which can selectively be blocked by SK&F 96365 in rat pancreatic acini.
Busik
J
J
Department of Molecular Physiology, National Institute for Physiological Sciences, Okazaki, Japan.
Habara
Y
Y
Maruyama
T
T
Kanno
T
T
D000681:Amylases / Q000378:metabolism; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002217:Carbachol / Q000494:pharmacology; D016257:Fura-2; D007091:Image Processing, Computer-Assisted; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D012844:Sincalide / Q000494:pharmacology
D002121:Calcium Channel Blockers; D007093:Imidazoles; D002217:Carbachol; D000681:Amylases; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D012844:Sincalide; D016257:Fura-2