CGS 9343B and W7 (calmodulin antagonists) inhibit KCl-induced increase in cytosolic free calcium and insulin secretion of RINm5F cells.
CGS 9343B:1,3-Dihydro-1-[1-[4-methyl-4H,6H-pyrrolo[1,2-a]-[4,1] benzoxazepin-4-yl)methyl)-4-piperidinyl]-2H-benzimidazol-2-o ne maleate and W7:N-6(aminohexyl)-5-chloro-1-naphthalenesulfonamide) are calmodulin antagonists with different specificities. The effects of CGS 9343B and W7 on cytosolic free calcium concentration ([ Ca2+]i) and insulin release were investigated in rat insulinoma cells (RINm5F). As measured with the Quin-2 technique, preincubation with CGS 9343B (0.3-10 microM) and W7 (5-50 microM) concentration dependently decreased KCl (25 mM)-mediated accumulation of cytosolic calcium. Both, CGS 9343B (10 microM) and W7 (50-100 microM) almost abolished the alanine- and KCl-induced increase in [Ca2+]i and significantly inhibited KCl (25 mM)- and alanine (10 mM)-mediated insulin release. W5 (100 microM), the chlorine-deficient analogue of W7 with decreased affinity for calmodulin, did not inhibit the KCl-induced increase in [Ca2+]i and enhanced basal and KCl-mediated insulin release by 56% and 189%, respectively. Our data suggest that CGS 9343B and W7 inhibit the depolarization-induced calcium uptake and subsequent increase in [Ca2+]i.
Safayhi
H
H
Department of Pharmacology, University of Tübingen, Federal Republic of Germany.
Kühn
M
M
Koopmann
I
I
Ammon
H P
HP
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D003600:Cytosol / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism; D010640:Phenothiazines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology*; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D001562:Benzimidazoles; D002132:Calcium Radioisotopes; D002147:Calmodulin; D007328:Insulin; D010640:Phenothiazines; D013449:Sulfonamides; C052087:CGS 9343B; C017967:W 7; D011189:Potassium Chloride; D002118:Calcium